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Neuron Groups, Not Single Cells, Maintain Brain Stability
3/2/2015

TAU researchers find neural networks preserve memories better than individual neurons

To compensate for erratic shifts and spikes in its neuronal communications, the brain relies on the stabilizing mechanism called "homeostasis" — the ability to maintain relatively stable equilibrium between different elements of its composition — to preserve overall network function. Disruptions in stability cause disorders such as epilepsy, but precious little is known about this macro-level regulatory phenomenon.

A new study published in eLife by Dr. Inna Slutsky of Tel Aviv University's Sackler Faculty of Medicine and TAU's Sagol School of Neuroscience finds that homeostatic regulation occurs mainly in groups of neurons rather than in the individual neurons themselves. Contradicting established assumptions, Edden Slomowitz and Boaz Styr, doctoral students in Dr. Slutsky's laboratory, discovered that single brain cells, on an individual basis, were unable to autonomously stabilize "spikes" in neuron communication over long periods. "Spikes" or "firing," as they are also known, are neurons' response to stimulation; they relay messages to the rest of the body.

"Neurological and psychiatric disorders often see similar or overlapping neurological symptoms, and the failure of the neuronal homeostatic system may lead to these common endpoints," said Dr. Slutsky. "Understanding the principles and mechanisms involved in neuronal homeostasis may lead to new approaches in the treatment of these and other brain disorders like Alzheimer's disease."

Seeking stability in a constantly changing environment

The brain's ability to adapt to a constantly changing environment and to form and store memories is due to the extreme flexibility, or plasticity, of its neural network. But the extreme plasticity of the brain also makes it inherently prone to instability and subsequent illnesses and disorders.

"Through homeostasis, organisms are able to maintain a stable internal environment," said Slomowitz. "One common example is the secretion of insulin in response to a meal to keep blood sugar levels within the normal range. While there was evidence to support the theory that there were homeostatic mechanisms at work in the brain to stabilize neuronal activity, it was unclear which precise properties were regulated."

For the purpose of the study, Slomowitz grew a neural network on an array of electrodes and recorded the activity of single individual neurons in the network. He then applied a drug which severely inhibited neural activity. In collaboration with Prof. Eli Nelken of Hebrew University and Dr. Michael Slutsky of Mantis Vision, Slomowitz found that the network returned to its original firing rate over the course of two days despite the continued presence of the drug — and even though the firing rates and patterns of individual neurons did not reflect homeostatic tendencies.

"These results were unexpected and contradicted the current dogma in the field stating that individual neurons can regulate their own firing rates in an autonomous manner," said Dr. Slutsky.

The trade-off of population stability

Following up, Styr repeated the experiment in the lab using calcium imaging, which can monitor the activity of visually identifiable neurons. The calcium images revealed similar results, bolstering the conclusion that homeostasis occurs at the level of neuron populations, not on a cell-by-cell basis.

The team also examined the ability of the network to differentiate between low- and high-frequency spikes, a capability critical for short-term memory. They found this detection was severely compromised two days after the introduction of the drug, even though network firing rates and patterns had been homeostatically restored.

"Our study demonstrates that neurons in a neural network act synergistically in order to keep the population spiking rates and patterns in a constant physiological range," said Dr. Slutsky. "This may occur at the cost of a diminished ability to form new memories, a process which may underlie the loss of short-term memory observed in brain diseases such as Alzheimer’s disease. This understanding may bring us one step closer to the understanding of the processes that precede cognitive decline in neurodegenerative disorders."

Together, Nanotechnology and Genetic Interference May Tackle “Untreatable” Brain Tumors
2/24/2015

TAU researchers' groundbreaking strategy stops brain tumor cell proliferation with targeted nanoparticles

There are no effective available treatments for sufferers of Glioblastoma multiforme (GBM), the most aggressive and devastating form of brain tumor. The disease, always fatal, has a survival rate of only 6-18 months.

Now a new Tel Aviv University study may offer hope to the tens of thousands diagnosed with gliomas every year. A pioneer of cancer-busting nanoscale therapeutics, Prof. Dan Peer of TAU's Department of Department of Cell Research and Immunology and Scientific Director of TAU's Center for NanoMedicine has adapted an earlier treatment modality — one engineered to tackle ovarian cancer tumors — to target gliomas, with promising results.

Published recently in ACS Nano, the research was initiated by Prof. Zvi R. Cohen, Director of the Neurosurgical Oncology Unit and Vice Chair at the Neurosurgical Department at Sheba Medical Center at Tel Hashomer. The Israeli Cancer Association provided support for this research.

Trying a new approach to gliomas

"I was approached by a neurosurgeon insistent on finding a solution, any solution, to a desperate situation," said Prof. Peer. "Their patients were dying on them, fast, and they had virtually no weapons in their arsenal. Prof. Zvi Cohen heard about my earlier nanoscale research and suggested using it as a basis for a novel mechanism with which to treat gliomas."

Dr. Cohen had acted as the primary investigator in several glioma clinical trials over the last decade, in which new treatments were delivered surgically into gliomas or into the surrounding tissues following tumor removal. "Unfortunately, gene therapy, bacterial toxin therapy, and high-intensity focused ultrasound therapy had all failed as approaches to treat malignant brain tumors," said Dr. Cohen. "I realized that we must think differently. When I heard about Dan's work in the field of nanomedicine and cancer, I knew I found an innovative approach combining nanotechnology and molecular biology to tackle brain cancer."

Dr. Peer's new research is based on a nanoparticle platform, which transports drugs to target sites while minimizing adverse effects on the rest of the body. Prof. Peer devised a localized strategy to deliver RNA genetic interference (RNAi) directly to the tumor site using lipid-based nanoparticles coated with the polysugar hyaluronan (HA) that binds to a receptor expressed specifically on glioma cells. Prof. Peer and his team of researchers tested the therapy in mouse models affected with gliomas and control groups treated with standard forms of chemotherapy. The results were, according to the researchers, astonishing.

"We used a human glioma implanted in mice as our preclinical model," said Prof. Peer. "Then we injected our designed particle with fluorescent dye to monitor its success entering the tumor cells. We were pleased and astonished to find that, a mere three hours later, the particles were situated within the tumor cells."

A safer, more promising approach

Rather than chemotherapy, Prof. Peer's nanoparticles contain nucleic acid with small interference RNAs, which silence the functioning of a key protein involved in cell proliferation. "Cancer cells, always dividing, are regulated by a specific protein," said Prof. Peer. "We thought if we could silence this gene, they would die off. It is a basic, elegant mechanism and much less toxic than chemotherapy. This protein is not expressed in normal cells, so it only works where cells are highly proliferated."

100 days following the treatment of four injections over 30 days, 60 percent of the afflicted mice were still alive. This represents a robust survival rate for mice, whose average life expectancy is only two years. The control mice died 30-34.5 days into treatment.

"This is a proof of concept study which can be translated into a novel clinical modality," said Prof. Peer. "While it is in early stages, the data is so promising — it would be a crime not to pursue it."

Crowdfunding Helps Solve Rare Disease Mystery
2/10/2015

TAU researcher identifies novel genetic mutations through DNA sequencing of afflicted child and family

Rare diseases — those that affect fewer than one in 200,000 people — are often identified early in life. Some 30 percent of children afflicted by these "orphan diseases" do not live to see their fifth birthday. While the US Orphan Drug Act of 1983 was written into law to promote research on the topic, the cost of identifying the source and progression of these diseases remains prohibitive for many families.

But there is hope for them in our Internet age. Researchers at Tel Aviv University recently concluded a successful experiment to identify a novel genetic mutation as the source of a specific rare disease, and their experiment was supported through crowdfunding — contributions from a large number of individuals over the Internet.

In the study, led by Dr. Noam Shomron of TAU's Sackler Faculty of Medicine and published recently in the Journal of Genetics and Genomics, analysis of DNA sequencing of a three-year-old girl and her family revealed a novel mutation that causes mental retardation and severe developmental delays in children. Research for the study was conducted by TAU doctoral student Ofer Isakov together with Dr. Dorit Lev and Dr. Esther Lishinsky of Wolfson Medical Center.

A roadmap to hope

"How does it help to know?" said Dr. Shomron. "It's the missing piece of the genetic puzzle, eliminating from the picture all other diseases that are known to cause death at an early age and allowing the parents to connect with families with similar problems or mutations to build a lifelong support network. The parents can connect with scientists working in the field to learn about advancements. In some cases, a change in lifestyle, drug therapy, and physiotherapy can help their child's situation. Finally, by knowing what to look for, the parents can feel free to have more children as long as they screen for the identified mutation.

"By knowing a child's DNA, you also unlock a family secret that can possibly reflect on cousins, siblings and so on. It goes around and around in a circle — who else is carrying this gene?"

The power of the crowd

"Parents look to comprehensive genetic analysis, like the one we carried out, when they don't know where else to look," said Dr. Shomron. "They are desperate to understand why their children are sick, and the medical community is challenged to identify the source of the suffering. By travelling through the complete human genome, we are able to locate, map, and analyze mutations involved in triggering certain rare diseases.

"Crowdfunding provides the means for economically disadvantaged patients to pursue a genetic diagnosis for their ailment. Our project reached its financial goal of $5,000 within 50 days. We were pleased, to say the least. Crowdfunding is a simple and efficient solution for families with rare genetic diseases who lack private or outside funding sources."

The study harnessed whole exome sequencing (WES) to identify the genetic cause of a three-year-old girl's involuntary eye movements, small-sized head, involuntary muscle contraction, developmental delay, and progressive neurological decline. The patient had a healthy brother and there was no recent family history of neurological disorders. Although she had smiled at six weeks, laughed at three months, and reached for toys at four months, over the next two years her motor functions had degenerated and she was unable to produce words. She could neither sit nor stand unassisted and she walked only with aids. At the age of 33 months, there was no progress. Extensive medical testing produced no answers. Desperate to understand what was happening to their daughter, the parents sought answers through genetic sequencing.

But because WES costs around $1,500 per individual, and the DNA of the patient and her parents had to be sequenced as well, the price of the project came to $4,500. Due to the high expense, Dr. Shomron sought to raise the necessary funds from individual donors over the Internet. The platform they used was that of Rare Genomics Institute (RGI; at http://raregenomics.org/), which specializes in this kind of fundraising in the US. Dr. Shomron opened the Israeli branch of RGI to cater to the local rare genetic mutation population.

Dr. Shomron is continuing his research on gene mutations to help other families struggling with rare diseases.

Acute Psychological Stress Reduces Ability to Withstand Physical Pain
2/5/2015

New TAU study exposes damaging effect of psychosocial stress on the body's pain modulation capabilities

Traffic slows to a crawl, then a stop. You are trapped in a bottleneck nightmare, and late for a meeting. The stress takes a toll on you psychologically — but your body is at risk as well, according to a Tel Aviv University researcher.

A new study by Prof. Ruth Defrin of the Department of Physical Therapy at TAU's Sackler Faculty of Medicine published in the journal PAIN finds that acute psychosocial stress has a dramatically deleterious effect on the body's ability to modulate pain. Prof. Defrin, together with TAU doctoral student Nirit Geva and Prof. Jens Pruessner of McGill University, applied acute stress tests on a large group of healthy young male adults to evaluate the behavior of the body's pain modulation mechanisms prior to and after the induction of stress.

The researchers found that although pain thresholds and pain tolerance seemed unaffected by stress, there was a significant increase in pain intensification and a decrease in pain inhibition capabilities.

Doing the math

For the purpose of the study, 29 healthy men underwent several commonly accepted pain tests to measure their heat-pain thresholds and pain inhibition, among other factors. In one test, for example, subjects were asked to signal the moment a gradually increasing heat stimulus became painful to identify their respective pain thresholds. They underwent a series of pain tests before and immediately after exposure to the Montreal Imaging Stress Task (MIST), a computer program of timed arithmetic exercises, designed to induce acute psychosocial stress.

In a way, the stress test is a psychological trick. MIST provides live feedback on submitted responses, registering only 20-45% of the responses as correct, whether or not a submitted response is the right answer. Because the subject has been previously informed that the average participant tends to score 80%–90%, he is reminded of his "poor performance" but has no way of improving his score, despite his best efforts. This provides the "stress" element of the experiment.

"To further test the effect of stress on pain, we divided the group according to stress levels," said Prof. Defrin. "We found that not only does psychosocial stress reduce the ability to modulate pain, the changes were significantly more robust among subjects with stronger reaction to stress ('high responders'). The higher the perceived stress, the more dysfunctional the pain modulation capabilities became. In other words, the type of stress and magnitude of its appraisal determine its interaction with the pain system.

"We know from our previous studies and studies of others that chronic stress is far more damaging than acute stress, associated not only with dysfunctional pain modulation capabilities but also with chronic pain and systemic illnesses," said Prof. Defrin.

Defining stress

"Stress is defined as a sense of uncontrollability and unpredictability, precisely like being stuck in traffic where you are helpless and have no control over the situation," said Prof. Defrin. "Stress can have positive repercussions in a challenging work environment, for example, but overall it has primarily negative effects."

The results were also somewhat surprising. "We were sure we would see an increased ability to modulate pain, because you hear anecdotes about people who are injured during fighting or sports having greater pain modulation," said Prof. Defrin. "But we were surprised to find quite the opposite. While there was no visible effect of acute stress on the subject's pain threshold or tolerance, pain modulation decreased in a very dramatic way.

"Modern life exposes individuals to many, recurrent stressful situations," Prof. Defrin observes. "While there is no way to predict the type of stress we will feel under different circumstances, it is advisable to do everything in our power — adopt relaxation and stress reduction techniques as well as therapy — to reduce the amount of stress in our lives."

Protective Brain Protein Reveals Gender Implications for Autism, Alzheimer’s Research
2/3/2015

TAU study finds a mutated gene is expressed differently in male and female brains

For parents of children struggling with autism, the dearth of information is heartbreaking. Medical professionals are hard put to answer the primary questions: Who is autistic? What causes autism? What treatments are available? The situation is similar for Alzheimer's patients and relatives, who are helpless before the aggressive disease devouring a sufferer's identity.

A new study by Tel Aviv University's Prof. Illana Gozes, published in Translational Psychiatry, may offer insight into the pathology of both autism and Alzheimer's by revealing that different activities of certain proteins in males and females cause gender-specific tendencies toward these diseases. While the three-to-one ratio of autism in boys to girls is well known, as is the greater number of female Alzheimer's patients, the reasons for these phenomena are less clear.

According to Prof. Gozes, "If we understand how ADNP, an activity-related neuroprotective protein which is a major regulatory gene, acts differently in males and females, we can try to optimize drugs for potential future therapeutics to treat both autism and Alzheimer’s disease."

Prof. Gozes is the incumbent of the Lily and Avraham Gildor Chair for the Investigation of Growth Factors, Head of the Elton Laboratory for Molecular Neuroendocrinology at TAU's Sackler Faculty of Medicine, a member of TAU's Adams Super Center for Brain Studies and the Sagol School of Neuroscience. Research for the study was conducted by graduate students Anna Malishkevich, Noy Amram, and Gal Hacohen-Kleiman, in collaboration with post-doctoral fellow Dr. Iddo Magen, and staff scientist Dr. Eliezer Giladi, all of TAU.

The gender factor

For the purpose of the new study, Prof. Gozes and her team examined the behavioral response of male and female mice, both ADNP-altered and normal, to different cognitive challenges and social situations. To do so, they removed one copy of the ADNP gene — which regulates over 400 proteins involved in development — from some mice, and then examined their respective responses to unfamiliar objects, odors, and other mice.

Their results revealed sex-specific learning and memory differences in the mice, reflecting hippocampal expression changes in ADNP, resulting in ADNP-controlled autism and in genes which indicate a risk for Alzheimer's disease. For example, ADNP-deficient male mice exhibited deficiencies in object recognition and social memory, whereas ADNP-altered female mice were more socially deficient compared to the non-altered females.

Providing new hope?

"ADNP may be new to the world of autism, but I have been studying it for 15 years," said Prof. Gozes. "Its gender-dependent expression changes male and female chemical tendencies toward different neurological disorders. Male and female mice may look the same and their brains may look the same, but they are not. When the expression of ADNP is different, it may cause different behaviors and different cognitive abilities.

"This study emphasizes the need to analyze men and women separately in clinical trials to find cures for diseases because they may respond differently," she concludes.

Prof. Gozes hopes the new study will prompt further research into the drug Davunetide (NAP) as a means of treating social and cognitive deficits with special attention to gender differences. Prof. Gozes discovered Davunetide (NAP), a snippet of ADNP, by looking at the nerve cell protective activity of ADNP fragments. Proof-of-concept clinical studies performed in adults have shown that Davunetide protects memory in patients suffering from the mild cognitive impairment that precedes Alzheimer's disease as well as functional activity in schizophrenia patients.

New Protein Detonates “Invincible” Bacteria from Within
1/27/2015

TAU researchers identify protein capable of neutralizing antibiotic-resistant bacterial cells

Antibiotic-resistant infections are on the rise, foiling efforts to reduce death rates in developing countries where uncontrolled use of antibiotics and poor sanitation run amok. The epidemic of "superbugs," bacteria resistant to antibiotics, knows no borders — presenting a clear and present danger around the globe.

A groundbreaking discovery from Tel Aviv University researchers may strengthen efforts by the medical community to fight this looming superbug pandemic. By sequencing the DNA of bacteria resistant to viral toxins, TAU researchers identified novel proteins capable of stymieing growth in treacherous antibiotic-resistant bacteria.

The research, published last month in PNAS, was led by Prof. Udi Qimron of the Department of Clinical Microbiology and Immunology at TAU's Sackler Faculty of Medicine and conducted primarily by TAU researcher Shahar Molshanski-Mor.

Fighting from within

"Because bacteria and bacterial viruses have co-evolved over billions of years, we suspected the viruses might contain precisely the weapons necessary to fight the bacteria," Prof. Qimron said. "So we systematically screened for such proteins in the bacterial viruses for over two and a half years."

Using high-throughput DNA sequencing, the researchers located mutations in bacterial genes that resisted the toxicity of growth inhibitors produced by bacterial viruses. In this way, the team identified a new small protein, growth inhibitor gene product (Gp) 0.6, which specifically targets and inhibits the activity of a protein essential to bacterial cells.

The inhibitor was found to cripple the activity of a protein vital to bacterial cells — a protein that maintains the bacterial cell structure. Malfunction of this bacterial protein consequently resulted in the rupture and consequent death of the bacterial cell.

Technology and collaboration

"The new technology and our new interdisciplinary collaboration, drawing from bioinformatics and molecular biology, promoted our study more than we could have anticipated," said Prof. Qimron. "We hope our approach will be used to further identify new growth inhibitors and their targets across bacterial species and in higher organisms."

The researchers are continuing their study of bacterial viruses in the hope of identifying compounds and processes that facilitate improved treatment of antibiotic-resistant bacteria using yet uncharacterized bacterial viruses' proteins. They believe that further basic knowledge on bacterial viruses biology will eventually lead to unexpected breakthroughs in the fight against antibiotic-resistant bacteria.

TAU’s Prof. Yosef Shiloh Receives First Olav Thon Foundation Prize
1/21/2015

Norway's largest charitable foundation bestows cash prize for TAU cancer geneticist's research on cell survival and DNA stability

Prof. Yosef ShilohNorway's largest charitable organization, the Olav Thon Foundation, which invests heavily in medical research, awarded its first international research award in the medical and natural sciences to Tel Aviv University's Prof. Yosef Shiloh and Prof. Judith Campisi of the Buck Institute for Research on Aging, California. The prize money, NOK 5,000,000 (approximately $660,000), was split between the two winners.

Prof. Shiloh, the Myers Professor of Cancer Genetics and Research Professor of the Israel Cancer Research Fund at TAU's Sackler School of Medicine, was recognized for his pioneering research on the mechanisms that maintain the survival of human cells and the stability of human genetic material.

A member of the Israel National Academy of Sciences and Humanities, Prof. Shiloh was a recipient of the prestigious Israel Prize (considered "Israel's Nobel") in Life Sciences in 2011, the 2011 American Association of Cancer Research G.H.A. Clowes Award, and the 2005 EMET Prize in Life Sciences.

"A prize means scientific recognition," said Prof. Shiloh. "Scientists do not work in order to get prizes or any other monetary benefits, but the award of a prize means that our work is recognized by our colleagues, and this is probably the true reward of a scientist."

Unraveling the genome

Prof. Shiloh has spent much of his career investigating the processes that maintain genome stability and the defense mechanisms against substances that damage our DNA. He has investigated how the harmful effects of such substances can be countered and offered insights into how mammalian cells react to DNA damage produced by environmental factors, such as radiation and carcinogenic chemicals.

According to the Foundation, "The laureates have provided us with new insights into the molecular basis of aging, aging-related diseases, and cellular degenerative processes."

Prof. Shiloh has dedicated most of his scientific career to understanding the genomic instability syndrome, ataxia-telangiectasia (A-T). (Watch a video on Prof. Shiloh’s research.) He began his work on A-T while working on his PhD thesis, and this quest culminated in 1995 with the identification of the responsible gene, ATM, in his lab. He and his team have since been engaged in exploring its function, its mode of action, and its many roles in cellular metabolism.

Prof. Shiloh obtained his BSc degree at the Technion Institute of Technology and his PhD in Human Genetics at The Hebrew University of Jerusalem. A Fogarty Fellow at the National Institutes of Health, Prof. Shiloh also studied at Harvard Medical School, the University of Michigan, and New York University Medical Center.

In addition to his research, Prof. Shiloh devotes considerable time to giving popular scientific lectures to the general public and high school students on the medical, social, and ethical implications of the genome revolution and its effect on cancer research and therapy.

Smoke Signals: New Evidence Links Air Pollution to Congenital Defects
12/22/2014

TAU study examines effect of air pollution on pregnancies

The health effects of air pollution are a major concern for urban populations all over the world. Children, the elderly, and people with impaired respiratory systems (such as asthmatics) tend to be especially sensitive to the impact of exposure to ozone, nitrogen dioxide, sulphur dioxide, and particulate matter.

A recent study by Tel Aviv University researchers provides new evidence linking high exposure to air pollution to an increased risk of congenital malformations. The research, published in Environmental Research, was led by Prof. Liat Lerner-Geva of TAU's Sackler Faculty of Medicine and School of Public Health and the Gertner Institute for Epidemiology and Health Policy Research, Dr. Adel Farhi of the Gertner Institute for Epidemiology and Health Policy Research, in collaboration with Prof. Itzhak Benenson of TAU's Department of Geography and Human Environment and Prof. Yinon Rudich of the Weizmann Institute of Science. The nationwide study is the first to assess the association between different modes of conception — assisted reproductive technology (ART) versus spontaneous conception (SC) — and the risks of exposure to air pollution to each.

"Our results suggest that exposure to higher levels of air pollution during pregnancy is associated with various adverse pregnancy outcomes," said Prof. Lerner-Geva. "While our study mainly followed SC infants, we also had the opportunity to assess a small sample of pregnancies that were conceived through ART, and observed a higher impact of air pollution — particularly with regard to ozone exposure. This is clearly a uniquely susceptible population that should be further explored."

Statistics link pollution to defects

For the study, funded by the Environmental Health Fund (EHF), the research team analyzed data on 216,730 born in Israel between 1997 and 2004. Air pollution data, including levels of sulfur dioxide (SO2), particulate matter (PM10), nitrogen oxides (NOx), and ozone (O3), were obtained from air monitoring stations for the study period. Using a geographic information system, exposure to air pollution during both the first trimester and the entire pregnancy was assessed for each woman according to her place of residence.

The researchers found that exposure to PM10 and NOX pollutants throughout full-term pregnancies were associated with an increased risk of congenital malformations, with specific defects evident in the circulatory system (from PM10 and NOX exposure) and genital organs (from NOX exposure). They also discovered that exposure to SO2 and O3 in ART pregnancies were associated, although not significantly, with a higher risk of congenital defects.

"Considering the worldwide decline in fertility, and the increasing number of children born through ART treatments, our findings about their increased risk of congenital malformations are very relevant," said Prof. Lerner-Geva. "It is essential we continue to evaluate this unique population."

According to Prof. Lerner-Geva, a national ART registry has been established in Israel to provide important data on all ART cycles. This database will serve as a basis for a future larger study to identify susceptible subpopulations at higher risk of adverse pregnancy outcomes. Prof. Lerner-Geva is currently engaged in a more detailed assessment of environmental exposure during pregnancy.

Genetic Mutation Found to Cause Ovarian Failure
12/17/2014

TAU researchers discover unique genetic disorder responsible for ovarian insufficiency in women under 40

Premature ovarian failure, also known as primary ovarian insufficiency (POI), affects 1% of all women worldwide. In most cases, the exact cause of the condition, which is often associated with infertility, is difficult to determine.

A new Tel Aviv University study throws a spotlight on a previously-unidentified cause of POI: a unique mutation in a gene called SYCE1 that has not been previously associated with POI in humans. The research, published in the Journal of Clinical Endocrinology and Metabolism, was led by Dr. Liat de Vries and Prof. Lina Basel-Vanagaite of TAU's Sackler Faculty of Medicine and Schneider Children's Medical Center and conducted by a team of researchers from both TAU and Schneider.

While the genes involved in chromosome duplication and division had been shown to cause POI in animal models, this is the first time a similar mutation has been identified in humans.

A new insight

"Researchers know that POI may be associated with Turner's syndrome, a condition in which a woman has only one X chromosome instead of two, or could be due to toxins like chemotherapy and radiation therapy," said Dr. de Vries. "However, in 90% of the cases, the exact cause remains a mystery."

The idea for the study surfaced when Dr. de Vries was asked to treat two POI patients, daughters of two sets of Israeli-Arab parents who were related to each other. The girls presented with typical POI symptoms: one had the appearance of puberty but had not gotten her period, and the other one had not started puberty at all. After ruling out the usual suspects (toxins, autoimmune disease, and known chromosomal and genetic diseases), the researchers set out to identify the genetic cause of POI in the two young women.

"One of my main topics of interest is puberty," said Dr. de Vries. "The clinical presentation of the two sisters, out of 11 children of first-degree cousins, was interesting. In each of the girls, POI was expressed differently. One had reached puberty and was almost fully developed but didn't have menses. The second, 16 years old, showed no signs of development whatsoever."

The researchers performed genotyping in the patients, their parents, and siblings. For this, DNA from the affected sisters was subjected to whole-exome sequencing. Genotyping was also performed in 90 ethnically matched control individuals.

Finding the culprit

The genotyping revealed a mutation that results in nonfunctional protein product in the SYCE1 gene in both affected sisters. The parents and three brothers were found to be carriers of the mutation, and an unaffected sister did not carry the mutation.

"By identifying the genetic mutation, we saved the family a lot of heartache by presenting evidence that any chance of inducing fertility in these two girls is slight," said Dr. de Vries. "As bad as the news is, at least they will not spend years on fertility treatments and will instead invest efforts in acquiring an egg donation, for example. Knowledge is half the battle — and now the entire family knows it should undergo genetic testing for this mutation."

The researchers are currently investigating evidence of the effects of this genetic mutation on male members of the family. "We are trying to get more family members tested, but it is not always easy in traditional societies. There is still a lot to be done on this subject," said Dr. de Vries.

A Better Biomonitor for Children with Asthma
12/10/2014

TAU takes groundbreaking new diagnostic technique from Ground Zero to the playground

For the firefighters and rescue workers conducting the rescue and cleanup operations at Ground Zero from September 2001 to May 2002, exposure to hazardous airborne particles led to a disturbing "WTC cough" — obstructed airways and inflammatory bronchial hyperactivity — and acute inflammation of the lungs. At the time, bronchoscopy, the insertion of a fiber optic bronchoscope into the lung, was the only way to obtain lung samples. But this method is highly invasive and impractical for screening large populations.

That motivated Prof. Elizabeth Fireman of Tel Aviv University's Sackler Faculty of Medicine and the Institute for Pulmonary and Allergic Diseases at TAU-affiliated Tel Aviv Sourasky Medical Center to experiment with a new technique: Induced Sputum (IS). Hypertonic saline is inhaled to produce a mucus expectorate which can be tested for hazardous particles. She flew to Ground Zero and tested 39 New York City firefighters using the IS biomonitoring method and then compared these results against a control group of Israeli firefighters. Her technique identified very dangerous metals such as mercury in the rescue workers' lungs.

Now, in a new study published in the International Archives of Occupational and Environmental Health, Prof. Fireman and a team of researchers at Tel Aviv Sourasky Medical Center examine the benefits of using the IS technique to assess the effect of pollution on urban asthmatic children, revealing that environmental sampling stations located in cities around the world are not sufficient to protect the health of these children.

A boon to children

"After our last study on occupational exposure, I decided to examine the most vulnerable sector in the field of asthma — children," said Prof. Fireman. "Environmental monitoring systems are only capable of measuring large particle matter, which is mostly expelled by the lungs. I wanted to know what happened to the small particle matter capable of evading the body's immunological mechanisms. And I wanted to know how they affected asthmatic kids."

For the purposes of the study, Prof. Fireman's team recruited 136 children from two to twelve years of age who had already been referred for asthmatic evaluations to Tel Aviv Sourasky Medical Center. Their parents completed a clinical and demographic International Study of Asthma and Allergy in Childhood (ISAAC)-based questionnaire that included passive smoking status, known present and past diseases, and respiratory symptoms. Afterward, all of the children underwent IS testing in order to detect and measure particulate matter in their lungs.

In the course of the IS testing, the children inhaled 3% nebulised material for up to twenty minutes through an ultrasonic nebulizer, which harnesses mist to administer medication.

A solution for larger populations?

"We compared our results with the indices published by rooftop pollution stations in Tel Aviv," said Prof. Fireman. "And while we do not discount the importance of maintaining such environmental stations, we found their measurements to be at odds with our own findings, suggesting they cannot be used as the sole measurement of pollution levels."

While further studies are necessary to investigate the practicality and feasibility of using IS to assess large populations, Prof. Fireman is confident her findings demonstrate the capability of IS to biologically monitor the accumulation of airborne particles in the lungs of children with asthma.

"Most important, perhaps, we have found that environmental monitoring is not enough. You need a biomonitoring technique, like IS, which is a more physiologically sensitive," said Prof. Fireman. "This study suggests that we are not well protected by environmental stations. To help parents determine whether they should continue to live with their children in polluted areas, we will need to combine our strategies."

Nanotubes May Restore Sight to Blind Retinas
12/2/2014

TAU researchers develop groundbreaking wireless material capable of sparking neuronal activity in response to light

The aging process affects everything from cardiovascular function to memory to sexuality. Most worrisome for many, however, is the potential loss of eyesight due to retinal degeneration.

New progress towards a prosthetic retina could help alleviate conditions that result from problems with this vital part of the eye. An encouraging new study published in Nano Letters describes a revolutionary novel device, tested on animal-derived retinal models, that has the potential to treat a number of eye diseases. The proof-of-concept artificial retina was developed by an international team led by Prof. Yael Hanein of Tel Aviv University's School of Electrical Engineering and head of TAU's Center for Nanoscience and Nanotechnology and including researchers from TAU, the Hebrew University of Jerusalem, and Newcastle University.

"Compared to the technologies tested in the past, this new device is more efficient, more flexible, and can stimulate neurons more effectively," said Prof. Hanein. "The new prosthetic is compact, unlike previous designs that used wires or metals while attempting to sense light. Additionally, the new material is capable of higher spatial resolution, whereas older designs struggled in this area."

A natural shape

The researchers combined semiconductor nanorods and carbon nanotubes to create a wireless, light-sensitive, flexible film that could potentially replace a damaged retina. The researchers tested the new device with chick retinas which were not yet light sensitive to prove that the artificial retina is able to induce neuronal activity in response to light.

Patients with age-related macular degeneration (AMD), which usually affects people age 60 or older who have damage to a specific part of the retina, will stand to benefit from the nanotube device if it is proved compatible in animals over the long term.

According to TAU doctoral student and research team member Dr. Lilach Bareket, there are already medical devices that attempt to treat visual impairment by sending sensory signals to the brain. While scientists are trying different approaches to develop an implant that can "see" light and send visual signals to a person's brain, to counter the effects of AMD and related vision disorders, many of these approaches require the use of metallic parts and cumbersome wiring or result in low resolution images. The researchers set out to make a more compact device.

Progress in the right direction

"In comparison with other technologies, our new material is more durable, flexible, and efficient, as well as better able to stimulate neurons," said Prof. Hanein. "We hope our carbon nanotube and semiconductor nanorod film will serve as a compact replacement for damaged retinas."

"We are still far away from actually replacing the damaged retina," said Dr. Bareket. "But we have now demonstrated that this new material stimulates neurons efficiently and wirelessly with light. If you compare this to other devices based on silicon technology, which require wiring to outside energy or light sources, this is a groundbreaking new direction."

The research team received funding for their study from the Israel Ministry of Science and Technology, the European Research Council, and the Biotechnology and Biological Sciences Research Council.

Enriched Environments Hold Promise for Brain Injury Patients
11/11/2014

TAU study finds improved living conditions led to rehabilitation of mice following traumatic brain injury

As football players are learning, a violent blow to the head has the potential to cause mild to severe traumatic brain injury — physical damage to the brain that can be debilitating, even fatal. The long-term effects run the gamut of human functioning, from trouble communicating to extensive cognitive and behavioral deterioration. To date, there is no effective medical or cognitive treatment for patients with traumatic brain injuries.

But a new study from Tel Aviv University researchers points to an "enriched environment" — specially enhanced surroundings — as a promising path for the rehabilitation of mild traumatic brain injury (mTBI) patients. The research, published in Behavioral Brain Research, was led by Prof. Chagi Pick of TAU's Sagol School of Neuroscience and Sackler Faculty of Medicine and conducted by a team of researchers from both TAU and TAU-affiliated Tel Aviv Sourasky Medical Center.

Mice move on up

The study, conducted on mice at a TAU laboratory, followed two groups of animals with minimal traumatic brain injury. The first group was kept in standard cages and maintained under routine conditions, while the second enjoyed "enriched environments," replete with sensory stimuli, open space, and plentiful opportunities to eat and exercise.

"A house may survive an earthquake, but up close you will see cracks in the walls. This is what may happen following traumatic brain injury," said Prof. Pick. "An MRI might determine that the brain looks normal, but fast forward two years and the patient, who was married and successful, is suddenly unemployed, divorced, and miserable — without any awareness or understanding that new and lasting cognitive and emotional difficulties (including various degrees of amnesia, difficulty concentrating, depression, apathy, anxiety, and even a prominent personality change) emerged due to a car accident two years earlier.

"Doctors in the emergency room harness the Glasgow Coma Scale to assess the extent of brain trauma in incoming patients — from a child who falls off the bed to a victim of a major accident," Prof. Pick continued. "In the majority of cases, doctors determine minimal damage according to the symptoms that appear over a very short period of monitoring — just 30 minutes. In 85% of cases, this is accurate, but in 15% of cases, a cascade of serious damage has just begun, and we don't really know why. But this is what we are trying to figure out."

An environment of riches

According to the study, an "enriched environment" may play a critical role in brain regulation, behavior, and physiology. Using a model of minimal TBI in mice, the team evaluated the effect of transition to an enriched environment on behavioral and cognitive parameters. Using the Novel Object Recognition task, in which mice exhibit different levels of curiosity about new objects placed in their cages, and run different mazes to establish navigation abilities, the researchers sought to determine the mice's level of functioning in standard cages versus enriched environments — cages with additional stimuli, running wheels, plenty of food, open space, and water. The mice exposed to an enriched environment showed a marked improvement in recovery from brain injuries.

"We have shown that just six weeks in an enriched environment can help animals recover from cognitive dysfunctions after traumatic brain injury," said Prof. Pick. "Possible clinical implications indicate the importance of adapting elements of enriched environments to humans, such as prolonged and intensive physical activity, possibly combined with intensive cognitive stimulation. Through proper exercise, stimuli, and diet, we can improve a patient's condition. No one is promising a cure, but now we have evidence that this can help."

Obesity Plays Major Role in Triggering Autoimmune Diseases
11/10/2014

TAU study says obesity is a primary environmental factor sparking disorders like Crohn's Disease and multiple sclerosis

Autoimmune diseases like Crohn's Disease and multiple sclerosis, in which the immune system attacks its own body rather than predatory invaders, affect 5-20% of the global community. A study published recently in Autoimmunity Reviews by Prof. Yehuda Shoenfeld, the Laura Schwarz-Kipp Chair for Research of Autoimmune Diseases at Tel Aviv University's Sackler Faculty of Medicine and Head of Zabludowicz Center for Autoimmune Diseases at Chaim Sheba Medical Center, Tel Hashomer, points to the major role obesity plays in triggering and prolonging these autoimmune diseases.

According to the research, obesity leads to a breakdown of the body's protective self-tolerance, creating the optimal environment for autoimmune diseases, and generates a pro-inflammatory environment likely to worsen the disease's progression and hinder its treatment.

"We've been aware of a long list of causes of autoimmune disorders — infections, smoking, pesticides, lack of vitamins, and so forth. But in last five years, a new factor has emerged that cannot be ignored: obesity," said Prof. Shoenfeld. "According to the World Health Organization, approximately 35% of the global community is overweight or obese, and more than ten autoimmune diseases are known to be associated with increased weight. So it's critical to investigate obesity's involvement in the pathology of such diseases."

The culprit in fat: Adipokines

In addition to their own research, Prof. Shoenfeld and his team from Tel Hashomer hospital conducted a systematic review of 329 studies from around the world on the relationship between obesity, adipokines (compounds secreted by fat tissue and involved in numerous physiological functions, including the immune response), and immune-related conditions like rheumatoid arthritis, multiple sclerosis, type-1 diabetes, psoriasis, inflammatory bowel disease, psoriatic arthritis, and Hashimoto thyroiditis.

"According to our study and the clinical and experimental data reviewed, the involvement of adipokines in the pathogenesis of these autoimmune diseases is clear," said Prof. Shoenfeld. "We were able to detail the metabolic and immunological activities of the main adipokines featured in the development and prognosis of several immune-related conditions."

A dose of Vitamin D

Prof. Shoenfeld conducted a study on mouse populations with multiple sclerosis given a Mediterranean diet rich in unsaturated fats. He found that Vitamin D deficiency was also a result of obesity and, once corrected, alleviated paralysis and kidney deterioration associated with the disorder. It also improved the prognosis and survival of the mice.

"Modern life makes us all prone to Vitamin D deficiency," said Prof. Shoenfeld. "We live in labs, offices, and cars. When Vitamin D is secreted in fat tissue, it is not released into the body, which needs Vitamin D to function properly. Since Vitamin D supplements are very cheap and have no side effects, they are an ideal compound that should be prescribed to anyone at risk of a compromised immune system."

Prof. Shoenfeld welcomes the general trend toward personalized medicine, and believes his research can be a basis for specific therapies to treat autoimmune syndrome. "If a patient is at risk, he or she should be told to do everything in his or her power to maintain a healthy weight," he said.

TAU Professors Awarded Inaugural Prize for Groundbreaking Innovation in Cancer Treatment
11/7/2014

Profs. Dan Peer and Rimona Margalit selected among top Israeli inventors for Untold News Awards

Prof. Dan Peer
Prof. Dan Peer

Prof. Rimona Margalit
Prof. Rimona Margalit

Tel Aviv University's Prof. Dan Peer of the Department of Cell Research and Immunology and Prof. Rimona Margalit of the Department of Biochemistry and Molecular Biology will be awarded $10,000 for their groundbreaking development in cancer treatment at the inaugural Untold News Awards on Wednesday, November 12, 2014, from 6:00 to 8:00 p.m. at the Harmonie Club in New York City. Theirs is one of three Israeli inventions to be selected for the award out of a pool of candidates submitted by prestigious Israeli institutions including TAU, Weizmann Institute of Science, Technion Israel Institute of Technology, and Hebrew University, amongst others.

An American non-profit, Untold News is dedicated to promoting Israeli inventors and educating Americans on the positive news generated from the State of Israel.

Prof. Peer, who is also Head of Nanomedicine and the Scientific Director of the Center for Nanoscience and Nanotechnology at TAU, and Prof. Margalit will be honored for their development of the "cancer bullet." The treatment is an injectable form of patient-friendly chemotherapy that targets only diseased cells. According to Peer, this is the first time nanoparticles are used in clusters instead of individually and has shown little to now side effects in trials.

Winners were selected by a jury of American leaders including Mr. David Schizer, former Dean of Columbia Law School; Dr. Barry Coller, Chief Medical Officer, Rockefeller University; Tony Tether, former Director of DARPA; and Heidi Jacobus, Chariman and CEO of Cybernet Systems. This year's winners also include Israeli professor Shlomo Magdassi and engineer Idan Tobis.

Following their New York appearance, the winners will visit Philadelphia, Boston, and Washington DC.

A global hub of inventions

Untold News was founded by lifelong New Yorker and former advertising executive Marcella Rosen, who discovered that Israel is home to almost as many start-ups, inventions, and patents as the entirety of the European Union and has attracted twice as much venture capital per capita as the United States. "My mission," says Rosen, "is to help the world understand that Israel is more than a country at war. Our first ever Untold News Awards reception will showcase three amazing inventors and their inventions, whom the jury and I feel will unequivocally make a mark on the worldwide stage."

All Kidding Aside: Medical Clowns Calm Children During Uncomfortable Allergy Test
11/6/2014

For the first time, TAU study empirically confirms effectiveness of "medical clowns" in puncture tests

The dreaded scratch or puncture test is the most common way of assessing allergic reactions to as many as 40 different substances at once. But because the test involves needles that prick multiple points along the skin's surface, it's a particularly high-stress examination for children — and their understandably anxious parents.

A new study by Tel Aviv University researchers provides the first quantitative analysis of the role of "medical clowns" in assuaging the anxiety and pain felt by children undergoing allergy tests. The research, published in Allergy, was conducted by a team led by Prof. Arnon Goldberg and Dr. Ronit Confino-Cohen of TAU's Sackler Faculty of Medicine and Meir Medical Center.

The study found that not only do medical clowns significantly decrease the level of anxiety expressed by children undergoing these tests, but they also assuage the pain the children experience.

Caring for the kids

"Our research group is comprised of experienced allergists," said Prof. Goldberg, "so we all knew that children, and occasionally their parents, express deep anxiety and fear of the skin tests. We wanted to see what could be done to improve the situation."

The study involved 91 children, aged two to 17 years, who underwent skin-prick testing at the Allergy and Clinical Immunology Unit of Meir Medical Center in Israel. A clown from Dream Doctors, an organization that provides Israeli medical centers with medical clowns, accompanied 45 of the children, while 46 kids underwent testing without clowns. Children with coulrophobia, a fear of clowns, were excluded. Children aged eight and older and all the children's parents rated their anxiety in questionnaires administered before and after testing.

Both older and younger children accompanied by clowns were far less anxious during testing than the control group. Their parents were also less anxious preceding the testing than parents in the control group, and their anxiety was further reduced after testing. No change in either anxiety level was recorded in control parents.

"The intervention of medical clowns during various medical procedures performed on children has been used to relieve anxiety and pain, but their role in allergy skin testing has never been evaluated," said Prof. Goldberg. "Our work offers a better method for easing the pain and anxiety induced in children by these tests. Children and parents will definitely benefit from the contribution of medical clowns to stressful medical tests like the skin prick test."

Frozen "Poop Pills" May Help Treat Life-Threatening Infection
11/3/2014

Joint study by TAU, Harvard, and other researchers finds feces capsules effective and more accessible than other treatments

The stubborn bacterium Clostridium difficile (C. difficile) is severe enough to send its victims to the hospital with life-threatening diarrhea. Americans spend an estimated $3.2 billion battling this bacterium, involved in some 14,000 deaths in the U.S. each year.

A study published recently in the Journal of the American Medical Association suggests an unconventional way of treating the C. difficile infections — capsules that contain frozen feces. The research, conducted by a team from Tel Aviv University, Harvard University, Massachusetts General Hospital, and Boston Children's Hospital, suggests the solution may be found in frozen fecal samples of healthy people, whose gastrointestinal tracts contain just the right mix of bacteria. By transplanting fecal samples from healthy patients into guts infected by C. difficile, the researchers were able to resuscitate the ailing gastrointestinal tracts.

For their study, the scientists collected samples from four healthy donors who hadn't taken antibiotics for at least six months. The donated stool was screened for diseases and harmful bacteria, placed in a blender and mixed with saline, then strained. The remaining "slurry" was concentrated and packed into capsules, which were then frozen.

Overall, the researchers found, the frozen "poop pills" led to a clinical resolution of diarrhea in 90% of the patients. On average, it took four days for the pills to work. Though the researchers described the results as preliminary, they said they could help make fecal transplants "accessible to a wider population of patients, in addition to potentially making the procedure safer."

For more, read the story in the Los Angeles Times: "Study: Frozen poop pills may make fecal transplants simpler and safer"

Geneticist and Humanitarian: Prof. Mary-Claire King Receives Lasker Award
10/29/2014

TAU honorary doctor recognized with "American Nobel" for cancer research and genetic identification of human rights victims

Prof. Karen Avraham and Prof. Mary-Claire King
TAU's Prof. Karen Avraham (left) with Prof. Mary-Claire King at the Lasker Award ceremony in New York

At a ceremony held in New York City on September 19, 2014, leading geneticist and humanitarian Prof. Mary-Claire King, the American Cancer Society Professor of Genome Sciences and Medicine at the University of Washington in Seattle and 2008 Honorary Doctor of Philosophy of Tel Aviv University, was awarded the 2014 Lasker-Koshland Special Achievement Award in Medical Science.

In addition to her honorary degree from TAU, Prof. King was the 2012-2013 Sackler Lecturer at the TAU School of Medicine, and for the past 18 years she has been the research partner of Prof. Karen Avraham, Professor of Human Molecular Genetics and Vice Dean at the Sackler Faculty of Medicine.

The prize, awarded annually since 1946 by the Albert and Mary Lasker Foundation, is considered by many the "American Nobel."

"Prof. Mary-Claire King has employed her intellect, dedication, and ethical sensibilities to generate knowledge that has catalyzed profound changes in health care, and she has applied her expertise to promote justice where nefarious governments have terrorized their citizens," the foundation stated.

Prof. King is one of the world's leading scientists in the field of human molecular genetics. She was the first to demonstrate that a genetic predisposition for breast cancer exists as the result of inherited mutations in the gene she named BRCA1. More recently, she devised a plan to screen for all genes that predispose to breast and ovarian cancers.

Prof. King also pioneered the use of genetic identification to identify victims of human rights violations. Beginning in the 1980s, Prof. King helped find children in Argentina taken from their families during the "Dirty War" of the late 1970s and early 1980s, using a novel approach based on mitochondrial DNA sequencing. She used the same method to identify victims of the bombing of the Jewish community center in Buenos Aires in 1994, and victims of other human rights abuses, natural disasters and man-made tragedies.

For more, visit the Lasker Foundation Web site at http://www.laskerfoundation.org/awards/2014_s_description.htm

Breathe Easier: Get Your D
10/28/2014

TAU study finds asthmatics with Vitamin D deficiency are 25 percent more likely to experience acute attacks

Asthma, which inflames and narrows the airways, has become more common in recent years. While there is no known cure, asthma can be managed with medication and by avoiding allergens and other triggers. A new study by a Tel Aviv University researcher points to a convenient, free way to manage acute asthmatic episodes — catching some rays outside.

According to a paper recently published in the journal Allergy, measuring and, if need be, boosting Vitamin D levels could help manage asthma attacks. The research, conducted by Dr. Ronit Confino-Cohen of TAU's Sackler Faculty of Medicine, Meir Medical Center, and the Clalit Research Institute, and Dr. Becca Feldman of the Clalit Research Institute drew on the records of millions of patients and used physician diagnoses, rather than self-reports, for evidence of asthma episodes.

"Vitamin D has significant immunomodulatory effects and, as such, was believed to have an effect on asthma — an immunologically mediated disease," said Dr. Confino-Cohen. "But most of the existing data regarding Vitamin D and asthma came from the pediatric population and was inconsistent. Our present study is unique because the study population of young adults is very large and 'uncontaminated' by other diseases."

A broad study

Dr. Confino-Cohen and her team of researchers analyzed the medical records of nearly four million members of Clalit Health Services, Israel's largest health care provider. The Vitamin D levels of 307,900 people were measured between 2008 and 2012. Researchers also took into account key predictors of asthma, such as obesity, smoking, and other chronic diseases. Of some 21,000 asthma patients in Israel studied, those with a Vitamin D deficiency were 25 percent more likely than other asthmatics to have had at least one flare-up in the recent past.

The researchers found that Vitamin D-deficient asthmatics were at a higher risk of an asthma attack. "Uncontrolled asthma" was defined as being prescribed at least five rescue inhalers, one prescription of oral corticosteroids, or visiting the doctor for asthma at least four times in a single year.

"Our results add more evidence to the link between Vitamin D and asthma, suggesting beneficial effects of Vitamin D on asthma exacerbations," said Dr. Confino-Cohen. "We expect that further prospective studies will support our results. In the meantime, our results support a recommendation for screening of Vitamin D levels in the subgroup of asthma patients who experience recurrent exacerbations. In those with Vitamin D deficiency, supplementation may be necessary."

Sunny side up?

While most of the Vitamin D in people's bodies comes from exposure to the sun, dermatologists recommend obtaining the ingredient from other sources — fish, eggs, cod liver oil, fortified milk, or a dietary supplement — due to the dangers of overexposure to the sun.

"We know a lot about this disease and many therapeutic options are available. So it's quite frustrating that the prevalence of asthma is not decreasing and many patients suffer exacerbations and significant impairment in their quality of life," Dr. Confino-Cohen, an allergy and clinical immunology specialist, said. "Increasing Vitamin D levels is something we can easily do to improve patients' quality of life."

Based on the findings, the researchers recommend that people whose asthma cannot be controlled with existing treatments have their Vitamin D levels tested. For those with a vitamin D deficiency, supplements may make sense.

"This study provided an exceptional opportunity to research asthma. I received a research grant from Clalit Health Services, which provided us with the opportunity to use their very large database and to conduct the study with the professional staff of Clalit Research Institute," said Dr. Confino-Cohen. "We anticipate further prospective research that will support our findings and open a new treatment modality to the population of uncontrolled asthmatics."

Slowing the Biological Clock
10/27/2014

TAU study finds neutralizing an immune system gene could improve the success of fertility treatments in women

Difficulty in conceiving a child is a major challenge for one in seven heterosexual couples in America, especially for those over the age of 35. Now a new discovery by researchers at Tel Aviv University and Chaim Sheba Medical Center at Tel Hashomer could boost the chances of conception in women undergoing in vitro fertilization (IVF) treatments.

Their new research reveals a linkage between the genes of the innate immune system — immunity with which human beings are born, rather than immunity they acquire during their lives — and ovarian longevity. The study, published recently in the Proceedings of the National Academy of Sciences, constituted the doctoral work of Dr. Shiri Uri-Belapolsky of TAU's Sackler School of Medicine. The research was led by Prof. Ruth Shalgi, of the Department of Cell and Developmental Biology at TAU's Sackler School of Medicine, Dr. Yehuda Kamari and Prof. Dror Harats of TAU's Sackler Faculty of Medicine and Sheba Medical Center, and Dr. Aviv Shaish of Sheba Medical Center.

According to research conducted on laboratory mice, the genetic deletion of the protein Interleukin-1 (IL-1), a key player in the innate immune system, could improve the number of eggs available for fertilization as well as improve the ovarian response to hormonal stimulation involved in IVF procedures. This could prove especially effective in women who initially respond poorly to hormonal treatment.

Neutralizing the risks

"We revealed a clear linkage between the genes of the innate immune system and female reproduction," said Dr. Uri-Belapolsky. "The results of our study, which point to neutralizing the effects of the IL-1 protein to slow down the natural processes that destroy the eggs, may set the basis for the development of new treatments, such as an IL-1 blockade that would raise the number of eggs recovered during an IVF cycle and reduce the amount of hormones injected into women undergoing the treatment."

The connection between IL-1 and fertility was discovered by accident in the course of research performed by the scientists on the role of IL-1 in atherosclerosis, the hardening of the arteries. In a surprise result of the research, the fertility lifespan of IL-1-deficient mice was found to be 20% longer than that of control wild-type mice.

Keeping the clock ticking

Female mammals, including humans, are born with a finite number of eggs and are subject to a biological clock that dictates the end of the reproductive lifespan at around 50 years of age. Over the past decade, a trend of postponing childbearing into advanced age has led to a corresponding upward trend in the number of IVF treatments. Inflammation has been reported to affect both IVF outcomes and the ovarian reserve adversely. "Identifying a possible culprit, such as Interleukin-1, may offer new insight into the mechanisms responsible for egg loss as well as practical interventions," the study reports.

"Our revelation is secured with a patent application, and naturally, further study in mice and in humans is required to examine this therapeutic opportunity," said Prof. Shalgi. "I believe we will take this research forward into human clinical trials. However, there is still research to be done before we can start these trials."

The "Cyberwar" Against Cancer Gets a Boost from Intelligent Nanocarriers
10/7/2014

TAU researcher advances novel strategy to fight cancer by shoring up the immune system

Two years ago, Prof. Eshel Ben-Jacob of Tel Aviv University's School of Physics and Astronomy and Rice University's Center for Theoretical Biological Physics made the startling discovery that cancer, like an enemy hacker in cyberspace, targets the body's communication network to inflict widespread damage on the entire system. Cancer, he found, possessed special traits for cooperative behavior and used intricate communication to distribute tasks, share resources, and make decisions.

In research published in the Early Edition of the Proceedings of the National Academy of Sciences, Prof. Ben-Jacob and researchers from Rice University and the University of Texas M.D. Anderson Cancer Center, the leading cancer treatment center in the U.S., offer new insight into the lethal interaction between cancer cells and the immune system's communications network. Prof. Ben-Jacob and the study co-authors developed a computer program that models a specific channel of cell-to-cell communication involving exosomes (nanocarriers with crucial cellular "intelligence") that both cancer and immune cells harness to communicate with other cells.

"Recent research has found that cancer is already adept at using a kind of 'cyberwarfare' against the immune system. We studied the interplay between cancer and the immune system to see how we might be able to shift the balance against cancer," said Prof. Ben-Jacob, noting a difference between the innate and the adaptive qualities of the immune system. "In the beginning, cancer is inhibited by the body's innate immunity. But once cancer escapes the immunity, there is a race between the progression of cancer and the ability of the adaptive immune system to recognize and act against it."

Cyberwarfare of the body

"What we are dealing with is cyberwarfare, pure and simple. Cancer uses the immune systems' own communications network to attack not the soldiers but the generals that are coordinating the body's defense," said Prof. Ben-Jacob.

To better understand the role of exosome-mediated cell-to-cell communication in the battle between cancer and the immune system, the researchers created a computer model that captured the exosomal exchange between cancer cells, dendritic cells, and the other cells in the immune system.

The new model is based on earlier research, which showed that dendritic cells, mediators between the body's innate and adaptive immune systems (the former protects against all threats at all times and the latter guards more efficiently against specific, established dangers), employed exosomes to fulfil their task. The researchers discovered that, overtaken by cancer, these nanocarriers, which contain such vital components as signaling proteins, RNA snippets, and microRNAs, can command cells to change their tasks, placing the entire system at risk.

Finding a better balance between the strong and the weak

According to the new research, three possible cancer states can exist: strong, intermediary, and weak. The intermediary state — in which cancer is neither strong nor weak and in which the immune system is on high alert — could be the key to a new therapeutic approach with reduced side effects. Prof. Ben-Jacob believes it is possible to force cancer from a strong to moderate state, and then from a moderate to weak state, by alternating cycles of radiation or chemotherapy with immune-boosting treatments.

"Our first important discovery is that this situation is due to the exosome-based cyberwar between cancer and the immune system," said Prof. Ben-Jacob. "Without exosomes, the two possible states are only strong-weak and weak-strong. With exosomes, an intermediary state opens a new way to treat cancer using very a different approach."

Prof. Ben-Jacob likened the exchange to a tug-of-war between cancer and the immune system. "The challenge is to be familiar with the battlefield so that we can manipulate cancer therapies to change the balance in favor of the immune system. When cancer is detected, it is almost always in the context of a cancer-immunity competition," said Prof. Ben-Jacob. "We showed that the way to stop and reverse tumor progression without causing strong side effects is an individualized approach of mixed treatments — i.e., four days of radiation followed by a few days of immune system boosting, followed again by four days of radiation, and so on. If provided in the right order, the treatments could indeed shift the balance toward the immune system's 'victory' in reducing the cancer to the moderate-strong state."

The study was supported by the Cancer Prevention and Research Institute of Texas, the National Science Foundation, and the Tauber Family Funds.

How Rabies "Hijacks" Neurons to Attack the Brain
10/6/2014

Groundbreaking TAU study tracks precise path of deadly virus to the central nervous system

Rabies causes acute inflammation of the brain, producing psychosis and violent aggression. The virus, which paralyzes the body's internal organs, is always deadly for those unable to obtain vaccines in time. Some 55,000 people die from rabies every year.

For the first time, Tel Aviv University scientists have discovered the exact mechanism this killer virus uses to efficiently enter the central nervous system, where it erupts in a toxic explosion of symptoms. The study, published in PLOS Pathogens, was conducted by Dr. Eran Perlson and Shani Gluska of TAU's Sackler Faculty of Medicine and Sagol School of Neuroscience, in collaboration with the Friedrich Loeffler Institute in Germany.

"Rabies not only hijacks the nervous system’s machinery, it also manipulates that machinery to move faster," said Dr. Perlson. "We have shown that rabies enters a neuron in the peripheral nervous system by binding to a nerve growth factor receptor, responsible for the health of neurons, called p75. The difference is that its transport is very fast, even faster than that of its endogenous ligand, the small molecules that travel regularly along the neuron and keep the neuron healthy."

Faster than a speeding train

To track the rabies virus in the nervous system, the researchers grew mouse sensory neurons in an observation chamber and used live cell imaging to track the path taken by the virus particles. The researchers "saw" the virus hijack the "train" transporting cell components along a neuron and drove it straight into the spinal cord. Once in the spinal cord, the virus caught the first available train to the brain, where it wrought havoc before speeding through the rest of the body, shutting it down organ by organ.

Nerve cells, or neurons, outside the central nervous system are highly asymmetric. A long protrusion called an axon extends from the cell body to another nerve cell or organ along a specific transmission route. In addition to rapid transmission of electric impulses, axons also transport molecular materials over these distances.

"Axonal transport is a delicate and crucial process for neuronal survival, and when disrupted it can lead to neurodegenerative diseases," said Dr. Perlson. "Understanding how an organism such as rabies manipulates this machinery may help us in the future to either restore the process or even to manipulate it to our own therapeutic needs."

Hijacking the hijacker

"A tempting premise is to use this same machinery to introduce drugs or genes into the nervous system," Dr. Perlson added. By shedding light on how the virus hijacks the transport system in nerve cells to reach its target organ with maximal speed and efficiency, the researchers hope their findings will allow scientists to control the neuronal transport machinery to treat rabies and other neurodegenerative diseases.

Disruptions of the neuron train system also contribute to neurodegenerative diseases, like Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis (ALS). According to Dr. Perlson, "An improved understanding of how the neuron train works could lead to new treatments for these disorders as well."

Viral Infection May Trigger Childhood Diabetes in Utero
10/3/2014

TAU research says prenatal exposure to viruses may cause type 1 diabetes and other autoimmune diseases in children

The incidence of type 1 childhood diabetes has been increasing rapidly worldwide. If blood sugar levels aren't well-controlled, juvenile diabetes can affect nearly every organ of a child's body. And while long-term complications of the disease develop gradually, they may become disabling and even life-threatening. The exact cause of juvenile diabetes has eluded scientists, but a new study from Tel Aviv University suggests a likely trigger before birth.

In a recent paper published in Diabetic Medicine, Prof. Zvi Laron, Professor Emeritus of Pediatric Endocrinology at TAU's Sackler Faculty of Medicine, Director of the Endocrinology and Diabetes Research Unit at Schneider Children's Medical Center of Israel, and Head of the WHO Collaborating Center for the Study of Diabetes in Youth, puts forth evidence that the autoimmune disease is initiated in utero. According to the research, conducted in collaboration with an international team of researchers, women who contract a viral infection during pregnancy transmit viruses to their genetically susceptible fetuses, sparking the development of type 1 diabetes.

Prof. Laron is internationally known for the discovery of the Laron Syndrome, also known as Laron-type Dwarfism, an autosomal recessive disorder characterized by an insensitivity to growth hormone.

The "right season" for diabetes

"We knew that type 1 diabetes was associated with other autoimmune diseases like Hashimoto Thyroiditis, celiac disease, and multiple sclerosis, so we investigated the seasonality of birth months for these respective diseases in Israel and other countries," said Prof. Laron. "We found that the seasonality of the birth of children who went on to develop these diseases did indeed differ from that of the general public.

"In further studies, we found evidence that viral infections of the mother during pregnancy induced damage to the pancreas of the mother and/or the fetus, evidenced by specific antibodies including those affecting the pancreatic cells producing insulin," Dr. Laron said.

For the study, Prof. Laron and his team of researchers from Israel, the University of Washington, and Lund University, Sweden, conducted blood tests of 107 healthy pregnant women, testing for islet cell autoantibodies — evidence of diabetes that appears years before initial symptoms do. They also tested for anti-rotavirus and anti-CoxB3 antibodies.

The researchers found a striking difference between women tested in different seasons, suggesting a link to winter epidemics. The concurrent presence of GAD65 antibodies in cord blood and their mothers indicated autoimmune damage to islet cells during gestation, possibly caused by cross-placental transmission of viral infections and/or antivirus antibodies. In other words, during viral epidemics of winter months, ten percent of the healthy pregnant women who had no family background of autoimmune diseases tested positive for damaging antibodies.

Vaccination before conception

In addition, the cord blood antibody concentrations that exceeded those of the corresponding maternal sample, or antibody-positive cord blood samples with antibody-negative maternal samples, implied an in utero immune response by the fetus.

"If our hypothesis can be verified, then preventive vaccine before conception would be useful in stopping the increasing incidence of type 1 diabetes and other autoimmune diseases," said Prof. Laron. "There is no cure for this diabetes, so true intervention would be important not only medically but also psychologically and financially, as the costs of the lifelong treatment of this chronic disease and other autoimmune diseases are great."

Prof. Laron and his international collaborators are currently raising funds to expand their research to include nearly 1,000 women and newborns.

A Heartbeat Away? Hybrid "Patch" Could Replace Transplants
9/30/2014

TAU researcher harnesses gold nanoparticles to engineer novel biocompatible cardiac patch

Because heart cells cannot multiply and cardiac muscles contain few stem cells, heart tissue is unable to repair itself after a heart attack. Now Tel Aviv University researchers are literally setting a new gold standard in cardiac tissue engineering.

Dr. Tal Dvir and his graduate student Michal Shevach of TAU's Department of Biotechnology, Department of Materials Science and Engineering, and Center for Nanoscience and Nanotechnology, have been developing sophisticated micro- and nanotechnological tools — ranging in size from one millionth to one billionth of a meter — to develop functional substitutes for damaged heart tissues. Searching for innovative methods to restore heart function, especially cardiac "patches" that could be transplanted into the body to replace damaged heart tissue, Dr. Dvir literally struck gold. He and his team discovered that gold particles are able to increase the conductivity of biomaterials.

In a study published by Nano Letters, Dr. Dvir's team presented their model for a superior hybrid cardiac patch, which incorporates biomaterial harvested from patients and gold nanoparticles. "Our goal was twofold," said Dr. Dvir. "To engineer tissue that would not trigger an immune response in the patient, and to fabricate a functional patch not beset by signalling or conductivity problems."

A scaffold for heart cells

Cardiac tissue is engineered by allowing cells, taken from the patient or other sources, to grow on a three-dimensional scaffold, similar to the collagen grid that naturally supports the cells in the heart. Over time, the cells come together to form a tissue that generates its own electrical impulses and expands and contracts spontaneously. The tissue can then be surgically implanted as a patch to replace damaged tissue and improve heart function in patients.

According to Dr. Dvir, recent efforts in the scientific world focus on the use of scaffolds from pig hearts to supply the collagen grid, called the extracellular matrix, with the goal of implanting them in human patients. However, due to residual remnants of antigens such as sugar or other molecules, the human patients' immune cells are likely to attack the animal matrix.

In order to address this immunogenic response, Dr. Dvir's group suggested a new approach. Fatty tissue from a patient's own stomach could be easily and quickly harvested, its cells efficiently removed, and the remaining matrix preserved. This scaffold does not provoke an immune response.

Using gold to create a cardiac network

The second dilemma, to establish functional network signals, was complicated by the use of the human extracellular matrix. "Engineered patches do not establish connections immediately," said Dr. Dvir. "Biomaterial harvested for a matrix tends to be insulating and thus disruptive to network signals."

At his Laboratory for Tissue Engineering and Regenerative Medicine, Dr. Dvir explored the integration of gold nanoparticles into cardiac tissue to optimize electrical signaling between cells. "To address our electrical signalling problem, we deposited gold nanoparticles on the surface of our patient-harvested matrix, 'decorating' the biomaterial with conductors," said Dr. Dvir. "The result was that the nonimmunogenic hybrid patch contracted nicely due to the nanoparticles, transferring electrical signals much faster and more efficiently than non-modified scaffolds."

Preliminary test results of the hybrid patch in animals have been positive. "We now have to prove that these autologous hybrid cardiac patches improve heart function after heart attacks with minimal immune response," said Dr. Dvir. "Then we plan to move it to large animals and after that, to clinical trials."

Dr. Dvir has been awarded a fellowship from the American Heart Association, the Marie Curie Award for Young Investigators, the Alon Fellowship for Young Investigators from the Israeli Ministry of Education, and the Slezak Super Center Award for Cardiac Research.

Single-Neuron “Hub” Orchestrates Activity of an Entire Brain Circuit
9/29/2014

TAU maps precise triggers that activate and neutralize brain cell networks

The idea of mapping the brain is not new. Researchers have known for years that the key to treating, curing, and even preventing brain disorders such as Alzheimer's disease, epilepsy, and traumatic brain injury, is to understand how the brain records, processes, stores, and retrieves information.

New Tel Aviv University research published in PLOS Computational Biology makes a major contribution to efforts to navigate the brain. The study, by Prof. Eshel Ben-Jacob and Dr. Paolo Bonifazi of TAU's School of Physics and Astronomy and Sagol School of Neuroscience, and Prof. Alessandro Torcini and Dr. Stefano Luccioli of the Instituto dei Sistemi Complessi, under the auspices of TAU's Joint Italian-Israeli Laboratory on Integrative Network Neuroscience, offers a precise model of the organization of developing neuronal circuits.

In an earlier study of the hippocampi of newborn mice, Dr. Bonifazi discovered that a few "hub neurons" orchestrated the behavior of entire circuits. In the new study, the researchers harnessed cutting-edge technology to reproduce these findings in a computer-simulated model of neuronal circuits. "If we are able to identify the cellular type of hub neurons, we could try to reproduce them in vitro out of stem cells and transplant these into aged or damaged brain circuitries in order to recover functionality," said Dr. Bonifazi.

Flight dynamics and brain neurons

"Imagine that only a few airports in the world are responsible for all flight dynamics on the planet," said Dr. Bonifazi. "We found this to be true of hub neurons in their orchestration of circuits' synchronizations during development. We have reproduced these findings in a new computer model."

According to this model, one stimulated hub neuron impacts an entire circuit dynamic; similarly, just one muted neuron suppresses all coordinated activity of the circuit. "We are contributing to efforts to identify which neurons are more important to specific neuronal circuits," said Dr. Bonifazi. "If we can identify which cells play a major role in controlling circuit dynamics, we know how to communicate with an entire circuit, as in the case of the communication between the brain and prosthetic devices."

Conducting the orchestra of the brain

In the course of their research, the team found that the timely activation of cells is fundamental for the proper operation of hub neurons, which, in turn, orchestrate the entire network dynamic. In other words, a clique of hubs works in a kind of temporally-organized fashion, according to which "everyone has to be active at the right time," according to Dr. Bonifazi.

Coordinated activation impacts the entire network. Just by alternating the timing of the activity of one neuron, researchers were able to affect the operation of a small clique of neurons, and finally that of the entire network.

"Our study fits within framework of the 'complex network theory,' an emerging discipline that explores similar trends and properties among all kinds of networks — i.e., social networks, biological networks, even power plants," said Dr. Bonifazi. "This theoretical approach offers key insights into many systems, including the neuronal circuit network in our brains."

Parallel to their theoretical study, the researchers are conducting experiments on in vitro cultured systems to better identify electrophysiological and chemical properties of hub neurons. The joint Italy-Israel laboratory is also involved in a European project aimed at linking biological and artificial neuronal circuitries to restore lost brain functions.

Life, Liberty, and the Pursuit of Healthcare?
9/23/2014

TAU study finds wealthiest older Americans worse off than poorest counterparts in other countries

The Affordable Care Act — "Obamacare" — was signed into law in 2010 and promised the largest overhaul of the U.S. healthcare system since the 1960s. Designed to provide medical care to uninsured Americans, it has been widely decried as an unwarranted intrusion into the affairs of private businesses and individuals.

However, an independent comparative study of healthcare systems in six Western countries, published last month in Social Science and Medicine, supports a move away from privatized medicine toward state-sponsored healthcare systems. In her research, Dina Maskileyson of Tel Aviv University's Gershon H. Gordon Faculty of Social Sciences found that privatized medical care in the U.S. has contributed to greater wealth-health inequality than state-sponsored healthcare systems in Sweden, the U.K., Israel, Germany, and the Czech Republic. According to her new study, the wealthiest older people in the U.S. surprisingly suffered from worse health than the poorest older people in the other countries reviewed. Moreover, household wealth has a far more powerful effect on the state of an older person's health in the U.S. than in any of the other countries.

"The positive association between household wealth and health is about twice as strong in the U.S. than in the other countries examined," said Ms. Maskileyson. "In the U.S., every additional percentage point in household wealth increased physical health by about twice as much as it did in the other countries. Among the six countries, household wealth was the most important factor in predicting health outcomes of older Americans."

A survey of surveys

Using a statistical model estimating individual-level data for 41,533 individuals aged 50 and older, Ms. Maskileyson drew her information from the Survey on Health, Ageing and Retirement in Europe (SHARE), the U.S. Health and Retirement Study (HRS), and the English Longitudinal Study of Ageing (ELSA). She decided to focus on total household wealth instead of income because household wealth reflects the cumulative and dynamic nature of economic well-being that is especially relevant for older citizens and retirees who do not receive a monthly salary but rely on medical care substantially more than younger sectors of society.

According to the study, the U.S.'s private-based healthcare system not only produced poorer health outcomes and increased the wealth-health inequality gap, it also left the wealthiest Americans, with access to the "best money can offer," still worse off than the poorest citizens in the U.K., Germany, Sweden, and the Czech Republic.

Trends to privatization in Israel

"The fact that Israel in recent decades has shifted from public to private healthcare — the opposite direction of other developed countries — reinforced my motivation to examine how differently funded healthcare systems may influence population health and health inequality," said Ms. Maskileyson. "Dangerous trends of privatization in the Israeli healthcare system may lead to an increase in total national expenditure on health by promoting expensive health services, like those in the U.S. that only wealthy people can access."

"I hope policy makers in the United States and Israel look to the experiences of other countries for guidance," said Ms. Maskileyson.

Ms. Maskileyson is currently researching health disparities among immigrants in the U.S.

Lack of Thyroid Hormone Blocks Hearing Development
9/22/2014

TAU researchers discover that a genetic form of deafness is due to absence of thyroid hormone


Scanning electron microscopy of inner hair cells from cochleas of wild type (top) and mutant (bottom) mice. Image courtesy Dr. Karen Avraham and Dr. Amiel Dror.

Fatigue, weight gain, chills, hair loss, anxiety, excessive perspiration — these symptoms are a few of the signs that the thyroid gland, which regulates the body's heart rate and plays a crucial role in its metabolism, has gone haywire. Now, new research from Tel Aviv University points to an additional complication caused by thyroid imbalance: congenital deafness.

The study, published in Mammalian Genome, was conducted by Prof. Karen B. Avraham and Dr. Amiel Dror of the Department of Human Molecular Genetics and Biochemistry at TAU's Sackler School of Medicine. Using state-of-the-art imaging, the researchers found that congenital deafness can be caused by an absence of a thyroid hormone during development.

"Since our laboratory mainly focuses on the system of the inner ear, the study of a system such as the thyroid gland was new to us and therefore challenging," said Dr. Dror. "My curiosity as to how these two systems interact together to develop normal hearing led to this multidisciplinary study."

A colorful approach

Prof. Karen Avraham and Dr. Amiel Dror
Dr. Karen Avraham and Dr. Amiel Dror.

The researchers used mouse populations to study a form of congenital deafness that affects humans. Harnessing electron microscopy at the Sackler Cellular & Molecular Imaging Center, researchers tracked the inner hair cells of the cochlea (the auditory portion of the inner ear) in two groups — control (wild) mice and mutant (congenitally deaf) mice. Inner-ear hair bundles in the affected mice were labelled with bright colors to highlight the disorganization of the ear's hair cells.

Examination of the inner ear showed a spectrum of structural and molecular defects consistent with hypothyroidism or disrupted thyroid hormone action. The researchers' analysis of the images revealed defective formation of the mice's thyroid glands: labelled thyroid follicles did not grow or grew incompletely.

"Our work demonstrated that normal hearing fails to develop when thyroid hormone availability is insufficient as a result of a genetic mutation," said Dr. Dror. "Our model provides a platform to test therapeutic approaches in order to prevent hearing loss before it occurs. There is still long way ahead before we get to the point of practical treatments with our research, but we believe we are moving in the right direction."

A lifelong commitment

"My attraction to sound began very early as a child," said Dr. Dror. "I play string instruments and pay great attention to sound quality and perception. As a graduate student in the Avraham laboratory, I was exposed to the fascinating world of genetics and the opportunity to combine two fields of research that I am interested in: genetics and hearing. Now that I have continued this research as a medical student, the direct interaction with patients with hearing impairments encouraged me to explore the clinical significance of my research."

As a physician, Dr. Dror believes it is important to pursue research with clinical consequences for his patients. "The basis of all advanced medicine relies on both basic science and clinical research. I hope that our study will contribute a modest part to global efforts for improved medical care and treatment of hearing impairments," Dr. Dror said.

The study was supported by the National Institutes of Health and I-CORE Gene Regulation in Complex Human Disease.

Study Finds Drop in Death Rates from Strokes Over Last Two Decades
9/15/2014

But positive trend is inconsistent among different age groups, warns TAU researcher

Despite the significant reduction in the overall incidence and death rates from strokes in the United States over the past twenty years, more attention needs to be paid to specific age groups, a recent study found.

The new research, conducted by Dr. Silvia Koton of Tel Aviv University's Sackler Faculty of Medicine and the Bloomberg School of Public Health at Johns Hopkins University, Prof. Josef Coresh of the Bloomberg School of Public Health, and a team of experts at Hopkins, the University of North Carolina, Chapel Hill and the University of Arizona, found a 24 percent decline per decade in first‐time strokes and a 20 percent drop per decade in deaths after strokes in the last 24 years.

Published in the Journal of the American Medical Association, the study provides empirical evidence of a decline in stroke incidence and subsequent mortality across racial and gender groups. However, it also indicates a disparity of stroke incidence across different age groups.

An ounce of prevention

According to the study, the decline in stroke risk was concentrated mainly in the over‐65 set, with little progress in reducing the risk of strokes among young people. In contrast, the drop in stroke‐related deaths was primarily found among those under age 65, with mortality rates holding firm in older people.

If the obesity epidemic in the U.S. and other countries progresses as expected, the incidence of high blood pressure, diabetes, and high cholesterol levels will rise, and millions will face an increased risk of stroke, says Dr. Koton. "Stroke is not only the number four cause of death in the U.S., but the leading cause of long-term disability in adults. As a result, the prevention of strokes is crucial," said Dr. Koton.

"Since strokes mainly affect older populations, and our population is aging, it is important to learn about changes in stroke incidence and mortality. Our findings are encouraging, but they also suggest that there are specific groups that require more attention. Adopting a healthy life style and controlling cardiovascular risk factors is important for everybody, but apparently there is a need to focus stroke prevention efforts on particular population subgroups."

Extensive study population

The study based its findings on data presented by Atherosclerosis Risk in Communities (ARIC) research, which monitored 15,792 residents between the ages of 45 and 64 in four U.S. communities starting in the late 1980s. In the new study, researchers followed the progress of 14,357 participants who were free of stroke in 1987, with an eye to stroke hospitalizations and deaths between 1987-2011.

Extensive information was collected through interviews and physical exams at baseline (1987-1989) and in three follow-up visits (1990-92, 1993-95, and 1996-98). In addition to the check-ups, annual phone interviews were conducted as well as active surveillance of discharges from local hospitals until December 31, 2011.

"Decreases in stroke incidence and mortality have previously been demonstrated, but empirical data on validated stroke incidence are scarce," said Dr. Koton. "In the ARIC study, each stroke was confirmed by expert review of medical charts using uniform criteria. In addition, previous reports on long-term trends in stroke incidence by race have not been consistent, with some studies in the U.S. showing decreases in stroke incidence over time only among whites — but not African-Americans. Our study shows that stroke incidence and mortality are decreasing also among African-Americans."

The researchers hope their findings will provide a basis for future studies that focus on the reasons for age disparities in stroke incidence and subsequent mortality.

Back to School? Bring Your Inhaler
9/10/2014

TAU research says September is the cruellest month for kids with asthma

A Tel Aviv University study suggests that the riskiest time for children with asthma is September — just as they head back to school.

In a study published in the journal Pediatrics, Dr. Herman Avner Cohen of TAU's Sackler Faculty of Medicine, found that the incidence of asthma attacks is twice as high in September as in August. Not surprisingly, the research points to more than double the prescriptions for asthma rescue inhalers issued in September compared to those issued in August.

To study the phenomenon, researchers reviewed five years of health data from more than 900,000 Israeli children between the ages of 2 and 15. From that group, nearly 9 percent (or more than 82,000) had been diagnosed with asthma.

"Returning to school after summer is strongly associated with an increased risk for asthma exacerbation and unscheduled visits to the primary care physician," said Dr. Cohen. By identifying trends in asthma incidence, parents and physicians can be better prepared to treat their children's asthma flare-ups, he says.

The researchers suggest that the use of asthma-controlling medications is likely at its lowest level of the year just before children return to school. Factors that may cause a rise in September are additional exposures to fall allergens and greater exposure to infections as children congregate at school.

For more, read the story in U.S. News and World Report:

September Peak Month for Kids' Asthma Flares: Study

New Molecular Target is Key to Enhanced Brain Plasticity
9/9/2014

TAU researcher says discovery may lead to improved memory, cognitive function in Alzheimer's patients

As Alzheimer's disease progresses, it kills brain cells mainly in the hippocampus and cortex, leading to impairments in "neuroplasticity," the mechanism that affects learning, memory, and thinking. Targeting these areas of the brain, scientists hope to stop or slow the decline in brain plasticity, providing a novel way to treat Alzheimer's. Groundbreaking new research has discovered a new way to preserve the flexibility and resilience of the brain.

The study, led by Tel Aviv University's Prof. Illana Gozes and published in Molecular Psychiatry, reveals a nerve cell protective molecular target that is essential for brain plasticity. According to Prof. Gozes, "This discovery offers the world a new target for drug design and an understanding of mechanisms of cognitive enhancement."

Prof. Gozes is the incumbent of the Lily and Avraham Gildor Chair for the Investigation of Growth Factors and director of the Adams Super Center for Brain Studies at the Sackler Faculty of Medicine and a member of TAU's Sagol School of Neuroscience. Also contributing to the study were Dr. Saar Oz, Oxana Kapitansky, Yanina Ivashco-Pachima, Anna Malishkevich, Dr. Joel Hirsch, Dr. Rina Rosin-Arbersfeld, and their students, all from TAU. TAU staff scientists Dr. Eliezer Gildai and Dr. Leonid Mittelman provided the state-of-the-art molecular cloning and cellular protein imaging necessary for the study.

Building on past breakthroughs

The new finding is based on Prof. Gozes' discovery of NAP, a snippet of a protein essential for brain formation (activity-dependent neuroprotective protein [ADNP]). As a result of this discovery, a drug candidate that showed efficacy in mild cognitive impairment patients, a precursor to Alzheimer's disease, is being developed. NAP protects the brain by stabilizing microtubules — tiny cellular cylinders that provide "railways and scaffolding systems" to move biological material within cells and provide a cellular skeleton. Microtubules are of particular importance to nerve cells, which have long processes and would otherwise collapse. In neurodegenerative diseases like Alzheimer's, the microtubule network falls apart, hindering cellular communication and cognitive function.

"Clinical studies have shown that Davunetide (NAP) protects memory in patients suffering from mild cognitive impairment preceding Alzheimer's disease," said Prof. Gozes. "While the mechanism was understood in broad terms, the precise molecular target remained a mystery for years. Now, in light of our new research, we know why and we know how to proceed."

Stabilizing microtubules

The breakthrough was the discovery of the mechanism promoting microtubule growth at the tips of the tubes ("rails"). The researchers found that the NAP structure allows it to bind to the tip of the growing microtubule, the emerging "railway," through specific microtubule end-binding proteins, which adhere to microtubules a bit like locomotors to provide for growth and forward movement, while the other end of the microtubule may to be disintegrating. These growing tips enlist regulatory proteins that are essential for providing plasticity at the nerve cell connection points, the synapses.

"We have now revealed that ADNP through its NAP motif binds the microtubule end binding proteins and enhances nerve cell plasticity, providing for brain resilience. We then discovered that NAP further enhances ADNP microtubule binding," said Prof. Gozes.

Researchers hope their discovery will help move Davunetide (NAP) and related compounds into further clinical trials, increasing the potential of future clinical use. Prof. Gozes is continuing to investigate microtubule end-binding proteins to better understand their protective properties in the brain.

Innovative Algorithm Spots Interactions Lethal to Cancer
9/3/2014

TAU research identifying cancer-busting "genetic partners" can personalize cancer treatment

Despite the revolutionary biotechnological advancements of the last few decades, an ideal anti-cancer treatment — one that's immediately lethal to cancer cells, harmless to healthy cells, and resistant to cancer's relapse — is still a dream.

But a concept called "synthetic lethality" holds great promise for researchers. Two genes are considered synthetically lethal when their combined inactivation is lethal to cells, while inhibiting just one of them is not. Synthetic lethality promises to deliver personalized, more effective, and less toxic therapy. If a particular gene is found to be inactive in a tumor, then inhibiting its synthetic lethal partner with a drug is likely to kill only the cancer cells, causing little damage to healthy cells.

While this promising approach has been widely anticipated for almost two decades, its potential could not be realized due to the difficulty experimentally identifying synthetic lethal pairs in cancer. Now new research published last week in the highly prestigious journal Cell overcomes this fundamental hurdle and presents a novel strategy for identifying synthetic lethal pairs in cancer with the potential to bust cancer cells.

Tel Aviv University researchers have developed a computational data-driven algorithm, which identifies synthetic lethal interactions. In their comprehensive, multidisciplinary study, Dr. Eytan Ruppin of TAU's Blavatnik School of Computer Science and the Sackler School of Medicine and Ms. Livnat Jerby-Arnon of TAU's Blavatnik School of Computer Science worked together with other researchers from TAU, The Beatson Institute for Cancer Research (Cancer Research UK), and the Broad Institute of Harvard and MIT.

Taking cancer personally

Analyzing large sets of genetic and molecular data from clinical cancer samples, the scientists were able to identify a comprehensive set of synthetic lethal pairs that form the core synthetic lethality network of cancer. They have demonstrated for the first time that such a network can be used to successfully predict the response of cancer cells to various treatments and predict a patient's prognosis based on personal genomic information.

"We started this research from a very simple observation: If two genes are synthetically lethal, they are highly unlikely to be inactive together in the same cell," said Dr. Ruppin. "As cancer cells undergo genetic alterations that result in gene inactivation, we were able to identify synthetic lethal interactions by analyzing large sets of cancer genetic profiles. Genes that were found to be inactive in some cancer samples, but were almost never found to be inactive together in the same sample, were identified as synthetically lethal."

The crux of the study, according to Ms. Jerby-Arnon, is the synergy between the computational research and the ensuing experiments, conducted at the Beatson Institute and the Broad Institute, to verify the predictive power of the new algorithm.

A road to new therapies

In addition to their promising role in tailoring personalized cancer treatment, the synthetic lethal pairs discovered may also be used to repurpose drugs, which are currently used to treat other non-cancer disorders, to target specific cancer types. "We applied our pipeline to search for drugs that may be used to treat certain forms of renal cancer. We identified two such drugs, currently used to treat hypertension and cardiac dysrhythmia, that may be quite effective," said Dr. Ruppin. "Experiments in cell lines performed by the Gottlieb lab at the Beatson Institute support these findings, and we are now working on additional validations in mice."

The researchers are hopeful that their study will help boost the experimental detection of synthetic lethality in cancer cells and offer further insight into the unique susceptibilities of these pathological cells. "In this study, we have demonstrated the clinical utility of our framework, showing that it successfully predicts the response of cancer cells to various treatments as well as patient survival," said Ms. Jerby-Arnon. "In the long-run, we hope this research will help improve cancer treatment by tailoring the most effective treatment for a given patient."

The researchers are in the process of forming experimental and clinical international collaborations to test key emerging leads for novel drug targets and drug repurposing.

"Junk" Blood Tests May Offer Life-Saving Information
8/27/2014

TAU says contaminated blood cultures can serve as diagnostic predictor for more targeted antibiotics

Some 30 percent of all positive hospital blood culture samples are discarded every day because they're "contaminated" — they reflect the presence of skin germs instead of specific disease-causing bacteria.

Rather than toss these compromised samples into the trash, clinicians may be able to use the resistance profiles of skin bacteria identified by these tests to treat patients with antibiotics appropriate to their ailment, Tel Aviv University researchers say. Dr. Gidi Stein and Dr. Danny Alon of TAU's Sackler Faculty of Medicine and the Department of Internal Medicine B. at Beilinson Hospital, Rabin Medical Center, and Prof. Lilach Hadany and Uri Obolski of the Department of Molecular Biology and Ecology of Plants at TAU's Faculty of Life Sciences conducted a retrospective study on more than 2,500 patients. Their test results demonstrate the unique diagnostic value of "erroneous" cultures.

The study showed the immediate effects on both public health questions and the treatment of individuals whose blood has been contaminated. The results were published in the Journal of Antimicrobial Chemotherapy.

Think before you toss

The more resistant the skin germs, the higher the risk of the infecting bacteria to be resistant, the researchers found. "These results can certainly be used for on-site clinical decisions. Once a contaminated sample has been found to be highly resistant, it is likely that the blood-borne pathogens will have a similar resistance pattern. Thus antibiotic treatment may be better targeted for the actual pathogens," says Prof. Hadany.

In the study, the researchers processed the demographic information, hospital records, blood culture results, and date of death of all patients at the Rabin Medical Center with positive blood cultures from 2009-12. They found that out of 2,518 patients, 1,664 blood cultures drawn from 1,124 patients reflected the presence of a common skin contaminant, coagulase-negative staphylococci (CoNS). High overall CoNS resistance predicted high overall resistance of the bacteria causing disease or infection. Most importantly perhaps, highly resistant CoNS isolates were found to be associated with higher short-term mortality.

The researchers hope their conclusions will cause clinicians to pause before discarding contaminated blood test results.

"Because we have found a direct correlation between resistance profiles of CoNS contaminants and those of the actual infecting bacteria isolated from the same patient, the results of these 'junk' samples can be used to predict patient mortality and correct empirical antibiotic therapy," said Dr. Stein. "This should serve as an additional, non-invasive, diagnostic tool."

Public welfare

According to the researchers, most hospital patients are treated at the outset with broad spectrum antibiotics. Days later, after initial test results are known, clinicians replace broad spectrum antibiotics with more precise narrow-spectrum antibiotics, which treat the specific bacteria identified by the blood sample.

It is well known that narrow spectrum antibiotics are better for the body because they target specific bacteria as opposed to an entire microenvironment. Moreover, broad spectrum antibiotics might result in altered bacterial environments of the skin and gastro-intestinal tract, promoting inflammation and the emergence of resistant pathogens.

"The high rate of inappropriate antibiotic use puts patients and the general public at risk," said Prof. Hadany. "Improved matching of the treatment to the needs of the patient might reduce antibiotic load and the emergence of resistance."

Novel Nanovehicle Transports Drug Cocktail to Target Cancer
8/14/2014

TAU researcher demonstrates clear advantages of polymer carrier that combines several therapeutic drugs

Combination therapies, or "drug cocktails," are part and parcel of modern anti-cancer treatments today. The more researchers learn about cancer and its surreptitiously lethal impact on the body, the more urgent the need to diversify the arsenal at clinicians' disposal.

To that end, Prof. Ronit Satchi-Fainaro, and doctoral students Hemda Baabur-Cohen and Ela Markovsky of Tel Aviv University's Department of Physiology and Pharmacology, Sackler School of Medicine, have developed a novel nanomedical technique to more effectively attack and dismantle tumor cells, while staying "beneath the radar" of the body's immune system as the drugs travel through the body. The new research, to be published in the Journal of Controlled Release, demonstrates that this "synergistic" treatment is far more effective and less toxic than traditional chemotherapies or current combination therapies.

"For the first time, we conducted a systematic study to determine the requirements for a combination of biological materials and drugs: their different mechanisms of action, different toxicity profiles, and distinct defense mechanisms — acquired resistance — of tumor cells in response to them," said Prof. Satchi-Fainaro. "With these three criteria in hand, we were able to set the precise ratio of drugs required to be synergistically effective but not harmful to the body."

Working in combination

Prof. Satchi-Fainaro and her team leveraged the performance and toxicity of two common chemotherapy drugs — doxorubicin (DOX) and paclitaxel (PTX) — to produce the best combined ratio. Once an effective, safe level was established on mice afflicted with human breast cancer, the researchers sought the perfect carrier to safely transport these therapies to their ultimate destination: human cancer cells.

"When combination therapy is used, the drugs do not reach the tumor at the same time," said Prof. Satchi-Fainaro. "Each drug has a different pharmacokinetic profile — that is, a specific interaction between the drug and the body. So we looked for a unique nanocarrier that would bind the drugs and ensure they reach the tumor and release the drugs at the same time."

The researchers chose polyglutamic acid (PGA) as the nanovehicle to transport the two chemotherapies. The PGA-PTX-DOX combination demonstrated a major advantage over a combination of traditional therapies. Furthermore, it was the first time scientists were able to systematically demonstrate a model of combined nanomedicine that also exhibited superior anti-tumor efficacy.

"Stealth" carriers

"By putting several passengers in one 'taxi' made of a polymer, all of them can arrive at the same site at the same time," said Prof. Satchi-Fainaro. "This forces the drugs to share the same pharmacokinetic profile. The nanomedicine we designed is a pro-drug, activated by an enzyme produced in many types of cancers. Once the polymer 'taxi' is degraded, the drugs are released at the tumor site, facilitating a truly synergistic cooperation.

"We have developed a system that can be used for different chemotherapies and combined with drugs targeting the tumor microenvironment, such as anti-angiogenic and anti-inflammatory drugs. The applications are truly endless. This system can be exploited for personalized therapy in which we analyze each patient's tumor cells to tailor the right drug combination on the polymer for the cancer," Prof. Satchi-Fainaro continued.

"Our aim is to expand our arsenal of anti-cancer weapons while decreasing the toxicity of the chemotherapy drugs used. Our 'stealth' carriers travel under the radar of the immune system, straight to the tumor and its supporting microenvironment."

The researchers' innovative platform is patent pending.

Involuntary Eye Movement a Foolproof Indication for ADHD Diagnosis
8/13/2014

TAU researchers develop diagnostic tool for the most commonly misdiagnosed disorder

Attention Deficit Hyperactivity Disorder (ADHD) is the most commonly diagnosed — and misdiagnosed — behavioral disorder in children in America, according to the Centers for Disease Control and Prevention. Unfortunately, there are currently no reliable physiological markers to diagnose ADHD. Doctors generally diagnose the disorder by recording a medical and social history of the patient and the family, discussing possible symptoms and observing the patient's behavior. But an incorrect evaluation can lead to overmedication with Ritalin (methylphenidate), which has parents everywhere concerned.

Now a new study from Tel Aviv University researchers may provide the objective tool medical professionals need to accurately diagnose ADHD. According to the research, published in Vision Research, involuntary eye movements accurately reflect the presence of ADHD, as well as the benefits of medical stimulants that are used to treat the disorder.

Keeping an eye on the eyes

Dr. Moshe Fried, Dr. Anna Sterkin, and Prof. Uri Polat of TAU's Sackler Faculty of Medicine, Dr. Tamara Wygnanski-Jaffe, Dr. Eteri Tsitsiashvili, Dr. Tamir Epstein of the Goldschleger Eye Research Institute at Sheba Medical Center, Tel Hashomer, and Dr. Yoram S. Bonneh of the University of Haifa used an eye-tracking system to monitor the involuntary eye movements of two groups of 22 adults taking an ADHD diagnostic computer test called the Test of Variables of Attention (TOVA). The exercise, which lasted 22 minutes, was repeated twice by each participant. The first group of participants, diagnosed with ADHD, initially took the test un-medicated and then took it again under the influence of methylphenidate. A second group, not diagnosed with ADHD, constituted the control group.

"We had two objectives going into this research," said Dr. Fried, who as an adult was himself diagnosed with ADHD. "The first was to provide a new diagnostic tool for ADHD, and the second was to test whether ADHD medication really works — and we found that it does. There was a significant difference between the two groups, and between the two sets of tests taken by ADHD participants un-medicated and later medicated."

Foolproof, affordable, and accessible diagnosis

The researchers found a direct correlation between ADHD and the inability to suppress eye movement in the anticipation of visual stimuli. The research also reflected improved performance by participants taking methylphenidate, which normalized the suppression of involuntary eye movements to the average level of the control group.

"This test is affordable and accessible, rendering it a practical and foolproof tool for medical professionals," said Dr. Fried. "With other tests, you can slip up, make 'mistakes' — intentionally or not. But our test cannot be fooled. Eye movements tracked in this test are involuntary, so they constitute a sound physiological marker of ADHD.

"Our study also reflected that methylphenidate does work. It is certainly not a placebo, as some have suggested."

The researchers are currently conducting more extensive trials on larger control groups to further explore applications of the test.

A "Magnetic" Solution to Identify and Kill Tumors
8/13/2014

Though a valuable weapon against cancerous tumors, radiation therapy often harms healthy tissue as it tries to kill malignant cells. Now, Prof. Israel Gannot of Tel Aviv University's Department of Biomedical Engineering is developing a new way to destroy tumors with fewer side effects and minimal damage to surrounding tissue.

His innovative method, soon to be published in the journal Nanomedicine, uses heat to kill the tumor cells but leaves surrounding healthy tissue intact. Using specific biomarkers attached to individual tumors, Prof. Gannot's special mixture of nano-particles and antibodies locates and binds to the tumor itself.

"Once the nano-particles bind to the tumor, we excite them with an external magnetic field, and they begin to heat very specifically and locally," says Prof. Gannot. The magnetic field is manipulated to create a targeted rise in temperature, and it is this directed heat elevation which kills the tumors, he says.

The treatment has been proven effective against epithelial cancers, which can develop in almost any area of the body, such as the breast or lung. By using a special feedback process, also developed in his laboratory, the process can be optimized for individual treatment.

A cure without casualty

The specialized cocktail of nano-particles and antibodies is administered safely and simply, through topical local injection or injection into the blood stream. As an added benefit, the mixture washes out of the body without leaving a trace, minimizing side effects.

If clinical trials are successful, the technique may become a mainstay of patient care. The nano-particles themselves are already FDA-approved, and according to Prof. Gannot, the method is effective almost any type of tumor, as long as its specific markers and its antibodies can be identified.

The countdown to demolition

In addition to being minimally invasive, this treatment boasts sheer speed. It can be applied during an out-patient procedure — the entire technique lasts only six hours — which allows patients to recuperate in the comfort of their own homes.

Prof. Gannot is currently applying his technique to cell lines and to ex vivo tissues and tissue-like substitutes in his lab, and plans to start in vivo experiments by next year.


"Junk DNA" Can Sense Viral Infection
8/6/2014

Promising tool in the battle between pathogen and host, TAU research confirms

Once considered unimportant "junk DNA," scientists have learned that non-coding RNA (ncRNA) — RNA molecules that do not translate into proteins — play a crucial role in cellular function. Mutations in ncRNA are associated with a number of conditions, such as cancer, autism, and Alzheimer's disease.

Now, through the use of "deep sequencing," a technology used to sequence the genetic materials of the human genome, Dr. Noam Shomron of Tel Aviv University's Sackler Faculty of Medicine has discovered that when infected with a virus, ncRNA gives off biological signals that indicate the presence of an infectious agent, known as a pathogen. Not only does this finding give researchers a more complete picture of the interactions between pathogens and the body, but it provides scientists with a new avenue for fighting off infections.

His findings have been published in the journal Nucleic Acid Research.

Another battleground between pathogen and host

"If we see that the number of particular RNA molecules increases during a specific viral infection, we can develop treatments to stop or slow their proliferation," explains Dr. Shomron.

In the lab, the researchers conducted a blind study in which some cells were infected with the HIV virus and others were left uninfected. Using the deep sequencer, which can read tens of millions of sequences per experiment, they analyzed the ncRNA to discover if the infection could be detected in non-coding DNA materials. The researchers were able to identify with 100% accuracy both infected and non-infected cells — all because the ncRNA was giving off significant signals, explains Dr. Shomron.

These signals, which can include either the increase or decrease of specific ncRNA molecules within a cell, most likely have biological significance, he says. "With the introduction of a pathogen, there is a reaction in both the coding and non-coding genes. By adding a new layer of information about pathogen and host interactions, we better understand the entire picture. And understanding the reactions of the ncRNA following infection by different viruses can open up the battle against all pathogens."

Finding an “Achilles heel” of infections

The researchers believe that if an ncRNA molecule significantly manifests itself during infection by a particular pathogen, the pathogen has co-opted this ncRNA to help the pathogen devastate the host — such as the human body. To help the body fight off the infection, drugs that stop or slow the molecules' proliferation could be a novel and effective strategy.

This new finding allows researchers to develop treatments that attack a virus from two different directions at once, targeting both the coding and non-coding genetic materials, says Dr. Shomron. He suggests that ncRNA could prove to be the "Achilles heel" of pathogens.

Dr. Shomron and his team of researchers developed new software, called RandA, which stands for "ncRNA Read-and-Analyze," that performs ncRNA profiling and analysis on data generated through deep sequencing technology. It's this software that has helped them to uncover the features that characterize virus-infected cells.


A New “Whey” to Control Diabetes
8/5/2014

A whey protein drink before breakfast can control erratic glucose levels associated with type 2 diabetes, say Tel Aviv University researchers

Blood sugar surges — after-meal glucose "spikes" — can be life threatening for the 29 million Americans with diabetes. Diabetic blood sugar spikes have been linked to cardiovascular disease, cancer, Alzheimer’s disease, kidney failure, and retinal damage. Now a new Tel Aviv University study, published in Diabetologia, suggests a novel way to suppress these deadly post-meal glucose surges: the consumption of whey protein concentrate, found in the watery portion of milk separated from cheese curds, before breakfast.

According to TAU's Prof. Daniela Jakubowicz and Dr. Julio Wainstein of the Wolfson Medical Center's Diabetes Unit, Prof. Oren Froy of the Hebrew University of Jerusalem, and Prof. Bo Ahrén of Lund University in Sweden, the consumption of whey protein before meals may even keep diabetics' need for insulin treatment at bay.

"What's remarkable is that consuming whey protein before meals reduces the blood sugar spikes seen after meals. It also improves the body's insulin response, putting it in the same range or even higher than that produced by novel anti-diabetic drugs," said Prof. Jakubowicz. "High milk intake has long been associated with lower risk for type 2 diabetes and cardiovascular disease, and milk whey protein increases the production of a gut hormone called glucagon-like peptide-1 (GLP-1) that stimulates insulin secretion. This, in turn, reduces the blood glucose rise after meals."

A whey cocktail before breakfast

"We hypothesized that stimulating GLP-1 production by consuming whey protein before a meal would enhance insulin secretion and have beneficial glucose-lowering effects in type 2 diabetes," Prof. Jakubowicz said.

The study was conducted on 15 individuals with well-controlled type 2 diabetes at Wolfson Medical Center. The participants were randomized to receive either 50 grams of whey in 250 ml water or a placebo, followed by a standardized high-glycemic index breakfast of three slices of white bread and sugary jelly — a meal designed to produce the maximum post-meal glucose spike.

Blood samples were taken 30 minutes before the meal, when the whey protein or placebo drinks were consumed. Further blood samples, assessing plasma concentration of glucose, intact GLP-1, and insulin concentrations, were taken when the breakfast was served and at 15, 30, 60, 90, 120, 150, and 180 minute intervals after the meal.

The most important meal of the day?

The researchers found that glucose levels were reduced by 28 percent after the whey pre-load over the 180-minute post-meal period, with a uniform reduction during early and late phases. With whey pre-load, insulin and GLP-1 responses also were significantly higher (105 and 141 percent, respectively), producing a 96 percent increase in early insulin response.

"The early insulin response that usually is deficient in type-2 diabetes was significantly higher after whey protein than with placebo, and the whey protein preload significantly reduced the elevation of blood glucose after breakfast," said Prof. Jakubowicz. "Whey protein could therefore represent a novel approach for enhancing glucose-lowering strategies in type 2 diabetes."

Based on the findings of this study, the authors are considering a long-term clinical trial to test the enduring benefits of whey protein consumption for diabetics.


Heat, Not Heart, Poses Biggest Risk to Athletes
8/4/2014

TAU study says heatstroke is more threatening to marathon runners than cardiac arrest

The sudden cardiac arrest of a young and healthy runner in the middle of a race is a shocking event that can draw media attention. But according to a new Tel Aviv University study published in the Journal of the American College of Cardiology, endurance athletes are actually ten times more likely to develop severe and life-threatening heatstroke — with a fever above 104 degrees that can cause the kidneys, brain, and other organs to fail.

According to lead author Dr. Sami Viskin of TAU's Sackler Faculty of Medicine and Tel Aviv Medical Center, "This research shows that heatstroke is a real threat to marathon and long-distance runners; however, there are no clinical studies of potential strategies to prevent heat stroke during these types of events."

Races longer than 6.2 miles have become increasingly popular among endurance athletes. To assess the greatest health risks associated with these types of events, the researchers analyzed information compiled on all deaths and hospitalizations that occurred in the course of 14 long-distance races in Tel Aviv between March 2007 and November 2013.

Out of nearly 140,000 runners, only two serious heart-related events were reported during the study period, and neither of these were life-threatening. The researchers also found, however, that 21 people developed heatstroke. Of these cases, two were fatal and 12 were considered life-threatening.

"It's important that clinicians educate runners on the ways to minimize their risk of heatstroke, including allowing 10 to 14 days to adjust to a warm climate, discouraging running if a person is ill or was recently ill. ... A pre-existing fever impairs the body's ability to dissipate additional heat stress," Viskin said. He added that better methods of monitoring body core temperature during physical activity need to be developed.

For more, read the story in Forbes:
http://www.forbes.com/sites/larryhusten/2014/07/28/death-by-running-its-the-heat-and-not-the-heart-2/

From the Cockpit to the Operating Table
7/28/2014

TAU researcher says doctors, like pilots, should use simulators to prepare for high-stakes scenarios

As a young combat pilot in the Israeli Air Force, Dr. Amitai Ziv of Tel Aviv University's Sackler School of Medicine practiced on a simulator for every possible nightmare scenario. But when he started medical school, he was surprised to find that medical trainees honed their skills not on simulators, but on real patients.

"We expect both health care and aviation to have very low tolerance for errors. But in health care, we are very much behind aviation in that respect," Dr. Ziv told the recent 2014 Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) meeting. "Our health care training, despite the simulation movement, is still by and large the old model: See one, teach one, do one, kill one. ... The patients are the ones who pay the price."

Dr. Ziv, a pediatrician, has spent the past 20 years trying to adapt the lessons of flight simulation training to the field of medical training. In 2001, Dr. Ziv founded the Israel Center for Medical Simulation (MSR) at the Sheba Medical Center, home to more than 100 different kinds of simulators and employing more than 150 professional actors for its courses. MSR trains health care workers for run-of-the-mill scenarios but also for the catastrophic "unimaginable" ones. Israel is known for its extensive mass casualty preparedness; much of that training is conducted at MSR.

The center is founded on the principle that simulation-based medical training and assessment can revolutionize the culture of safety in medicine.

For more, read the story in General Surgery News:
http://www.generalsurgerynews.com/ViewArticle.aspx?d=In%2bthe%2bNews&d_id=69&i=July+2014&i_id=1079&a_id=27707


In the area of training dental professionals, Tel Aviv University has been a pioneer for decades. Dr. Ben Williamowsky, a member of the Amercan Friends of Tel Aviv University Board and namesake of TAU's new Rothstein-Williamowsky Post-Graduate Clinics, notes:

It may be of interest to note that the Dental School at TAU was the first in the world to introduce the "Simadent," a simulator for teaching dental procedures and later developed to allow one instructor to view the simulated work of students from a single screen in his examining office.

It was developed by young (typically young) Israeli computer-savvy technicians in a facility located on a chicken farm near Jerusalem. Ralph Rothstein and I were taken there to see the "pilot" in use before it made its debut at TAU's School of Dental Medicine, perhaps in the 1980's. I believe the first dental school in the States to adopt it was at the University of Alabama.

Today, every dental school employs a type of teaching simulator ... often, one at every dental chair used by a student! I still remember the name of the young "scientist" who demonstrated the instrument. Her name was Imbal (age 30) and when I asked her where she studied Dentistry ... in great surprise ... informed us that she was not a dentist ... but a computer scientist! Of course she studied at TAU.

Proof: Parkinson's Enhances Creativity
7/14/2014

New TAU study confirms creative energy in Parkinson's sufferers is greater than in healthy individuals

Prof. Rivka Inzelberg of Tel Aviv University's Sackler Faculty of Medicine and the Sagol Neuroscience Center at Sheba Medical Center, Tel Hashomer, documented the exceptional creativity of Parkinson's patients two years ago in a review for Behavioral Neuroscience. Since then, she has conducted the first empirical study to verify a link between Parkinson's disease and artistic inclination.

That empirical study, now published in the Annals of Neurology, definitively demonstrates that Parkinson's patients are more creative than their healthy peers, and that those patients taking higher doses of medication are more artistic than their less-medicated counterparts.

"It began with my observation that Parkinson's patients have a special interest in art and have creative hobbies incompatible with their physical limitations," said Prof. Inzelberg. "In my last paper, I reviewed case studies from around the world and found them to be consistent. In my present research, we conducted the first comprehensive study to measure the creative thinking of Parkinson's patients. This was not a simple task, because how does one measure, or quantify, creativity? We had to think creatively ourselves."

Measuring artistic creativity

Prof. Inzelberg and a team of researchers from TAU, the Sheba Medical Center, and Bar-Ilan University conducted a full battery of tests on 27 Parkinson's patients treated with anti-Parkinson's drugs and 27 age- and education-matched healthy controls. Some of the tests were well-known and others newly adapted for the purpose of the study. The tests included the Verbal Fluency exam, in which a person is asked to mention as many different words beginning with a certain letter and in a certain category (fruit, for example) as possible.

The participants were then asked to undergo a more challenging Remote Association Test, in which they had to name a fourth word (following three given words) within a fixed context. The groups also took the Tel Aviv University Creativity Test, which tested their interpretation of abstract images and assessed the imagination inherent in answers to questions like "What can you do with sandals?" The final exam was a version of the Test for a Novel Metaphor, adapted specifically for the study.

Throughout the testing, Parkinson's patients offered more original answers and more thoughtful interpretations than their healthy counterparts.

In order to rule out the possibility that the creative process evident in the hobbies of patients was linked to obsessive compulsions like gambling and hoarding, to which many Parkinson's patients fall prey, participants were also asked to fill out an extensive questionnaire. An analysis indicated no correlation between compulsive behavior and elevated creativity.

Express yourself

The conclusions from the second round of testing — in which the Parkinson's participants were split into higher- and lower-medicated groups — also demonstrated a clear link between medication and creativity. Parkinson's patients suffer from a lack of dopamine, which is associated with tremors and poor coordination. As such, they are usually treated with either synthetic precursors of dopamine or dopamine receptor agonists.

According to Prof. Inzelberg, the results are hardly surprising, because dopamine and artistry have long been connected. "We know that Van Gogh had psychotic spells, in which high levels of dopamine are secreted in the brain, and he was able to paint masterpieces during these spells — so we know there is a strong relationship between creativity and dopamine," said Prof. Inzelberg.

Prof. Inzelberg hopes her research will be instrumental in spreading awareness. Parkinson's patients often feel isolated by their physical limitations, so artistic work could provide a welcome outlet of expression. "After my first paper, I helped organize exhibits of patients' paintings in Herzliya and Raanana and received feedback about similar exhibits in Canada and France," said Prof. Inzelberg. "These exhibits were useful in raising funds for Parkinson's research, providing occupational therapy for patients — and, most importantly, offering an opportunity for patients to fully express themselves."

Prof. Inzelberg is currently researching additional forms of creativity in Parkinson's patients.

New TAU Research Links Alzheimer's Disease to Brain Hyperactivity
6/30/2014

Study identifies molecular mechanism that triggers hyperactivity of brain circuits in early stages of the disease

Patients with Alzheimer's disease run a high risk of seizures. While the amyloid-beta protein involved in the development and progression of Alzheimer's seems the most likely cause for this neuronal hyperactivity, how and why this elevated activity takes place hasn't yet been explained — until now.

A new study by Tel Aviv University researchers, published in Cell Reports, pinpoints the precise molecular mechanism that may trigger an enhancement of neuronal activity in Alzheimer's patients, which subsequently damages memory and learning functions. The research team, led by Dr. Inna Slutsky of TAU's Sackler Faculty of Medicine and Sagol School of Neuroscience, discovered that the amyloid precursor protein (APP), in addition to its well-known role in producing amyloid-beta, also constitutes the receptor for amyloid-beta. According to the study, the binding of amyloid-beta to pairs of APP molecules triggers a signalling cascade, which causes elevated neuronal activity.

Elevated activity in the hippocampus — the area of the brain that controls learning and memory — has been observed in patients with mild cognitive impairment and early stages of Alzheimer's disease. Hyperactive hippocampal neurons, which precede amyloid plaque formation, have also been observed in mouse models with early onset Alzheimer's disease. "These are truly exciting results," said Dr. Slutsky. "Our work suggests that APP molecules, like many other known cell surface receptors, may modulate the transfer of information between neurons."

With the understanding of this mechanism, the potential for restoring memory and protecting the brain is greatly increased.

Building on earlier research

The research project was launched five years ago, following the researchers' discovery of the physiological role played by amyloid-beta, previously known as an exclusively toxic molecule. The team found that amyloid-beta is essential for the normal day-to-day transfer of information through the nerve cell networks. If the level of amyloid-beta is even slightly increased, it causes neuronal hyperactivity and greatly impairs the effective transfer of information between neurons.

In the search for the underlying cause of neuronal hyperactivity, TAU doctoral student Hilla Fogel and postdoctoral fellow Samuel Frere found that while unaffected "normal" neurons became hyperactive following a rise in amyloid-beta concentration, neurons lacking APP did not respond to amyloid-beta. "This finding was the starting point of a long journey toward decoding the mechanism of APP-mediated hyperactivity," said Dr. Slutsky.

The researchers, collaborating with Prof. Joel Hirsch of TAU's Faculty of Life Sciences, Prof. Dominic Walsh of Harvard University, and Prof. Ehud Isacoff of University of California Berkeley, harnessed a combination of cutting-edge high-resolution optical imaging, biophysical methods and molecular biology to examine APP-dependent signalling in neural cultures, brain slices, and mouse models. Using highly sensitive biophysical techniques based on fluorescence resonance energy transfer (FRET) between fluorescent proteins in close proximity, they discovered that APP exists as a dimer at presynaptic contacts, and that the binding of amyloid-beta triggers a change in the APP-APP interactions, leading to an increase in calcium flux and higher glutamate release — in other words, brain hyperactivity.

A new approach to protecting the brain

"We have now identified the molecular players in hyperactivity," said Dr. Slutsky. "TAU postdoctoral fellow Oshik Segev is now working to identify the exact spot where the amyloid-beta binds to APP and how it modifies the structure of the APP molecule. If we can change the APP structure and engineer molecules that interfere with the binding of amyloid-beta to APP, then we can break up the process leading to hippocampal hyperactivity. This may help to restore memory and protect the brain."

Previous studies by Prof. Lennart Mucke's laboratory strongly suggest that a reduction in the expression level of "tau" (microtubule-associated protein), another key player in Alzheimer's pathogenesis, rescues synaptic deficits and decreases abnormal brain activity in animal models. "It will be crucial to understand the missing link between APP and 'tau'-mediated signalling pathways leading to hyperactivity of hippocampal circuits. If we can find a way to disrupt the positive signalling loop between amyloid-beta and neuronal activity, it may rescue cognitive decline and the conversion to Alzheimer's disease," said Dr. Slutsky.

The study was supported by European Research Council, Israel Science Foundation, and Alzheimer's Association grants.

By Any Stretch
6/20/2014

TAU researchers devise a kinder, gentler way to measure newborns

After their hectic experience of delivery, newborns are almost immediately stretched out on a measuring board to assess their length. Medical staff, reluctant to cause infants discomfort, are tasked with measuring their length, because it serves as an indispensable marker of growth, health and development. But the inaccuracy and unreliability of current measurement methods restrict their use, so routine measurements are often not performed.

Now Tel Aviv University researchers have taken a 21st century approach to the problem, using new software that harnesses computer vision to more accurately measure infant length. The technique, which is much easier on infants and at least as accurate as conventional measuring methods, was developed by a research team led by Prof. Lea Sirota, of TAU's Sackler Faculty of Medicine and head of the Neonatal Intensive Care Unit at Schneider Children's Medical Center, and Prof. Moshe Philip, a vice dean at TAU's Sackler Faculty of Medicine and head of the Institute for Endocrinology and Diabetes at Schneider Children's Medical Center, together with Dr. Nir Sokolover of TAU's Sackler Faculty of Medicine and Schneider Children's Medical Center, and Prof. Nahum Kiryati and Ms. Amalia Potruch of TAU's School of Engineering.

Results of a clinical trial of the new stereoscopic measurement system were published in Archives of Disease in Childhood.

Don't force it!

"The need to forcibly extend the infants against their will leads to unreliability and inaccuracy of the measurement, and staff members are understandably reluctant to do it," said Dr. Sokolover. "We wanted to develop an accurate, reliable, and practical tool for infant length measurement to facilitate evaluation and follow-up of growth without exposing newborns to a cold environment, infection, or discomfort."

In the study, 54 newborns, roughly half male and half female, were measured using the stereoscopic vision system. Two digital cameras connected and operated by a computer took photographs of each infant. Technology developed by the research team later calculated the infants' length by summing up four body segments from the heel to the crown. Most importantly perhaps, infants could be photographed while lying naturally on their backs, with no need to physically restrict them in a certain position.

In terms of accuracy, the study recorded negligibly different results than those of meticulously performed standard measurements, with a mean average difference of only 0.2 millimeters. According to Dr. Sokolover, the stereoscopic system does not reflect light or radiation on the measured infants, and is therefore considered safe.

A safe alternative

"I am a neonatologist who works daily in a neonatal intensive care unit, so I have experienced first-hand the difficulties of the standard measuring practice," said Dr. Sokolover. "The new system has the potential to improve compliance with routine health and development surveillance measurements, and thereby improve public health."

The team is currently observing the impact of the new system on neonatal intensive care units, where premature and sick infants unable to leave their incubators cannot be measured with the standard stretching practice.

"We are now testing a new and improved prototype of our system and clinically validating its ability to measure through incubators," said Dr. Sokolover. "We are encouraged by the results so far and by positive feedback from both local and international colleagues."

Breathalyzer Test May Detect Deadliest Cancer
6/18/2014

Researchers from TAU and partner institutions develop groundbreaking device that spots lung cancer – to stop it in its tracks

Lung cancer causes more deaths in the U.S. than the next three most common cancers combined (colon, breast, and pancreatic). The reason for the striking mortality rate is simple: poor detection. Lung cancer attacks without leaving any fingerprints, quietly afflicting its victims and metastasizing uncontrollably — to the point of no return.

Now a new device developed by a team of Israeli, American, and British cancer researchers may turn the tide by both accurately detecting lung cancer and identifying its stage of progression. The breathalyzer test, embedded with a "NaNose" nanotech chip to literally "sniff out" cancer tumors, was developed by Prof. Nir Peled of Tel Aviv University's Sackler Faculty of Medicine, Prof. Hossam Haick (inventor) of the Technion — Israel Institute of Technology, and Prof. Fred Hirsch of the University of Colorado School of Medicine in Denver.

The study, presented at a recent American Society of Clinical Oncology conference in Chicago, was conducted on 358 patients who were either diagnosed with or at risk for lung cancer. The participants enrolled at UC Denver, Tel Aviv University, University of Liverpool, and a Jacksonville, Florida, radiation center. Other researchers included Prof. Paul Bunn of UC Denver; Prof. Douglas Johnson, Dr. Stuart Milestone, and Dr. John Wells in Jacksonville; Prof. John Field of the University of Liverpool; and Dr. Maya Ilouze and Tali Feinberg of TAU.

The smell of cancer

"Lung cancer is a devastating disease, responsible for almost 2,000 deaths in Israel annually — a third of all cancer-related deaths," said Dr. Peled. "Lung cancer diagnoses require invasive procedures such as bronchoscopies, computer-guided biopsies, or surgery. Our new device combines several novel technologies with a new concept — using exhaled breath as a medium of diagnosing cancer.

"Our NaNose was able to detect lung cancer with 90 percent accuracy even when the lung nodule was tiny and hard to sample. It was even able to discriminate between subtypes of cancer, which was unexpected," said Dr. Peled.

Lung cancer tumors produce chemicals called volatile organic compounds (VOCs), which easily evaporate into the air and produce a discernible scent profile. Prof. Haick harnessed nanotechnology to develop the highly sensitive NaNose chip, which detects the unique "signature" of VOCs in exhaled breath. In four out of five cases, the device differentiated between benign and malignant lung lesions and even different cancer subtypes.

The bigger the tumor ...

"Cancer cells not only have a different and unique smell or signature, you can even discriminate between subtypes and advancement of the disease," said Dr. Peled. "The bigger the tumor, the more robust the signature."

The device and subsequent analysis accurately sorted healthy people from people with early-stage lung cancer 85 percent of the time, and healthy people from those with advanced lung cancer 82 percent of the time. The test also accurately distinguished between early and advanced lung cancer 79 percent of the time.

"The device could prove valuable in helping determine patients who need more intensive screening for lung cancer," said Dr. Peled. "We're hoping to have a device that would be able to give you a go/no-go result — something's wrong, go get an X-ray."

The Boston-based company Alpha Szenszor has licensed the technology and hopes to introduce it to the market within the next few years. Meanwhile, a new, smaller version of the device has since been developed that can plug into a computer's USB port.

The study was supported by the European Union LCAOS grant, an EU-funded collaborative whose aim is to enable the earliest possible detection of lung cancer, and the International Association for the Study of Lung Cancer (IASLC).

Regenerating Our Kidneys
6/13/2014

TAU research uses new technique to uncover the building blocks of kidney regeneration

Doctors and scientists have for years been astonished to observe patients with kidney disease experiencing renal regeneration. The kidney, unlike its neighbor the liver, was universally understood to be a static organ once it had fully developed.

Now a new study conducted by researchers at Sheba Medical Center, Tel Aviv University, and Stanford University turns that theory on its head by pinpointing the precise cellular signalling responsible for renal regeneration and exposing the multi-layered nature of kidney growth. The research, in Cell Reports, was conducted by principal investigators Dr. Benjamin Dekel of TAU's Sackler School of Medicine and Sheba Medical Center and Dr. Irving L. Weissman of Stanford University's School of Medicine, working with teams of researchers from both universities.

"We wanted to change the way people thought about kidneys — about internal organs altogether," said Dr. Dekel, who specializes in stem-cell research, genetics, and nephrology. "Very little is known even now about the way our internal organs function at the single cell level. This study flips the paradigm that kidney cells are static — in fact, kidney cells are continuously growing, all the time."

Dr. Dekel began researching the subject three years ago while on sabbatical at Stanford University. While the laboratory experiments and stem cell research were conducted at Stanford, the results were analyzed by researchers at TAU and Stanford.

According to Dr. Dekel, scientists knew kidney cells could reproduce outside the body, but the physiological process taking place inside the body at the single cell level was never explored. Uncovering that process became the focus of his efforts.

Dr. Dekel and his research team conducted a study using a "rainbow mouse" model developed at Stanford's Weissman lab, a mouse genetically altered to express one of four alternative fluorescent markers called "reporters" in each cell. The markers allowed researchers to trace cell growth in vivo — growth, they were surprised to find, that was sectional and multi-directional.

"We were amazed to find that renal growth does not depend on a single stem cell, but is rather compartmentalized," said Dr. Dekel. "Each part of the nephron is responsible for its own growth, each segment responsible for its own development, like a tree trunk and branches — each branch grows at a different pace and in a different direction."

Using the rainbow mouse, the researchers were able to pinpoint a specific molecule responsible for renal cellular growth called the "WNT signal." Once activated in specific precursor cells in each kidney segment, the WNT signal results in robust renal cellular growth and generation of long branches of cells.

"Our aim was to use a new technique to analyze an old problem," said Dr. Dekel. "No one had ever used a rainbow mouse model to monitor development of kidney cells. It was exciting to use these genetic tricks to discover that cellular growth was occurring all the time in the kidney — that, in fact, the kidney was constantly remodelling itself in a very specific mode."

Dr. Dekel and the research team are paving the way for novel cellular and molecular therapeutics to achieve human kidney regeneration and alleviate the shortage of kidney organs for transplantation. "This study teaches us that in order to regenerate the entire kidney segments different precursor cells grown outside of our bodies will have to be employed,” he said. "In addition, If we were able to further activate the WNT pathway, then in cases of disease or trauma we could activate the phenomena for growth and really boost kidney regeneration to help patients. This is a platform for the development of new therapeutics, allowing us to follow the growth and expansion of cells following treatment."

A Vibrating “Pill” to Replace Laxatives?
6/10/2014

Research from TAU-affiliated Tel Aviv Sourasky Medical Center provides promising basis for treatment of constipation

Constipation, the most common digestive health disorder, affects up to 42 million Americans. Symptoms of chronic constipation include pain, bloating, infrequent bowel movements, and painful and hard stools.

Now a new treatment in the form of a vibrating pill-size capsule may serve to alleviate chronic constipation, as demonstrated by a new pilot study from researchers led by Dr. Yishai Ron of the Department of Gastroenterology and Hepatology at Tel Aviv University-affiliated Tel Aviv Sourasky Medical Center. The team presented its findings last month at the Digestive Disease Week convention in Chicago.

The capsule houses a small engine which is programmed to begin vibrating six to eight hours after ingestion. The mechanical stimulation caused by the pill produces contractions in the intestines, facilitating the movement of stool through the digestive tract.

According to the study, the vibrating capsule was found to nearly double the weekly bowel movements of patients suffering from chronic idiopathic constipation (CIC) and constipation predominant irritable bowel syndrome (C-IBS). The innovative non-drug therapy may offer a solution for anyone who suffers from chronic constipation but finds laxatives, fiber drinks, enemas, and other standard treatments unhelpful or uncomfortable.

When medicine isn't enough

"Despite the widespread use of medication to treat constipation, nearly 50 percent of patients are unsatisfied with the treatment either because of side effects, safety concerns about long-term use, or the fact that it simply doesn't work," Dr. Ron told Science Daily.

In the study, 26 patients took the vibrating capsule twice each week and responded to a questionnaire about their daily bowel movements and laxative use. Study participants reported an increase in spontaneous bowel movements from two to four times per week, as well as a decrease in constipation symptoms, including reduced difficulty in passing stools and incomplete evacuation. The study also found minimal side effects from the capsule use.

"Sometimes, drug therapies bring more issues than relief for these patients," Dr. Ron said. "The results of this study point to the potential for an alternative treatment that avoids the typical drug side effects, such as bloating and electrolyte imbalance, by imitating the body's natural physiology."

Dr. Ron and his team plan to initiate a controlled, double-blind study to expand on these findings and further explore the capsule's potential.

For more, read this USA Today story about the research:
http://www.usatoday.com/story/news/nation/2014/05/04/constipation-vibrating-capsule/8513473/

How Breast Cancer "Expresses Itself"
5/29/2014

A new study finds that gene patterns responsible for normal breast tissue may also play a role in the development of cancer

About one in eight women in the United States will contract breast cancer in her lifetime. Now new research from Tel Aviv University-affiliated researchers, in collaboration with Johns Hopkins University, has provided another tool to help women, clinicians, and scientists searching for a cure to the one of the most widespread yet incurable diseases on the planet.

Dr. Ella Evron and Dr. Ayelet Avraham of the TAU-affiliated Assaf Harofeh Medical Center, together with Prof. Saraswati Sukumar of Johns Hopkins, have found that "gene regulation," the process that shuts off certain parts of a cell's DNA code or blueprint in healthy breast tissue cells, may also play a critical role in the development of breast cancer. Their research, published in PLOS ONE, focused on one particular gene — TRIM29 — selected from a pool of 100 genes with regulatory patterns specific to normal breast tissue, to prove the link between breast-specific genes and the pathology of cancer.

"We found that normal tissue affects the cancer that grows in that organ — in other words, the specific pattern of gene regulation in the normal breast affects breast cancer, the characteristics of the disease, and its clinical behavior," said Dr. Avraham, a biologist and a researcher in the lab. "We hope that this study will lead to a better understanding of the cancer predisposition of mammary tissues and point to new targets for cancer intervention."

Searching for the right gene

In the study, normal tissue samples taken from conventional breast reduction surgeries were examined in a laboratory. The researchers isolated the milk ducts and purified the breast-tissue cells to create a cell culture, which was then tested for different gene regulation profiles.

While all cell types share the same genetic code (DNA), certain genes are specifically "expressed" or "silenced" in each cell type. Consequently, the unique gene expression patterns in every tissue dictate its structure and function. Various "gatekeeper" mechanisms either allow or block gene expression in our cells. One such mechanism is "DNA methylation," which shuts off or silences parts of the genetic code to form a specific pattern that identifies each tissue type.

The researchers compared the DNA methylation profiles of thousands of genes in breast, colon, lung, and endometrial tissues, selecting one gene, TRIM29, for further analysis. They found that the TRIM29 gene bore a unique DNA regulation in normal and cancerous breast tissues as opposed to other organ tissues.

"In breast tissue we found that this gene was expressed in normal cells and silenced in the cancer cells," said Dr. Avraham. "In contrast, in other bodily tissues, the gene was silenced in normal cells and over-expressed in tumors. This emphasizes the link between tissue-specific gene regulation and the development of cancer."

Silencing the cancer

"Tissue-specific genes often take part in carcinogenesis. A well known example is estrogen, which is involved in the normal differentiation of the breast and also in breast cancer development," said Dr. Evron, a senior oncologist and a researcher in the lab. "Thus, the estrogen receptor over-expresses in nearly 70% of breast cancers. It's the target of very effective anti breast cancer therapy. In this study we identify more genes that have specific regulation in normal breast tissue as compared with other organ tissues."

"Another example is women who carry a mutation in the BRCA1/2 genes and develop cancers almost exclusively in the breast and ovary," said Dr. Evron. "This led to the hypothesis that these tissues are 'marked' for cancer predisposition during differentiation. Searching for these marks may throw light on this process.

"Certainly the concept of looking for genes that are involved in both in differentiation and in carcinogenesis is promising, and the novel list of breast-specific regulated genes we found may encourage further study in this direction. But we can't stop here. If we know which genes are responsible for breast cancer, then we can tailor therapies to target those genes specifically."

Novel Protein Fragments May Protect Against Alzheimer's
5/13/2014

TAU researcher's discovery can lead to new drug candidates to treat the neurodegenerative disease

The devastating loss of memory and consciousness in Alzheimer's disease is caused by plaque accumulations and tangles in neurons, which kill brain cells. Alzheimer's research has centered on trying to understand the pathology as well as the potential protective or regenerative properties of brain cells as an avenue for treating the widespread disease.

Now Prof. Illana Gozes, the incumbent of the Lily and Avraham Gildor Chair for the Investigation of Growth Factors and director of the Adams Super Center for Brain Studies at the Sackler Faculty of Medicine and a member of Tel Aviv University's Sagol School of Neuroscience, has discovered novel protein fragments that have proven protective properties for cognitive functioning.

In a study published in the Journal of Alzheimer's Disease, Prof. Gozes examined the protective effects of two newly discovered protein fragments in mice afflicted with Alzheimer's disease-like symptoms. Her findings have the potential to serve as a pipeline for new drug candidates to treat the disease.

NAP time for Alzheimer's

"Several years ago we discovered that NAP, a snippet of a p

rotein essential for brain formation, which later showed efficacy in Phase 2 clinical trials in mild cognitive impairment patients, a precursor to Alzheimer’s," said Prof. Gozes. "Now, we're investigating whether there are other novel NAP-like sequences in other proteins. This is the question that led us to our discovery."

Prof. Gozes' research focused on the microtubule network, a crucial part of cells in our bodies. Microtubules act as a transportation system within nerve cells, carrying essential proteins and enabling cell-to-cell communications. But in neurodegenerative diseases like Alzheimer's, ALS, and Parkinson's, this network breaks down, hindering motor abilities and cognitive function.

"NAP operates through the stabilization of microtubules — tubes within the cell which maintain cellular shape. They serve as 'train tracks' for movement of biological material," said Prof. Gozes. "This is very important to nerve cells, because they have long processes and would otherwise collapse. In Alzheimer's disease, these microtubules break down. The newly discovered protein fragments, just like NAP before them, work to protect microtubules, thereby protecting the cell."

Down the tubes

In her new study, Prof. Gozes and her team looked at the subunit of the microtubule — the tubulin — and the protein TAU (tubulin-associated unit), important for assembly and maintenance of the microtubule. Abnormal TAU proteins form the tangles that contribute to Alzheimer's; increased tangle accumulation is indicative of cognitive deterioration. Prof. Gozes decided to test both the tubulin and the TAU proteins for NAP-like sequences. After confirming NAP-like sequences in both tubulin subunits and in TAU, she tested the fragments in tissue cultures for nerve-cell protecting properties against amyloid peptides, the cause of plaque build up in Alzheimer patients' brains.

"From the tissue culture, we moved to a 10-month-old transgenic mouse model with frontotemporal dementia-like characteristics, which exhibits TAU pathology and cognitive decline," said Prof. Gozes. "We tested one compound — a tubulin fragment — and saw that it protected against cognitive deficits. When we looked at the 'dementia'-afflicted brain, there was a reduction in the NAP parent protein, but upon treatment with the tubulin fragment, the protein was restored to normal levels."

Prof. Gozes and her team also measured the brain-to-body mass ratio, an indicator of brain degeneration, and saw a significant decrease in the mouse model compared to normal mice. Following the introduction of the tubulin fragments, however, the mouse's brain to body ratio returned to normal. "We clearly see here the protective effect of the treatment," said Prof. Gozes. "We witnessed the restorative and protective effects of totally new protein fragments, derived from proteins critical to cell function, in tissue cultures and on animal models."

Unlocking a mystery of thalidomide
5/1/2014

TAU research pinpoints mechanism causing rare and severe congenital syndrome

In the 1950s and 1960s, pregnant women with morning sickness were often prescribed the new drug thalidomide. Shortly after the medicine was released on the market, a reported 10,000 infants were born with an extreme form of the rare congenital phocomelia syndrome, which caused death in 50 percent of cases and severe physical and mental disabilities in others. Although various factors are now known to cause phocomelia, the prominent roots of the disease can be found in the use of the drug thalidomide.

Now, half a century later, new research by Dr. Noam Shomron, Prof Arkady Torchinsky, and doctoral student Eyal Mor at Tel Aviv University's Sackler Faculty of Medicine, published in Archives of Toxicology, identifies a regulator responsible for the malformation of limbs in phocomelia, pinpointing a specific target for possible future intervention.

"We were reading old textbooks from the 1950s and '60s, trying to understand th

e studies carried out then on this intriguing topic, and we saw that we could undertake an in-depth examination of the disorder's processes using careful planning and execution of experiments on mouse and rat models," said Dr. Shomron. "We hoped to gain a much better understanding of embryo malformation."

In the genes

Prof. Torchinsky worked together with Mor to carry out an experiment on animal models in the laboratory. They injected mice and rats with an embryo malformation factor or "teratogen" (called 5-aza-2'-deoxycytidin) with effects similar to thalidomide. The chemical is also used in chemotherapeutics. With the factor, the researchers induced phocomelia in either the forelimbs or hind limbs of the animals.

Afterward, by analyzing the entire gene and tiny regulatory RNA molecules called microRNAs in all the mouse limbs (both healthy and afflicted), the researchers were able to pinpoint the genetic regulator — the precise "switch" turned on or off during genetic processes — responsible for the malformation, p53, and its downstream target gene, MicroRNA34.

"We have added another perspective to the overall picture by investigating the genetic mechanisms involved — in other words, the gene expression rather than the genetic code affected during pathology," said Dr. Shomron. "I expect that further understanding of the mechanisms involved in teratogens and how they induce phocomelia will help reveal the dangers associated with toxins and will also reveal the underlying functional role of genes and microRNAs modulating genetic expression in the process."

Dr. Shomron said the work carried out by the team addresses a long-standing paradigm of limb malformation in mammals and reflects the role that epigenetic regulation, as opposed to genetic regulation, plays in the development of disease. In other words, embryonic development can be caused by a genetic mutation (a "mis-print" in the book of life) or, in this case, by turning the genes on or off without any change in the genetic code itself. Dr. Shomron and his team are currently studying the effects of other toxins on the mal-development of mammalian embryos.

On the Defensive
4/23/2014

TAU discovers that protein clusters implicated in neurodegenerative diseases actually serve to protect brain cells

People diagnosed with Huntington's disease, most in their mid-thirties and forties, face a devastating prognosis: complete mental, physical, and behavioral decline within two decades. "Mutant" protein clusters, long blamed for the progression of the genetic disease, have been the primary focus of therapies in development by pharmaceutical companies. But according to new research from Prof. Gerardo Lederkremer and Dr. Julia Leitman of Tel Aviv University's Department of Cell Research and Immunology, in collaboration with Prof. Ulrich Hartl of the Max Planck Institute for Biochemistry, these drugs may not only be ineffective — they may pose a serious threat to patients.

In two ground-breaking studies, published in the journals PLOS ONE and Nature Communications, Prof. Lederkremer and his team demonstrated that protein clusters are not the cause of toxicity in Huntington's disease. On the contrary, these aggregates actually serve as a defense mechanism for "stressed" brain cells. Conducted on tissue cultures using cutting-edge microscopic technology, their studies identified a different causative agent — the "stress response" of affected brain cells.

"The upsetting implication for therapy of this di

sease is that drugs being developed to interfere with the formation of protein aggregates may in fact be detrimental," said Prof. Lederkremer. "The identification of the new cause will hopefully lead to the development of new therapeutic approaches. This may hold true for other neurodegenerative diseases as well."

Starting from genetic scratch

Prof. Lederkremer and his team chose to examine the effect of protein aggregates in the pathology of Huntington's disease because its genetic cause is well-known, unlike those of other neurodegenerative diseases, such as Parkinson's, whose origins remain less clear.

"What we found in this study — a surprise, although we suspected it — was that damage to the cells, the cell 'stress' that leads to death of cells, appeared well before the protein aggregates did," said Prof. Lederkremer. "And even more surprising, when the aggregates finally appeared, the stress was reduced, in some cases even stopping. The actual process of forming an aggregate was protective, isolating and segregating the problematic proteins. This explains why in autopsies of people who died of Huntington's and other diseases like Alzheimer's or old age, the protein aggregates in the brains were all quite similar, reflecting no specific disease link."

By interfering with the stress response of brain cells, rather than the formation of protein clusters, scientists may be able to slow, or even halt, the progression of neurodegenerative diseases. According to Prof. Lederkremer, this research paves the way for a revolutionary new direction for pharmaceutical research to treat Huntington's, Alzheimer's, Parkinson's, and other neurodegenerative diseases.

Response to stress

"The practical consequences are that several companies are already in advanced stages of development of drugs inhibiting this form of protein aggregate, interfering with the body's natural process to protect the brain," said Prof. Lederkremer. "But the drugs should be focused on another area altogether, and the protein aggregates, a protective resource for the brain, should be left intact."

Samples of brain cells from mouse models afflicted with Huntington's disease were examined using "live cell imaging," the study of live cells through time-lapse microscopy. Prof. Lederkremer and his team were thus able to identify a compound that modified brain cells' response to stress, promoting their survival.

"Our approach was to interfere with the stress response instead of the formation of the protein aggregates, and the lab succeeded in identifying a compound that altered the response, rescuing affected cells from death," said Prof. Lederkremer. "Our findings are most encouraging for the development of a therapy for this devastating disease, which is presently incurable."

From Mouse Ears to Man's?
3/24/2014

TAU researcher uses DNA therapy in lab mice to improve cochlear implant functionality

 One in a thousand children in the United States is deaf, and one in three adults will experience significant hearing loss after the age of 65. Whether the result of genetic or environmental factors, hearing loss costs billions of dollars in healthcare expenses every year, making the search for a cure critical.

Now a team of researchers led by Karen B. Avraham of the Department of Human Molecular Genetics and Biochemistry at Tel Aviv University's Sackler Faculty of Medicine and Yehoash Raphael of the Department of Otolaryngology–Head and Neck Surgery at University of Michigan's Kresge Hearing Research Institute have discovered that using DNA as a drug — commonly called gene therapy — in laboratory mice may protect the inner ear nerve cells of humans suffering from certain types of progressive hearing loss.

In the study, doctoral student Shaked Shivatzki created a mouse population possessing the gene that produces the most prevalent form of hearing loss in humans: the mutated connexin 26 gene. Some 30 percent of American children born deaf have this form of the gene. Because of its prevalence and the inexp

ensive tests available to identify it, there is a great desire to find a cure or therapy to treat it.

"Regenerating" neurons

Prof. Avraham's team set out to prove that gene therapy could be used to preserve the inner ear nerve cells of the mice. Mice with the mutated connexin 26 gene exhibit deterioration of the nerve cells that send a sound signal to the brain. The researchers found that a protein growth factor used to protect and maintain neurons, otherwise known as brain-derived neurotrophic factor (BDNF), could be used to block this degeneration. They then engineered a virus that could be tolerated by the body without causing disease, and inserted the growth factor into the virus. Finally, they surgically injected the virus into the ears of the mice. This factor was able to "rescue" the neurons in the inner ear by blocking their degeneration.

"A wide spectrum of people are affected by hearing loss, and the way each person deals with it is highly variable," said Prof. Avraham. "That said, there is an almost unanimous interest in finding the genes responsible for hearing loss. We tried to figure out why the mouse was losing cells that enable it to hear. Why did it lose its hearing? The collaborative work allowed us to provide gene therapy to reverse the loss of nerve cells in the ears of these deaf mice."

Although this approach is short of improving hearing in these mice, it has important implications for the enhancement of sound perception with a cochlear implant, used by many people whose connexin 26 mutation has led to impaired hearing.

Embryonic hearing?

Inner ear nerve cells facilitate the optimal functioning of cochlear implants. Prof. Avraham's research suggests a possible new strategy for improving implant function, particularly in people whose hearing loss gets progressively worse with time, such as those with profound hearing loss as well as those with the connexin gene mutation. Combining gene therapy with the implant could help to protect vital nerve cells, thus preserving and improving the performance of the implant.

More research remains. "Safety is the main question. And what about timing? Although over 80 percent of human and mouse genes are similar, which makes mice the perfect lab model for human hearing, there's still a big difference. Humans start hearing as embryos, but mice don't start to hear until two weeks after birth. So we wondered, do we need to start the corrective process in utero, in infants, or later in life?" said Prof. Avraham.

"Practically speaking, we are a long way off from treating hearing loss during embryogenesis. But we proved what we set out to do: that we can help preserve nerve cells in the inner ears of the mouse," Prof. Avraham continued. "This already looks very promising."

The research team is currently working on finding better "vehicles" for the corrected gene, such as finding more suitable viruses to transport the injected gene to the appropriate place in the inner ear. The study was supported by grants from the NIDCD of the National Institutes of Health and I-CORE Gene Regulation in Complex Human Disease.

Not Just What You Eat
3/20/2014

TAU research shows fat mass in cells expands with disuse

Over 35 percent of American adults and 17 percent of American children are considered obese, according to the latest survey conducted by the Centers for Disease Control and Prevention. Associated with diabetes, heart disease, stroke, and even certain types of cancer, obesity places a major burden on the health care system and economy. It's usually treated through a combination of diet, nutrition, exercise, and other techniques.

To understand how obesity develops, Prof. Amit Gefen, Dr. Natan Shaked and Ms. Naama Shoham of Tel Aviv University's Department of Biomedical Engineering, together with Prof. Dafna Benayahu of TAU's Department of Cell and Developmental Biology, used state-of-the-art technology to analyze the accumulation of fat in the body at the cellular level. According to their findings, nutrition is not the only factor driving obesity. The mechanics of "cellular expansion" plays a primary role in fat production, they discovered.

By exposing the mechanics of fat production at a cellular level, the researchers offer insight into the development of obesity. And with a better understanding of the process, the team is now creating a platform to develop new therapies and technologies to prevent or even reverse fat gain. The research was published this week in the Biophysical Journal.

Getting to the bottom of obesity

"Two years ago, Dafna and I were awarded a grant from the Israel Science Foundation to investigate how mechanical forces increase the fat content within fat cells. We wanted to find out why a sedentary lifestyle results in obesity, other than making time to eat more hamburgers," said Prof. Gefen. "We found that fat cells exposed to sustained, chronic pressure — such as what happens to the buttocks when you're sitting down — experienced accelerated growth of lipid droplets, which are molecules that carry fats.

"Contrary to muscle and bone tissue, which get mechanically weaker with disuse, fat depots in fat cells expanded when they experienced sustained loading by as much as 50%. This was a substantial discovery."

The researchers discovered that, once it accumulated lipid droplets, the structure of a cell and its mechanics changed dramatically. Using a cutting-edge atomic force microscope and other microscopy technologies, they were able to observe the material composition of the transforming fat cell, which became stiffer as it expanded. This stiffness alters the environment of surrounding cells by physically deforming them, pushing them to change their own shape and composition.

"When they gain mass and change their composition, expanding cells deform neighboring cells, forcing them to differentiate and expand," said Prof. Gefen. "This proves that you're not just what you eat. You're also what you feel — and what you're feeling is the pressure of increased weight and the sustained loading in the tissues of the buttocks of the couch potato."

The more you know ...

"If we understand the etiology of getting fatter, of how cells in fat tissues synthesize nutritional components under a given mechanical loading environment, then we can think about different practical solutions to obesity," Prof. Gefen says. "If you can learn to control the mechanical environment of cells, you can then determine how to modulate the fat cells to produce less fat."

The team hopes that its observations can serve as a point of departure for further research into the changing cellular environment and different stimulations that lead to increased fat production.

Restoring Order in the Brain
3/11/2014

TAU finds that brain cell regeneration may alleviate symptoms of Alzheimer's disease

Alzheimer's disease is the most widespread degenerative neurological disorder in the world. Over five million Americans live with it, and one in three senior citizens will die with the disease or a similar form of dementia. While memory loss is a common symptom of Alzheimer's, other behavioral manifestations — depression, loss of inhibition, delusions, agitation, anxiety, and aggression — can be even more challenging for victims and their families to live with.

Now Prof. Daniel Offen and Dr. Adi Shruster of Tel Aviv University's Sackler School of Medicine have discovered that by reestablishing a population of new cells in the part of the brain associated with behavior, some symptoms of Alzheimer's disease significantly decreased or were reversed altogether.

The research, published in the journal Behavioural Brain Research, was conducted on mouse models; it provides a promising target for Alzheimer's symptoms in human beings as well.

"Until 15 years ago, the common belief was that you were born with a finite number of neurons. You would lose them as you aged or as the result of injury or disease," said Prof. Offen, who also serves as Chief Scientific Officer at BrainStorm, a biotech company at the forefront of innovative stem cell research. "We now know that stem cells can be used to regenerate areas of the brain."

Speeding up recovery

After introducing stem cells in brain tissue in the laboratory and seeing promising results, Prof. Offen leveraged the study to mice with Alzheimer's disease-like symptoms. The gene (Wnt3a) was introduced in the part of the mouse brain that controls behavior, specifically fear and anxiety, in the hope that it would contribute to the formation of genes that produce new brain cells.

According to Prof. Offen, untreated Alzheimer's mice would run heedlessly into an unfamiliar and dangerous area of their habitats instead of assessing potential threats, as healthy mice do. Once treated with the gene that increased new neuron population, however, the mice reverted to assessing their new surroundings first, as usual.

"Normal mice will recognize the danger and avoid it. Mice with the disease, just like human patients, lose their sense of space and reality," said Prof. Offen. "We first succeeded in showing that new neuronal cells were produced in the areas injected with the gene. Then we succeeded in showing diminished symptoms as a result of this neuron repopulation."

"The loss of inhibition is a cause of great embarrassment for most patients and relatives of patients with Alzheimer's," said Prof. Offen. "Often, patients take off their pants in public, having no sense of their surroundings. We saw parallel behavior in animal models with Alzheimer's."

Next: Memory

After concluding that increased stem cell production in a certain area of the brain had a positive effect on behavioral deficits of Alzheimer's, Prof. Offen has moved to research into the area of the brain that controls memory. He and his team are currently exploring it in the laboratory and are confident that the results of the new study will be similar.

"Although there are many questions to answer before this research produces practical therapies, we are very optimistic about the results and feel this is a promising direction for Alzheimer's research," said Prof. Offen.

Off with Your Glasses
3/4/2014

TAU researchers discover a link between sharp vision and the brain's processing speed

Middle-aged adults who suddenly need reading glasses, patients with traumatic brain injuries, and people with visual disorders such as "lazy eye" may have one thing in common — "visual crowding," an inability to recognize individual items surrounded by multiple objects. Visual crowding makes it impossible to read, as single letters within words are rendered illegible. And basic cognitive functions such as facial recognition can also be significantly hampered. Scientists and clinicians currently attribute crowding to a disorder in peripheral vision.

Now Prof. Uri Polat, Maria Lev, and Dr. Oren Yehezkel of Tel Aviv University's Goldschleger Eye Research Institute at the Sackler Faculty of Medicine have discovered new evidence that correlates crowding in the fovea — a small part of the retina responsible for sharp vision — and the brain's processing speed. These findings, published in Nature's Scientific Reports, could greatly alter earlier models of visual crowding, which emphasized peripheral impairment exclusively. And for many adults lost without their reading glasses, this could improve their vision significantly.

"Current theories strongly stress that visual crowding does not exist in the fovea, that it's a phenomenon that exists only in peripheral visual fields," said Prof. Polat. "But our study points to another part of the eye altogether — the fovea — and contributes to a unified model for how the brain integrates v

isual information."

A trained eye

According to Prof. Polat, vision is dynamic and changes rapidly, but it takes time for the brain to process this visual information. Rapidly moving tickers on TV, or traffic signs seen as the driver speeds past, are difficult for anyone to read. However, given enough time, someone with excellent vision can fully recognize the words. Those with slower processing speeds — usually the result of poor perceptive development or age — may not be able to decipher the tickers or the traffic signs. In the study, Prof. Polat employed his expertise in improving vision by retraining the brain and the foveal part of the eye, using exercises in which speed is a key element.

"Training adults to reduce foveal crowding leads to improved vision. A similar training we conducted two years ago allowed adults to eliminate their use of reading glasses altogether, using a technology provided by the GlassesOff company. Other patients who had lost sharp vision for whatever reason were also able to benefit from the same training and improve their processing speed and visual capabilities," said Prof. Polat.

Maria Lev, who performed the study as a part of her doctoral thesis, said one young subject had experienced significant limitations in school for years and had been unable to obtain a driver's license due to severe visual impairment from foveal crowding. After undergoing training that emphasized a foveal rather than a peripheral focus, he was able to overcome the handicap.

"He finally managed to learn to read properly and found his way forward," said Lev. "I'm proud to say that today he is not only eligible for a driver's license, he's also been able to earn his master's degree."

Prof. Polat and his team are currently exploring how visual integration and foveal crowding develop in various clinical cases.

Researchers Devise a Fast and Effective Mechanism to Combat One of the Most Aggressive Cancers
2/24/2014

TAU targets drug-resistant ovarian tumors with nanotechnology

Ovarian cancer accounts for more deaths of American women than any other cancer of the female reproductive system. According to the American Cancer Society, one in 72 American women will be diagnosed with ovarian cancer, and one in 100 will ultimately die of the condition.

Now Prof. Dan Peer of Tel Aviv University's Department of Cell Research and Immunology has proposed a new strategy to tackle an aggressive subtype of ovarian cancer using a new nanoscale drug-delivery system designed to target specific cancer cells. He and his team — Keren Cohen and Rafi Emmanuel from Peer's Laboratory of Nanomedicine and Einat Kisin-Finfer and Doron Shabbat, from TAU's Department of Chemistry — have devised a cluster of nanoparticles called gagomers, made of fats and coated with a kind of polysugar. When filled with chemotherapy drugs, these clusters accumulate in tumors, producing dramatically therapeutic benefits.

The objective of Peer's research is two-fold: to provide a specific target for anti-cancer drugs to increase their therapeutic benefits, and to reduce the toxic side effects of anti-cancer therapies. The study was published in February in the journal ACS Nano.

Why chemotherapy fails

According to Prof. Peer, traditional courses of chemotherapy are not an effective line of attack. Chemotherapy's failing lies in the inability of the medicine to be absorbed and maintained within the tumor cell long enough to destroy it. In most cases, the chemotherapy drug is almost immediately ejected by the cancer cell, severely damaging the healthy organs that surround it, leaving the tumor cell intact.

But with their new therapy, Peer and his colleagues saw a 25-fold increase in tumor-accumulated medication and a dramatic dip in toxic accumulation in healthy organs. Tested on laboratory mice, the gagomer mechanism effects a change in drug-resistant tumor cells. Receptors on tumor cells recognize the sugar that encases the gagomer, allowing the binding gagomer to slowly release tiny particles of chemotherapy into the cancerous cell. As more and more drugs accumulate within the tumor cell, the cancer cells begin to die off within 24-48 hours.

"Tumors become resistant very quickly. Following the first, second, and third courses of chemotherapy, the tumors start pumping drugs out of the cells as a survival mechanism," said Prof. Peer. "Most patients with tumor cells beyond the ovaries relapse and ultimately die due to the development of drug resistance. We wanted to create a safe drug-delivery system, which wouldn't harm the body's immune system or organs."

A personal perspective

Prof. Peer chose to tackle ovarian cancer in his research because his mother-in-law passed away at the age of 54 from the disease. "She received all the courses of chemotherapy and survived only a year and a half," he said. "She died from the drug-resistant aggressive tumors.

"At the end of the day, you want to do something natural, simple, and smart. We are committed to try to combine both laboratory and therapeutic arms to create a less toxic, focused drug that combats aggressive drug-resistant cancerous cells," said Prof. Peer. "We hope the concept will be harnessed in the next few years in clinical trials on aggressive tumors," said Prof. Peer.


Nipping Diabetes in the Bud
1/27/2014

TAU researchers find a simple blood test can predict diabetes risk much earlier

An estimated 25.8 million Americans have diabetes. Another 79 million are thought to have "prediabetes," meaning they are at risk of developing type-2 diabetes.

Now Dr. Nataly Lerner of Tel Aviv University's Sackler Faculty of Medicine and her colleagues have discovered that a simple blood test reveals an individual's risk of developing type-2 diabetes before they develop either condition — far earlier than previously believed. The findings, published in the European Journal of General Practice, could help doctors provide earlier diagnosis and treatment. Dr. Michal Shani and Prof. Shlomo Vinker of the Sackler Faculty of Medicine and Clalit Health Services collaborated on the study.

"Our study supports the idea that the A1c test, used to diagnose type-2 diabetes, can also be used at a much earlier stage to screen for the disease in the high risk population, like overweight patients," said Dr. Lerner.

Testing the test

In healthy people, glucose is absorbed from the blood for use by various tissues. But the cells of people with type-2 diabetes are resistant to insulin, which is produced by the pancreas and is central to regulating carbohydrate and fat metabolism in the body. These individuals have higher-than-normal blood glucose levels. People with prediabetes have blood glucose levels somewhere between normal and diabetic.

Blood glucose can be directly tested in several ways, but these tests only provide a snapshot. To get a picture of blood glucose levels over time, doctors test for levels of glycated hemoglobin, or A1c, in the blood. When blood glucose levels are high, more A1c is formed. So A1c serves as a biomarker, indicating average blood glucose levels over a two- to three-month period.

The A1c test has long been used to monitor type-2 diabetes. And in the past few years, the American Diabetes Association and World Health Organization have added the test to their guidelines as a criterion for diagnosing type-2 diabetes. According to the ADA, having an A1c level of 6.5 percent or more is an indicator of the disease and an A1c level of between 5.7 and 6.4 percent is an indicator of prediabetes. As a bonus, the test is simpler to administer than the most common blood glucose tests, requiring neither fasting nor consuming anything.

To evaluate the A1c test's ability to screen for diabetes in high-risk patients, the researchers analyzed the medical history of 10,201 patients who were given the test in central Israel between 2002 and 2005. They found that overall, 22.5 percent of the patients developed diabetes within five to eight years. Patients with A1c levels as low as 5.5 percent — below the official threshold for diagnosing diabetes were significantly more likely to develop diabetes than patients with A1c levels below 5.5 percent. Every 0.5 percent increase in A1c levels up to 7 percent doubled the patients' risk of developing diabetes. Obesity also doubled patients' risk of developing diabetes, the researchers found.

Risk management

"We were actually able to quantify how risk increases with A1c levels," said Dr. Lerner. "This could allow doctors to make more informed decisions regarding diabetes prevention."

The study, one of the most comprehensive of its kind, provides compelling new evidence that the A1c test can accurately gauge risk at an earlier stage than is currently recognized. In combination with blood glucose tests and the identification of risk factors — like family history, poor diet, lack of exercise, and obesity — the test could help doctors provide earlier treatment. In some cases, lifestyle changes or medication could head off the disease, which is difficult or impossible to cure once developed.


The Unexpected Power of Baby Math
1/22/2014

TAU researcher finds that adults still think about numbers like kids

Children understand numbers differently than adults. For kids, one and two seem much further apart then 101 and 102, because two is twice as big as one, and 102 is just a little bigger than 101. It's only after years of schooling that we’re persuaded to see the numbers in both sets as only one integer apart on a number line.

Now Dror Dotan, a doctoral student at Tel Aviv University's School of Education and Sagol School of Neuroscience and Prof. Stanislas Dehaene of the Collège de France, a leader in the field of numerical cognition, have found new evidence that educated adults retain traces of their childhood, or innate, number sense — and that it's more powerful than many scientists think.

"We were surprised when we saw that people never completely stop thinking about numbers as they did when they were children," said Dotan. "The innate human number sense has an impact, even on thinking about double-digit numbers." The findings, a significant step forward in understanding how people process numbers, could contribute to the development of methods to more effectively educate or treat children with learning disabilities and people with brain injuries.

Digital proof of a primal sense

Educated adults understand numbers "linearly," based on the familiar number line from 0 to infinity. But children and uneducated adults, like tribespeople in the Amazon, understand numbers "logarithmically" — in terms of what percentage one number is of another. To analyze how educated adults process numbers in real time, Dotan and Dehaene asked the participants in their study to place numbers on a number line displayed on an iPad using a finger.

Previous studies showed that people who understand numbers linearly perform the task differently than people who understand numbers logarithmically. For example, linear thinkers place the number 20 in the middle of a number line marked from 0 to 40. But logarithmic thinkers like children may place the number 6 in the middle of the number line, because 1 is about the same percentage of 6 as 6 is of 40.

On the iPad used in the study, the participants were shown a number line marked only with "0" on one end and "40" on the other. Numbers popped up one at a time at the top of the iPad screen, and the participants dragged a finger from the middle of the screen down to the place on the number line where they thought each number belonged. Software tracked the path the finger took.

Changing course

Statistical analysis of the results showed that the participants placed the numbers on the number line in a linear way, as expected. But surprisingly — for only a few hundred milliseconds — they appeared to be influenced by their innate number sense. In the case of 20, for example, the participants drifted slightly rightward with their finger — toward where 20 would belong in a ratio-based number line — and then quickly corrected course. The results provide some of the most direct evidence to date that the innate number sense remains active, even if largely dormant, in educated adults.

"It really looks like the two systems in the brain compete with each other," said Dotan.

Significantly, the drift effect was found with two-digit as well as one-digit numbers. Many researchers believe that people can only convert two-digit numbers into quantities using the learned linear numerical system, which processes the quantity of each digit separately — for example, 34 is processed as 3 tens plus 4 ones. But Dotan and Dehaene's research showed that the innate number sense is, in fact, capable of handling the complexity of two-digit numbers as well.


Heart Attacks Hit Poor the Hardest
1/8/2014

TAU researchers show that socioeconomic status is predictor of higher risk of disease and death after an attack

As people get older, their bodies wear down and become less resilient. In old age, it's common for people to become "clinically frail," and this "frailty syndrome" is emerging in the field of public health as a powerful predictor of healthcare use and death.

Now researchers Vicki Myers and Prof. Yariv Gerber of the Department of Epidemiology and Preventive Medicine at the School of Public Health at Tel Aviv University's Sackler Faculty of Medicine and colleagues have found that poor people are more than twice as likely as the wealthy to become frail after a heart attack. The findings, published in the International Journal of Cardiology, could help doctors and policymakers improve post-heart-attack care for the poor.

"By defining frailty, which combines many areas of medicine, we can predict which people are at the highest risk after a heart attack," said Ms. Myers. "And we found a strong connection between frailty and socioeconomic status."

Prof. Uri Goldbourt of the Department of Epidemiology and Preventive Medicine at the School of Public Health and Prof. Yaacov Drory of the Department of Rehabilitation at TAU's Sackler Faculty of Medicine collaborated on the study. Prof. Drory, the founder of the Israel Study of First Acute Myocardial Infarction, passed away last month. His colleagues remember him as a dedicated cardiologist and researcher, who published numerous papers and books and made a great contribution to the field of heart attack and cardiac rehabilitation.

The weakest among us

Because the definition of frailty covers physical, psychological, and functional aspects, it can be effectively diagnosed by looking at the accumulation of health problems in any given individual. Ms. Myers and her colleagues created an index of 40 health-related variables, which in a previous study were shown to be effective in diagnosing frailty in heart attack patients.

Using medical records and interviews, the researchers applied the index to 1,151 patients who had suffered heart attacks in central Israel from 10 to 13 years prior to the study. The most frequent health problems were type-2 diabetes, physical inactivity, lack of energy, work limitations, limitation climbing stairs, and self-rated health deterioration. The index also assessed the presence of a range of diseases, significant weight loss, limitations to activities of daily living, anxiety, depression, and pain.

The researchers found that 35 percent of the patients in the study had become frail in the decade following their heart attack. The frail patients were more likely to have suffered a severe heart attack and to have been older and obese when they were first evaluated in 1992 to 1993, just after their heart attacks. They were also more likely to have had a lower socioeconomic status (with fewer years of education and lower family income), to have been unemployed, and to have lived a neighborhood in one of Israel's lowest socioeconomic categories.

Surprisingly, despite being sicker in general, frail patients were less likely to have been admitted to intensive care, to have undergone surgery, or to have been prescribed certain medications commonly prescribed after a heart attack. These findings, the researchers say, may reflect poorer access to healthcare among the poor. "Not only was low income associated with twice the risk of becoming frail, living in a deprived neighborhood was linked to a 60 percent increased risk of frailty compared to living in a wealthy neighborhood, irrespective of personal circumstances," Myers said.

A holistic view of the heart

Low socioeconomic status has been shown to contribute to poor health in various ways. In general, poor people have less access to healthcare, lower health literacy, and a higher prevalence of risk factors, like smoking, inactivity, and unhealthy diet. But despite an abundance of theories, it remains uncertain exactly how socioeconomic status affects health after a heart attack in particular.

By providing some of the first compelling evidence linking socioeconomic status to frailty after a heart attack, Ms. Myers and her colleagues hope to provide doctors and decision-makers a solid basis on which to make healthcare decisions. They recommend initiatives to prevent frailty after a heart attack among high-risk groups, and additional healthcare services in disadvantaged areas to address socioeconomic inequalities, with a particular emphasis on cardiac rehabilitation. They also say doctors should take a more holistic view of patients after a heart attack to help prevent frailty and its associated risks.


Turning Off the "Aging Genes"
1/2/2014

Computer algorithm developed by TAU researchers identifies genes that could be transformed to stop the aging process

Restricting calorie consumption is one of the few proven ways to combat aging. Though the underlying mechanism is unknown, calorie restriction has been shown to prolong lifespan in yeast, worms, flies, monkeys, and, in some studies, humans.

Now Keren Yizhak, a doctoral student in Prof. Eytan Ruppin's laboratory at Tel Aviv University's Blavatnik School of Computer Science, and her colleagues have developed a computer algorithm that predicts which genes can be "turned off" to create the same anti-aging effect as calorie restriction. The findings, reported in Nature Communications, could lead to the development of new drugs to treat aging. Researchers from Bar-Ilan University collaborated on the research.

"Most algorithms try to find drug targets that kill cells to treat cancer or bacterial infections," says Yizhak. "Our algorithm is the first in our field to look for drug targets not to kill cells, but to transform them from a diseased state into a healthy one."

A digital laboratory

Prof. Ruppin's lab is a leader in the growing field of genome-scale metabolic modeling or GSMMs. Using mathematical equations and computers, GSMMs describe the metabolism, or life-sustaining, processes of living cells. Once built, the individual models serve as digital laboratories, allowing formerly labor-intensive tests to be conducted with the click of a mouse. Yizhak's algorithm, which she calls a "metabolic transformation algorithm," or MTA, can take information about any two metabolic states and predict the environmental or genetic changes required to go from one state to the other.

"Gene expression" is the measurement of the expression level of individual genes in a cell, and genes can be "turned off" in various ways to prevent them from being expressed in the cell. In the study, Yizhak applied MTA to the genetics of aging. After using her custom-designed MTA to confirm previous laboratory findings, she used it to predict genes that can be turned off to make the gene expression of old yeast look like that of young yeast. Yeast is the most widely used genetic model because much of its DNA is preserved in humans.

Some of the genes that the MTA identified were already known to extend the lifespan of yeast when turned off. Of the other genes she found, Yizhak sent seven to be tested at a Bar-Ilan University laboratory. Researchers there found that turning off two of the genes, GRE3 and ADH2, in actual, non-digital yeast significantly extends the yeast's lifespan.

"You would expect about three percent of yeast's genes to be lifespan-extending," said Yizhak. "So achieving a 10-fold increase over this expected frequency, as we did, is very encouraging."

Hope for humans

Since MTA provides a systemic view of cell metabolism, it can also shed light on how the genes it identifies contribute to changes in genetic expression. In the case of GRE3 and ADH2, MTA showed that turning off the genes increased oxidative stress levels in yeast, thus possibly inducing a mild stress similar to that produced by calorie restriction.

As a final test, Yizhak applied MTA to human metabolic information. MTA was able to identify a set of genes that can transform 40-to-70 percent of the differences between the old and young information from four different studies. While currently there is no way to verify the results in humans, many of these genes are known to extend lifespan in yeast, worms, and mice.

Next, Yizhak will study whether turning off the genes predicted by MTA prolongs the lifespan of genetically engineered mice. One day, drugs could be developed to target genes in humans, potentially allowing us to live longer. MTA could also be applied to finding drug targets for disorders where metabolism plays a role, including obesity, diabetes, neurodegenerative disorders, and cancer.


Crowdsourcing Medicine
12/24/2013

TAU medical faculty offers course on improving entries for the online encyclopedia Wikipedia

Tel Aviv University's Sackler Faculty of Medicine is this year offering a course on producing entries for Wikipedia, the crowd-edited online encyclopedia — the first Israeli university to do so.

"I'm convinced that the students who take the course will vastly improve the level of online medical information available to the public," the medical school's dean, Prof. Yosef Makori, told the Israeli newspaper Haaretz.

TAU designed the one-credit elective — called "Wiki-medicine: The Wonderful World of Wiki and Free Medical Information in Hebrew Wikipedia" — with the help of Wikipedia Israel. Participants will meet with regular contributors to Wikipedia in both Hebrew and English to learn how to write and edit reliable entries and to understand intellectual property rights.

Wikipedia has previously worked with educational institutions in Israel and around the world to offer instruction in writing for the web site. But TAU is the first academic institution in Israel to offer a course dedicated entirely to writing Wikipedia entries.

For more, see the Haaretz story at:
http://www.aftau.org/site/DocServer/Digital_age_doctors.pdf?docID=20241


Chewing Gum is Often the Culprit for Migraine Headaches in Teens
12/19/2013

TAU study finds that 87 percent of teens who quit chewing experience significant relief

Teenagers are notorious for chewing a lot of gum. The lip smacking, bubble popping, discarded gum stuck to the sole give teachers and parents a headache.

Now, Dr. Nathan Watemberg of Tel Aviv University-affiliated Meir Medical Center has found that gum-chewing teenagers, and younger children as well, are giving themselves headaches too. His findings, published in Pediatric Neurology, could help treat countless cases of migraine and tension headaches in adolescents without the need for additional testing or medication.

"Out of our 30 patients, 26 reported significant improvement, and 19 had complete headache resolution," said Dr. Watemberg. "Twenty of the improved patients later agreed to go back to chewing gum, and all of them reported an immediate relapse of symptoms."

Right under our noses

Headaches are common in childhood and become more common and frequent during adolescence, particularly among girls. Typical triggers are stress, tiredness, lack of sleep, heat, video games, noise, sunlight, smoking, missed meals, and menstruation. But until now there has been little medical research on the relationship between gum chewing and headaches.

At Meir Medical Center's Child Neurology Unit and Child Development Center and community clinics, Dr. Watemberg noticed that many patients who reported headaches were daily gum chewers. Teenage girl patients were particularly avid chewers — a finding supported by previous dental studies. Dr. Watemberg found that in many cases, when patients stopped chewing gum at his suggestion, they got substantially better.

Taking a more statistical approach, Dr. Watemberg asked 30 patients between six and 19 years old who had chronic migraine or tension headaches and chewed gum daily to quit chewing gum for one month. They had chewed gum for at least an hour up to more than six hours per day. After a month without gum, 19 of the 30 patients reported that their headaches went away entirely and seven reported a decrease in the frequency and intensity of headaches. To test the results, 26 of them agreed to resume gum chewing for two weeks. All of them reported a return of their symptoms within days.

Two previous studies linked gum chewing to headaches, but offered different explanations. One study suggested that gum chewing causes stress to the temporomandibular joint, or TMJ, the place where the jaw meets the skull. The other study blamed aspartame, the artificial sweetener used in most popular chewing gums. TMJ dysfunction has been shown to cause headaches, while the evidence is mixed on aspartame.

Gumming up the works

Dr. Watemberg favors the TMJ explanation. Gum is only flavorful for a short period of time, suggesting it does not contain much aspartame, he says. If aspartame caused headaches, he reasons, there would be a lot more headaches from diet drinks and artificially sweetened products. On the other hand, people chew gum well after the taste is gone, putting a significant burden on the TMJ, which is already the most used joint in the body, he says.

"Every doctor knows that overuse of the TMJ will cause headaches," said Dr. Watemberg. "I believe this is what's happening when children and teenagers chew gum excessively."

Dr. Watemberg says his findings can be put to use immediately. By advising teenagers with chronic headaches to simply stop chewing gum, doctors can provide many of them with quick and effective treatment, without the need for expensive diagnostic tests or medications.


Do Patients in a Vegetative State Recognize Loved Ones?
12/16/2013

TAU researchers find unresponsive patients' brains may recognize photographs of their family and friends

Patients in a vegetative state are awake, breathe on their own, and seem to go in and out of sleep. But they do not respond to what is happening around them and exhibit no signs of conscious awareness. With communication impossible, friends and family are left wondering if the patients even know they are there.

Now, using functional magnetic resonance imaging (fMRI), Dr. Haggai Sharon and Dr. Yotam Pasternak of Tel Aviv University's Functional Brain Center and Sackler Faculty of Medicine and the Tel Aviv Sourasky Medical Center have shown that the brains of patients in a vegetative state emotionally react to photographs of people they know personally as though they recognize them.

"We showed that patients in a vegetative state can react differently to different stimuli in the environment depending on their emotional value," said Dr. Sharon. "It's not a generic thing; it's personal and autobiographical. We engaged the person, the individual, inside the patient."

The findings, published in PLOS ONE, deepen our understanding of the vegetative state and may offer hope for better care and the development of novel treatments. Researchers from TAU's School of Psychological Sciences, Department of Neurology, and Sagol School of Neuroscience and the Loewenstein Hospital in Ranaana contributed to the research.

Talking to the brain

For many years, patients in a vegetative state were believed to have no awareness of self or environment. But in recent years, doctors have made use of fMRI to examine brain activity in such patients. They have found that some patients in a vegetative state can perform complex cognitive tasks on command, like imagining a physical activity such as playing tennis, or, in one case, even answering yes-or-no questions. But these cases are rare and don’t provide any indication as to whether patients are having personal emotional experiences in such a state.

To gain insight into "what it feels like to be in a vegetative state," the researchers worked with four patients in a persistent (defined as "month-long") or permanent (persisting for more than three months) vegetative state. They showed them photographs of people they did and did not personally know, then gauged the patients' reactions using fMRI, which measures blood flow in the brain to detect areas of neurological activity in real time. In response to all the photographs, a region specific to facial recognition was activated in the patients' brains, indicating that their brains had correctly identified that they were looking at faces.

But in response to the photographs of close family members and friends, brain regions involved in emotional significance and autobiographical information were also activated in the patients' brains. In other words, the patients reacted with activations of brain centers involved in processing emotion, as though they knew the people in the photographs. The results suggest patients in a vegetative state can register and categorize complex visual information and connect it to memories – a groundbreaking finding.

The ghost in the machine

However, the researchers could not be sure if the patients were conscious of their emotions or just reacting spontaneously. So they then verbally asked the patients to imagine their parents' faces. Surprisingly, one patient, a 60-year-old kindergarten teacher who was hit by a car while crossing the street, exhibited complex brain activity in the face- and emotion-specific brain regions, identical to brain activity seen in healthy people. The researchers say her response is the strongest evidence yet that vegetative-state patients can be "emotionally aware." A second patient, a 23-year-old woman, exhibited activity just in the emotion-specific brain regions. (Significantly, both patients woke up within two months of the tests. They did not remember being in a vegetative state.)

"This experiment, a first of its kind, demonstrates that some vegetative patients may not only possess emotional awareness of the environment but also experience emotional awareness driven by internal processes, such as images," said Dr. Sharon.

Research focused on the "emotional awareness" of patients in a vegetative state is only a few years old. The researchers hope their work will eventually contribute to improved care and treatment. They have also begun working with patients in a minimally conscious state to better understand how regions of the brain interact in response to familiar cues. Emotions, they say, could help unlock the secrets of consciousness.


Coffee or Beer? The Choice Could Affect Your Genome
12/5/2013

TAU says caffeine and alcohol can change a part of DNA linked to aging and cancer

Coffee and beer are polar opposites in the beverage world. Coffee picks you up, and beer winds you down.

Now Prof. Martin Kupiec and his team at Tel Aviv University's Department of Molecular Microbiology and Biotechnology have discovered that the beverages may also have opposite effects on your genome. Working with a kind of yeast that shares many important genetic similarities with humans, the researchers found that caffeine shortens and alcohol lengthens telomeres — the end points of chromosomal DNA, implicated in aging and cancer.

"For the first time we've identified a few environmental factors that alter telomere length, and we've shown how they do it," said Prof. Kupiec. "What we learned may one day contribute to the prevention and treatment of human diseases."

Researchers from TAU's Blavatnik School of Computer Science and Columbia University's Department of Biological Sciences collaborated on the research, published in PLOS Genetics.

Between death and immortality

Telomeres, made of DNA and proteins, mark the ends of the strands of DNA in our chromosomes. They are essential to ensuring that the DNA strands are repaired and copied correctly. Every time a cell duplicates, the chromosomes are copied into the new cell with slightly shorter telomeres. Eventually, the telomeres become too short, and the cell dies. Only fetal and cancer cells have mechanisms to avoid this fate; they go on reproducing forever.

The researchers set out to expand on a 2004 study by Nobel Prize-winning molecular biologist Prof. Elizabeth Blackburn, which suggested that emotional stress causes the shortening of the telomeres characteristic of aging, presumably by generating free radicals in the cells. The researchers grew yeast cells in conditions that generate free radicals to test the effect on telomere length. They were surprised to find that the length did not change.

They went on to expose the yeast cells to 12 other environmental stressors. Most of the stressors — from temperature and pH changes to various drugs and chemicals — had no effect on telomere length. But a low concentration of caffeine, similar to the amount found in a shot of espresso, shortened telomeres, and exposure to a 5-to-7 percent ethanol solution lengthened telomeres.

From yeasts to you

To understand these changes, the TAU researchers scanned 6,000 strains of the yeast, each with a different gene deactivated. They then conducted genetic tests on the strains with the longest and shortest telomeres, revealing that two genes, Rap1 and Rif1, are the main players mediating environmental stressors and telomere length. In total, some 400 genes interact to maintain telomere length, the TAU researchers note, underscoring the importance of this gene network in maintaining the stability of the genome. Strikingly, most of these yeast genes are also present in the human genome.

"This is the first time anyone has analyzed a complex system in which all of the genes affecting it are known," said Prof. Kupiec. "It turns out that telomere length is something that's very exact, which suggests that precision is critical and should be protected from environmental effects."

More laboratory work is needed to prove a causal relationship, not a mere correlation, between telomere length and aging or cancer, the researchers say. Only then will they know whether human telomeres respond to the same signals as yeast, potentially leading to medical treatments and dietary guidelines. For now, Prof. Kupiec suggests, "Try to relax and drink a little coffee and a little beer."


A New Weapon in the War Against Superbugs
12/2/2013

TAU researchers find a protein that viruses use to kill bacteria

In the arms race between bacteria and modern medicine, bacteria have gained an edge. In recent decades, bacterial resistance to antibiotics has developed faster than the production of new antibiotics, making bacterial infections increasingly difficult to treat. Scientists worry that a particularly virulent and deadly "superbug" could one day join the ranks of existing untreatable bacteria, causing a public health catastrophe comparable with the Black Death.

Now research led by Dr. Udi Qimron of Tel Aviv University's Department of Clinical Microbiology and Immunology at the Sackler Faculty of Medicine has discovered a protein that kills bacteria. The isolation of this protein, produced by a virus that attacks bacteria, is a major step toward developing a substitute for conventional antibiotics. "To stay ahead of bacterial resistance, we have to keep developing new antibiotics," said Dr. Qimron. "What we found is a small protein that could serve as a powerful antibiotic in the future."

Dr. Ido Yosef, Ruth Kiro, and Shahar Molshanski-Mor of TAU's Sackler Faculty of Medicine and Dr. Sara Milam and Prof. Harold Erickson of Duke University contributed to the research, published in the Proceedings of the National Academy of Sciences.

Teaming up with a killer

Bacterial resistance is a natural process. But over the past sixty years or so, the misuse and overuse of antibiotics has pushed more and more bacteria to become more and more resistant, undermining one of the pillars of modern health care. Recently, the World Health Organization named growing antibiotic resistance one of the three greatest threats to public health.

Bacteriophages, often referred to as "phages," are viruses that infect and replicate in bacteria. Because they coevolved with bacteria, they are optimized to kill them. As proof of their endurance, phages are the most common life form on earth, outnumbering bacteria 10 to one. In places like the former Soviet Union, phages have been used to treat bacterial infections for the past hundred years. Harmless to humans, they inject their DNA into bacteria and rapidly replicate, killing their hosts.

"Ever since the discovery of bacteriophages in the early 20th century, scientists have understood that, on the principle of the 'enemy of my enemy is my friend,' medical use could be made of phages to fight viruses," said Dr. Qimron.

Breaking out the little guns

Dr. Qimron and his colleagues set out to understand how all 56 proteins found in T7, a particularly virulent phage that infects Escherichia coli bacteria, contribute to its functioning. They discovered that one of the proteins, called 0.4, impedes cell division in E. coli, causing the cells of the bacteria to elongate and then die. The protein is common to many bacteria and a similar process occurs in all bacteria, so the finding may have wide application.

No bacteriophage preparation has been approved in Western medicine for treating systemic bacterial infections. One reason is their inability to penetrate body tissues effectively. They are filtered effectively from the bloodstream by the spleen and liver, and occasionally neutralized by antibodies. But the 0.4 protein is much smaller than a whole phage, and so should be able to penetrate tissue better, getting to the bacteria to do its deadly work.

The major challenge for pharmaceutical companies will be figuring out how exactly to deliver the protein as a drug, said Dr. Qimron. In the meantime, he continues to hunt for other proteins that kill bacteria.


New Hope for Victims of Traumatic Brain Injury
11/18/2013

Researchers from TAU demonstrate hyperbaric oxygen therapy significantly revives brain functions and life quality

Every year, nearly two million people in the United States suffer traumatic brain injury (TBI), the leading cause of brain damage and permanent disabilities that include motor dysfunction, psychological disorders, and memory loss. Current rehabilitation programs help patients but often achieve limited success.

Now Dr. Shai Efrati and Prof. Eshel Ben-Jacob of Tel Aviv University's Sagol School of Neuroscience have proven that it is possible to repair brains and improve the quality of life for TBI victims, even years after the occurrence of the injury.

In an article published in PLoS ONE, Dr. Efrati, Prof. Ben Jacob, and their collaborators present evidence that hyperbaric oxygen therapy (HBOT) should repair chronically impaired brain functions and significantly improve the quality of life of mild TBI patients. The new findings challenge the often-dismissive stand of the US Food and Drug Administration, Centers for Disease Control and Prevention, and the medical community at large, and offer new hope where there was none.

The research trial

The trial included 56 participants who had suffered mild traumatic brain injury one to five years earlier and were still bothered by headaches, difficulty concentrating, irritability, and other cognitive impairments. The patients' symptoms were no longer improving prior to the trial.

The participants were randomly divided into two groups. One received two months of HBOT treatment while the other, the control group, was not treated at all. The latter group then received two months of treatment following the first control period. The treatments, administered at the Institute of Hyperbaric Medicine at Assaf Harofeh Medical Center, headed by Dr. Efrati, consisted of 40 one-hour sessions, administered five times a week over two months, in a high pressure chamber, breathing 100% oxygen and experiencing a pressure of 1.5 atmospheres, the pressure experienced when diving under water to a depth of 5 meters. The patients' brain functions and quality of life were then assessed by computerized evaluations and compared with single photon emission computed tomography (SPECT) scans.

Persuasive confirmation

In both groups, the hyperbaric oxygen therapy sessions led to significant improvements in tests of cognitive function and quality of life. No significant improvements occurred by the end of the period of non-treatment in the control group. Analysis of brain imaging showed significantly increased neuronal activity after a two-month period of HBOT treatment compared to the control periods of non-treatment.

"What makes the results even more persuasive is the remarkable agreement between the cognitive function restoration and the changes in brain functionality as detected by the SPECT scans," explained Prof. Ben-Jacob. "The results demonstrate that neuroplasticity can be activated for months and years after acute brain injury."

"But most important, patients experienced improvements such as memory restoration and renewed use of language," Dr. Efrati said. "These changes can make a world of difference in daily life, helping patients regain their independence, go to work, and integrate back into society."

The regeneration process following brain injury involves complex processes, such as building new blood vessels and rebuilding connections between neurons, and requires much energy.

"This is where HBOT treatment can help," said Dr. Efrati. "The elevated oxygen levels during treatment supply the necessary energy for facilitating the healing process."

The findings offer new hope for millions of traumatic brain injury patients, including thousands of veterans wounded in action in Iraq and Afghanistan. The researchers call for additional larger scale, multi-center clinical studies to further confirm the findings and determine the most effective and personalized treatment protocols. But since the hyperbaric oxygen therapy is the only treatment proven to heal TBI patients, the researchers say that the medical community and the US Armed Forces should permit the victims of TBI benefit from the new hope right now, rather than waiting until additional studies are completed.


Putting the Brakes on Immunity
11/12/2013

TAU researchers discover a powerful mechanism that keeps white blood cells from going rogue

The immune system is a double-edged sword. While its primary role is to fight infections, it can also become overactive, leading to problems like allergies and autoimmune diseases.

For example, the part of the immune system responsible for resisting parasites acts by releasing white blood cells called eosinophil granulocytes into the blood. But elevated eosinophil levels are also responsible for allergic reactions, including most forms of asthma, gastrointestinal diseases, blood disorders, and cancers.

Now a study, led by Dr. Ariel Munitz of the Department of Clinical Microbiology and Immunology at the Sackler School of Medicine at Tel Aviv University, and conducted by graduate students Netali Baruch Morgenstern and Dana Shik, has found a mechanism that pushes eosinophils to die before they get into the blood and wreak havoc. The discovery is a breakthrough in science's understanding of the immune system and suggests powerful new treatments for eosinophilic diseases such as asthma.

"We've discovered an important and powerful pathway that works to kill eosinophils," says Dr. Munitz. "The fundamental knowledge we have gained may one day yield even bigger results and therapies."

Published online in Nature Immunology in November, the research was funded in part by the United States-Israel Binational Science Foundation, the Israel Science Foundation, the Israel Cancer Research Fund, and the Fritz Thyssen Stiftung. The Division of Allergy and Immunology at the Cincinnati Children's Hospital Medical Center collaborated on it.

The body's tug-of-war

The level of eosinophils in the blood is relatively low in healthy people, accounting for just 2 to 5 percent of white blood cells in circulation. But in eosinophilic disorders, a signalling protein called interleukin 5, or IL-5, triggers a rush of eosinophils from the bone marrow, where they are produced, and into the blood, where they are transported to various organs. IL-5 has lately been investigated as a new target for asthma medications, some of which have proven effective in clinical trials.

Analyzing the bone marrow of mice, the researchers found that the expansion of eosinophils caused by IL-5 is actually part of a broader mechanism that regulates the lifecycle of the cells. While IL-5 commands eosinophils to expand and enter the bloodstream, a cell receptor called paired immunoglobulin-like receptor A, or PIR-­A, commands eosinophils to die. So eosinophils are in a constant "tug-of-war" between survival signals delivered by IL-5 and death orders delivered by PIR-A.

Although the death order by PIR-A is dominant, it is never executed. Eosinophils express another receptor, called PIR-B, which closely resembles PIR-A and inhibits its actions. In order for PIR-A to carry out its death order to the cell, PIR-B must be shut down.

"PIR-A is always inhibited by PIR-B from the very early stages of eosinophil development," says Dr. Munitz. "We had to remove the expression of PIR-B from the cells to see PIR-A's powerful effects."

Two new approaches to nip disease in the bud

After identifying the mechanism in cell culture systems, the researchers verified that it also operates in mice. As expected, they found that asthmatic mice without PIR-B in their bodies had very little expansion of eosinophils into their blood and lungs and therefore less asthmatic inflammation in their lungs than normal mice. Unhindered by PIR-B, PIR-A appeared to keep eosinophils from reaching harmful levels in their bodies. Because human eosinophils also express PIR-like molecules, there is good reason to believe the same mechanism works in people.

In addition to advancing knowledge of eosinophils — a basic and important cell type — the researchers' work opens up two new avenues for treating eosinophilic disorders. Instead of lowering IL-5 levels to try to reduce eosinophil expansion, scientists can now target PIR-A to enhance its ability to kill eosinophils. Alternatively, they could weaken PIR-B so that it inhibits PIR-A less.

The researchers have preliminary evidence that PIR-B inhibits other mechanisms that drive cell death. Identifying them is the focus of their current research.


Torture Permanently Damages Normal Perception of Pain
11/5/2013

TAU researchers study the long-term effects of torture on the human pain system

Israeli soldiers captured during the 1973 Yom Kippur War were subjected to brutal torture in Egypt and Syria. Held alone in tiny, filthy spaces for weeks or months, sometimes handcuffed and blindfolded, they suffered severe beatings, burns, electric shocks, starvation, and worse. And rather than receiving treatment, additional torture was inflicted on existing wounds.

Forty years later, research by Prof. Ruth Defrin, of the Department of Physical Therapy, a part of the Stanley Steyer School of Health Professions in the Sackler Faculty of Medicine at Tel Aviv University, shows that the ex-prisoners of war (POWs), continue to suffer from dysfunctional pain perception and regulation, likely as a result of their torture. The study — conducted in collaboration with Prof. Zahava Solomon and Prof. Karni Ginzburg of TAU's Bob Shapell School of Social Work and Prof. Mario Mikulincer of the School of Psychology at the Interdisciplinary Center, Herzliya — was published in the European Journal of Pain.

"The human body's pain system can either inhibit or excite pain. It's two sides of the same coin," says Prof. Defrin. "Usually, when it does more of one, it does less of the other. But in Israeli ex-POWs, torture appears to have caused dysfunction in both directions. Our findings emphasize that tissue damage can have long-term systemic effects and needs to be treated immediately."

A painful legacy

The study focused on 104 combat veterans of the Yom Kippur War. Sixty of the men were taken prisoner during the war, and 44 of them were not. In the study, all were put through a battery of psychophysical pain tests — applying a heating device to one arm, submerging the other arm in a hot water bath, and pressing a nylon fiber into a middle finger. They also filled out psychological questionnaires.

The ex-POWs exhibited diminished pain inhibition (the degree to which the body eases one pain in response to another) and heightened pain excitation (the degree to which repeated exposure to the same sensation heightens the resulting pain). Based on these novel findings, the researchers conclude that the torture survivors' bodies now regulate pain in a dysfunctional way.

It is not entirely clear whether the dysfunction is the result of years of chronic pain or of the original torture itself. But the ex-POWs exhibited worse pain regulation than the non-POW chronic pain sufferers in the study. And a statistical analysis of the test data also suggested that being tortured had a direct effect on their ability to regulate pain.

Head games

The researchers say non-physical torture may have also contributed to the ex-POWs' chronic pain. Among other forms of oppression and humiliation, the ex-POWs were not allowed to use the toilet, cursed at and threatened, told demoralizing misinformation about their loved ones, and exposed to mock executions. In the later stages of captivity, most of the POWs were transferred to a group cell, where social isolation was replaced by intense friction, crowding, and loss of privacy.

"We think psychological torture also affects the physiological pain system," says Prof. Defrin. "We still have to fully analyze the data, but preliminary analysis suggests there is a connection."


Untangling Alzheimer's Disease
10/28/2013

TAU researchers identify specific molecules that could be targeted to treat the disorder

Plaques and tangles made of proteins are believed to contribute to the debilitating progression of Alzheimer's disease. But proteins also play a positive role in important brain functions, like cell-to-cell communication and immunological response. Molecules called microRNAs regulate both good and bad protein levels in the brain, binding to messenger RNAs to prevent them from developing into proteins.

Now, Dr. Boaz Barak and a team of researchers in the lab of Prof. Uri Ashery of Tel Aviv University's Department of Neurobiology at the George S. Wise Faculty of Life Sciences and the Sagol School of Neuroscience have identified a specific set of microRNAs that detrimentally regulate protein levels in the brains of mice with Alzheimer's disease and beneficially regulate protein levels in the brains of other mice living in a stimulating environment.

"We were able to create two lists of microRNAs — those that contribute to brain performance and those that detract — depending on their levels in the brain," says Dr. Barak. "By targeting these molecules, we hope to move closer toward earlier detection and better treatment of Alzheimer's disease."

Prof. Daniel Michaelson of TAU's Department of Neurobiology in the George S. Wise Faculty of Life Sciences and the Sagol School of Neuroscience, Dr. Noam Shomron of TAU's Department of Cell and Developmental Biology and Sagol School of Neuroscience, Dr. Eitan Okun of Bar-Ilan University, and Dr. Mark Mattson of the National Institute on Aging collaborated on the study, published in Translational Psychiatry .

A double-edged sword

Alzheimer's disease is the most common form of dementia. Currently incurable, it increasingly impairs brain function over time, ultimately leading to death. The TAU researchers became interested in the disease while studying the brains of mice living in an "enriched environment" — an enlarged cage with running wheels, bedding and nesting material, a house, and frequently changing toys. Such environments have been shown to improve and maintain brain function in animals much as intellectual activity and physical fitness do in people.

The researchers ran a series of tests on a part of the mice's brains called the hippocampus, which plays a major role in memory and spatial navigation and is one of the earliest targets of Alzheimer's disease in humans. They found that, compared to mice in normal cages, the mice from the enriched environment developed higher levels of good proteins and lower levels of bad proteins. Then, for the first time, they identified the microRNAs responsible for regulating the expression of both good and bad proteins.

Armed with this new information, the researchers analyzed changes in the levels of microRNAs in the hippocampi of young, middle-aged, and old mice with an Alzheimer's-disease-like condition. They found that some of the microRNAs were expressed in exactly inverse amounts in mice with Alzheimer's disease as they were in mice from the enriched environment. The results were higher levels of bad proteins and lower levels of good proteins in the hippocampi of old mice with Alzheimer's disease. The microRNAs the researchers identified had already been shown or predicted to regulate the expression of proteins in ways that contributed to Alzheimer's disease. Their finding that the microRNAs are inversely regulated in mice from the enriched environment is important, because it suggests the molecules can be targeted by activities or drugs to preserve brain function.

Brain-busting potential

Two findings appear to have particular potential for treating people with Alzheimer's disease. In the brains of old mice with the disease, microRNA-325 was diminished, leading to higher levels of tomosyn, a protein that is well known to inhibit cellular communication in the brain. The researchers hope that eventually microRNA-325 can be used to create a drug to help Alzheimer's patients maintain low levels of tomosyn and preserve brain function. Additionally, the researchers found several important microRNAs at low levels starting in the brains of young mice. If the same can be found in humans, these microRNAs could be used as biomarker to detect Alzheimer's disease at a much earlier age than is now possible — at 30 years of age, for example, instead of 60.

"Our biggest hope is to be able to one day use microRNAs to detect Alzheimer's disease in people at a young age and begin a tailor-made treatment based on our findings, right away," says Dr. Barak.


What Makes a Man?
10/10/2013

TAU doctors help an Israeli combat soldier with a testosterone disorder start a family

Dr. Karen Tordjman, a senior lecturer at Tel Aviv University's Sackler Faculty of Medicine didn't have an immediate diagnosis for the under-masculinized young man who walked into her office. A 25-year-old university student who had served in an elite commando unit in the Israeli navy, he was handsome in a fashion-model kind of way: rail thin, with a smooth face and delicate, feminine features. Closer inspection revealed no body hair other than sparse patches in his armpits and groin. His genitals were small and heavily scarred.

The young man had reluctantly agreed to visit the medical clinic at the insistence of his girlfriend, who wanted an explanation for his condition. He couldn't have known he was initiating a years-long medical journey that would lead Dr. Tordjman and a team of physicians to discover a new genetic mutation, bolster the case for a counterintuitive medical treatment, and push the limits of male fertility. "We offered treatment not for his future reproductive capabilities but for his appearance," says Dr. Tordjman. "We didn't guarantee him anything, but we said we'd try."

Her research, published in the journal Andrologia in June, will allow future genetic screening for the mutation.

Uncharted waters

Dr. Tordjman and her colleague Dr. Amnon Botchan, also a Sackler lecturer, began by obtaining the patient's medical records. The records showed that two of his uncles had been diagnosed with androgen receptor insensitivity — a rare condition that results in the body under-responding to the androgen hormones that drive male sexual development. Usually caused by a mutation in the androgen receptor gene, the condition impairs the development of male genitalia in the womb and of secondary male sexual characteristics during puberty.

In cases of complete androgen insensitivity, no male sexual development takes place. The result is men who look like women on the outside but have testes rather than female genitalia inside their bodies. Such cases are often diagnosed only during puberty, when the individuals develop breasts and other female sexual characteristics but do not start menstruating. In cases of partial androgen insensitivity, which range from mild to severe, the individuals are born with ambiguous genitalia. If doctors determine that surgically creating male genitalia is infeasible, they tend to assign the female gender.

Dr. Tordjman's patient, who reported a consistent heterosexual orientation, had not had sex reassignment surgery or been given androgen treatments to try to enhance his sexual development at birth. But he had been diagnosed with the same condition as his uncles and undergone operations to correct genital malformations at age three and to remove breast tissue during puberty. Genetic testing, performed with the help of French researchers Dr. Serge Lumbroso and Prof. Charles Sultan, confirmed that he had a mutation of his androgen receptor gene — one that had not previously been reported.

A family affair

Hoping to masculinize the patient per his wishes, Dr. Tordjman started him on high-dose testosterone therapy. Theoretically, this type of therapy makes little sense for patients with androgen receptor insensitivity, because their bodies create plenty of testosterone — it's just that they are unable to put it to use. But Tordjman had read about a case in which the therapy had worked and decided to give it a try.

After several months of weekly injections, the patient appeared dramatically more masculine. He gained 18 pounds — mostly of muscle — and grew hair on his face and body, leading him to shave for the first time in his life. His voice, which had always been high-pitched, did not change. (The voice, says Tordjman, is stubbornly resistant to hormone therapy.) The treatments continued for four years, during which the patient and his girlfriend got married and eventually began talking about having a baby.

Infertility in men with androgen receptor insensitivity is nearly universal, even in mild cases; and no one with a case as severe as the patient's was known to have successfully fathered a child. But having seen a significant improvement in his sperm count, Tordjman took another long shot and referred the couple for fertility treatment. When Tordjman next saw the patient several years later, he was pushing a baby girl into her office in a stroller.

Children have a 50-percent chance of inheriting a mutation for androgen receptor insensitivity from a parent. While fathers have typically been left out of the equation given the male sterility associated with the condition, this case will force a rethinking of that dogma and encourage the use of testosterone and fertility treatments in men with the condition, says Tordjman.

"My suggestion is in any case like this with partial androgen insensitivity, even if you don't know where in the androgen receptor gene the mutation lies, testosterone treatment is worth trying," she says.


TAU Smartphone App Brings Genetic Analysis to the Palm of Your Hand
10/8/2013

New software allows users to upload and then update the meaning of their genetic information

Until now, understanding and using genetic information has depended on the scientists and doctors who do the testing. No longer.

Now, software developed by researchers at Tel Aviv University is putting the power of genetic information in the hands of the people. GeneG, a smartphone app and associated web site created by Dr. Noam Shomron at TAU's Faculty of Medicine allows individuals to access and analyze their genome at any time. After undergoing whole genome sequencing, users can upload their data to the GeneG website for analysis. The results are available via the GeneG app on mobile devices.

"For the first time you can take your genome home and look at it whenever you want," says Shomron. "We are giving you eyes to peer into your genetics." And as new analytical tests are developed, you can apply them right away.

TAU graduate students Ofer Isakov and Gershon Celniker worked under Shomron to develop the software, which is to be released to physicians in October ahead of a public release. More information about the project can be found at http://www.geneg.org/.

Data-driven demand

The first map of the human genome, published in 2003, took eight years of work by thousands of researchers and cost $1 billion. Today, people can get their entire genome sequenced within a few weeks for around $1,000. Thousands have had it done, and the turnaround time and cost are fast decreasing as the technology advances. GeneG aims to meet the growing demand for ways to make sense of all this information.

At the moment, DNA sequencing focuses on specific areas, looking for quirks in sequences within individual genes, clusters of genes, or chromosomes. A downside of this targeted approach is that each genetic test requires donating new DNA and waiting for it to be processed. Shomron gives the example of a woman who wants to get tested before becoming pregnant. Currently, she has to take a day off work, travel to a lab to have her blood drawn, then wait for several weeks while a selection of her genes is amplified and sequenced. If she later decides to conceive again and wants the newest genetic tests, she has to start the whole process over again.

With GeneG, on the other hand, new tests are just a software update away. Users who have uploaded their genomes to the website can "query" them using digital genetic tests based on research from organizations like the National Institutes of Health, Stanford University, and the European Bioinformatics Institute. The software provides all the functions of more limited genetic testing, including diagnosing and predicting genetic diseases, checking potential parents for genetic traits that could cause disease in their future children, and screening unborn and newborn babies. And it can all be done without setting foot in a lab.

iGenome

But GeneG is not just a timesaver. By giving people instant access to their genomic information, Shomron hopes to help usher in an era of personalized medicine. He envisions people carrying their genomes with them on their mobile devices wherever they go, encouraging scientists to develop more tests and doctors to use the information in their treatment of patients.

"If we give this power to the general public, it will put pressure on the medical field to catch up with this information," said Shomron. But, he says, "It should be used with great caution and with sensible interpretation. Some people might not be ready to see all this information about themselves."

The software could be particularly effective, Shomron says, in advancing pharmacogenomics — the science of optimizing medications for each individual's unique genetic makeup. With the right tests, GeneG will tell patients and their doctors which medicines are likely to be the safest and most effective in treating whatever ails them. Specific applications could range from finding the right antidepressant to maximizing the effectiveness of cancer treatments.

Within a few iterations of the software, Shomron hopes the GeneG mobile app will be independent of the website. A bit further in the future, he says, you and your partner may be able to tap your smartphones together to see if you are as compatible genetically as you are personally.


Sending Multiple Sclerosis Up in Smoke
10/7/2013

TAU researchers find chemicals in marijuana could help treat MS

Multiple sclerosis is an inflammatory disease in which the immune system attacks the nervous system. The result can be a wide range of debilitating motor, physical, and mental problems. No one knows why people get the disease or how to treat it.

In a new study published in the Journal of Neuroimmune Pharmacology, Drs. Ewa Kozela, Ana Juknat, Neta Rimmerman and Zvi Vogel of Tel Aviv University's Dr. Miriam and Sheldon G. Adelson Center for the Biology of Addictive Diseases and Sackler Faculty of Medicine demonstrate that some chemical compounds found in marijuana can help treat MS-like diseases in mice by preventing inflammation in the brain and spinal cord.

"Inflammation is part of the body's natural immune response, but in cases like MS it gets out of hand," says Kozela. "Our study looks at how compounds isolated from marijuana can be used to regulate inflammation to protect the nervous system and its functions." Researchers from the Weizmann Institute of Science co-authored the study.

Mind-altering findings

Israel has a strong tradition of marijuana research. Israeli scientists Raphael Mechoulam and Yechiel Gaoni discovered THC, or tetrahydrocannabinol, in 1964, kick-starting the scientific study of the plant and its chemical constituents around the world. Since then, scientists have identified about 70 compounds — called cannabinoids — that are unique to cannabis and have interesting biological effects. In the 1990s, Prof. Vogel was among the first researchers to describe endocannabinoids, molecules that act like THC in the body.

Besides THC, the most plentiful and potent cannabinoid in marijuana is cannabidiol, or CBD. The TAU researchers are particularly interested in CBD, because it offers medicinal benefits without the controversial mind-altering effects of THC.

In a 2011 study, they showed that CBD helps treat MS-like symptoms in mice by preventing immune cells in their bodies from transforming and attacking the insulating covers of nerve cells in the spinal cord. After inducing an MS-like condition in mice — partially paralyzing their limbs — the researchers injected them with CBD. The mice responded by regaining movement, first twitching their tails and then beginning to walk without a limp. The researchers noted that the mice treated with CBD had much less inflammation in the spinal cord than their untreated counterparts.

High hopes for humans

In the latest study, the researchers set out to see if the known anti-inflammatory properties of CBD and THC could also be applied to the treatment of inflammation associated with MS — and if so, how. This time they turned to the immune system.

The researchers took immune cells isolated from paralyzed mice that specifically target and harm the brain and spinal cord, and treated them with either CBD or THC. In both cases, the immune cells produced fewer inflammatory molecules, particularly one called interleukin 17, or IL-17, which is strongly associated with MS and very harmful to nerve cells and their insulating covers. The researchers concluded that the presence of CBD or THC restrains the immune cells from triggering the production of inflammatory molecules and limits the molecules' ability to reach and damage the brain and spinal cord.

Further research is needed to prove the effectiveness of cannabinoids in treating MS in humans, but there are reasons for hope, the researchers say. In many countries, CBD and THC are already prescribed for the treatment of MS symptoms, including pain and muscle stiffness.

"When used wisely, cannabis has huge potential," says Kozela, who previously studied opiates like morphine, derived from the poppy plant. "We're just beginning to understand how it works."


What Makes Triathletes So Tough?
10/3/2013

TAU researchers find triathletes feel less pain than the rest of us

Triathletes participate in a grueling endurance sport, swimming, bicycling, and running long distances without rest. In training and competitions, they regularly push their bodies beyond the limits most of us can endure. But while there is no doubt that triathletes are tough, very little is known about what gives them their exceptional abilities.

Now researchers at Tel Aviv University have discovered a possible explanation. Prof. Ruth Defrin and her doctoral student Nirit Geva of TAU's Department of Physical Therapy, part of the Stanley Steyer School of Health Professions at TAU's Sackler Faculty of Medicine, have found that triathletes feel less pain than casual exercisers. Their findings were published in the journal Pain in August.

"In our study, triathletes rated pain lower in intensity, tolerated it longer, and inhibited it better than individuals in a control group," says Prof. Defrin. "We think both physiological and psychological factors underlie these differences and help explain how triathletes are able to perform at such a high level."

Mind over matter

Nineteen triathletes and 17 non-athletes participated in the TAU researchers' study. The triathletes were people who trained for and competed in at least two triathlons per year — including in some cases the notoriously challenging Ironman Triathlon, which consists of a 2.4-mile swim, a 112-mile bicycle ride, and a 26.2-mile marathon run. The non-athletes were people who did non-competitive exercises, like jogging, swimming, or aerobics classes.

All the participants were put through a battery of psychophysical pain tests, involving the application of a heating device to one arm and the submersion of the other arm in a cold-water bath. They also filled out questionnaires about their attitudes toward pain.

In the tests, the triathletes identified pain just as well as non-athletes, but they perceived it as less intense and were able to withstand it longer. The researchers explain that detecting pain is a relatively straightforward sensory experience, whereas evaluating pain and being willing and able to endure it involves attitude, motivation, and life experience. The triathletes reported fearing and worrying less about pain, which may help explain their higher tolerance, the researchers say.

The triathletes also showed a better ability to inhibit pain than non-athletes, as measured by conditioned pain modulation — the degree to which the body eases one pain in response to another. The researchers say psychology may be a factor here too. The triathletes with less fear of pain tended to exhibit better pain regulation. Previous studies have similarly found that psychological manipulation can affect pain perception.

The chicken or the egg?

Another explanation for triathletes' lower pain ratings, higher pain tolerance, and better pain regulation is that they have taught their bodies to respond powerfully to painful stimuli through their intense training. The TAU researchers say their study — along with existing literature — suggests that psychology and physiology together enable triathletes to do what they do.

"It is very difficult to separate physiology and psychology," says Prof. Defrin. "But in general, experience is the sum of these factors."

The researchers plan to do further research to determine whether triathletes participate in their sport because they feel less pain or feel less pain because they participate in their sport. If it turns out that intense training in fact helps reduce and regulate pain, it could be used to treat people with chronic pain. Like triathletes, chronic pain patients suffer daily, but their pain is out of their control and has the opposite effect, weakening rather than strengthening pain inhibition.


Vaccination and the Gentle Art of Persuasion
10/1/2013

TAU research recommends that pediatricians respect parents' rights to make the case for immunization

Controversy about the risks of measles, mumps, and rubella vaccines has been rumbling in the United States for years — and now it's Israel's turn. After finding traces of the polio virus in sewage, Israel's Ministry of Health launched a national vaccination campaign that reached more than half a million children. Surprisingly, dissenting voices flooded social media and the mainstream news, calling for a halt to the campaign. Endorsements by public figures, like Israel's president Shimon Peres, did little to calm the storm.

Now a study led by researchers at Tel Aviv University demonstrates that nearly all pediatricians in Israel strongly support the vaccination of infants, but most do not believe that their role is to force treatment on parents. The study recommends that pediatricians use the art of persuasion, with the help of communication experts, as they discuss the risks and virtues of vaccination with parents.

"Our advice is that pediatricians find ways to communicate their views to parents in a respectful way that doesn't discourage them from seeking treatment for their children," says Dr. Ayala Maayan-Metzger of TAU's Sackler Faculty of Medicine. "This is something experts in modern communication could help with." The study was published in September in the journal Acta Paediatrica.

A clash of values

Every major medical body in the world — including Israel's Ministry of Health, the American Medical Association, and the World Health Organization — recommends a battery of infant vaccinations. But over the past decade, an increasing number of parents have chosen not to comply. Studies have identified various reasons for this trend, including a growing distrust of professional expertise, unproven theories about a causal effect for autism, and the parents' insistence on their own right to decide on medical care for their children.

Dr. Maayan-Metzger, who also works at the Department of Neonatology at The Edmond and Lili Safra Children's Hospital at Sheba Medical Center, and Dr. Peri Kedem-Friedrich of Bar-Ilan University's Psychology Department, set out with other TAU researchers to examine for the first time the issue of infant vaccination from the perspective of the working clinical physician. They hoped to understand pediatricians' attitudes and treatment intentions toward parents who refuse to vaccinate their infants.

To this end, they distributed an anonymous questionnaire to 376 pediatricians who work in hospitals and primary health care clinics in Israel. The pediatricians completed the questionnaire between May and November of 2010.

Ninety-two percent of the pediatricians agreed that vaccinations, which are widely available free of charge in Israel, are in infants' best interest. Seventy-one percent expressed negative feelings toward parents who refuse to vaccinate their infants. But 37 percent agreed that parents have a right to decide, and another 37 percent agreed that vaccinations should be officially enforced. Two percent said they would object to treating children who had not been vaccinated.

"The findings show how strongly doctors here support the vaccination program and stand behind the Ministry of Health," says Maayan-Metzger. "It's not a decision handed down from on high. We feel passionately that it’s the right thing to do."

A better bedside manner?

The study concludes that pediatricians are torn between two opposing values: the importance of immunizing infants and the parents' right to determine what is medically best for their children. Despite their strong — even angry — feelings, pediatricians do not feel it is their place to force the vaccinations on the parents and their children, favoring gentle persuasion or official enforcement over coercion, according to the study.

To build trust, the study suggests that pediatricians communicate to parents that they genuinely respect their rights. But the study also acknowledges pediatricians may simply not be equipped to change parents' minds on such a complex and personal issue. Communication experts may be necessary, it says, to help physicians combat anti-vaccination sentiment and communicate to parents the benefits of vaccinating their infants.


Putting the Spring Back in Broken Hearts
9/23/2013

TAU researchers develop spring-like fibers to help repair damaged heart tissue

The threat from a heart attack doesn't end with the event itself. Blockage of blood flow to the heart can cause irreversible cell death and scarring. With transplants scarce, half the people who live through a heart attack die within five years. Scientists are trying to address this problem by engineering cardiac tissue to patch up damaged areas.

Now doctoral students Sharon Fleischer and Ron Feiner — under the supervision of Dr. Tal Dvir of Tel Aviv University's Department of Molecular Microbiology and Biotechnology and the Center for Nanoscience and Nanotechnology — have fabricated fibers shaped like springs that allow engineered cardiac tissue to pump more like the real thing. They reported their findings in the journal Biomaterials in August.

"Until now, when scientists have tried to engineer cardiac tissue, they've used straight fibers to support the contracting cells," says Dr. Dvir. "However, these fibers prevent the contraction of the engineered tissue. What we did was mimic the spring-like fibers that promote contraction and relaxation of the heart muscle. We found that by growing tissues on these fibers, we got more functional tissues.

Springing into action

Cardiac tissue is engineered by allowing cells taken from the hearts of patients or animals to grow on a three-dimensional scaffold, which replaces the extracellular matrix, a collagen grid that naturally supports the cells in the heart. Over time, the cells come together to form a tissue that generates its own electrical impulses and expands and contracts spontaneously. The tissue can then be surgically implanted to replace damaged tissue and improve heart function in patients.

Dr. Dvir's Laboratory for Tissue Engineering and Regenerative Medicine focuses on engineering complex tissues for medical use. When it comes to the heart, the researchers are always looking for ways to build a scaffold that better replicates the extracellular matrix and so yields more functional tissue. Earlier this year, they published research on integrating gold particles into cardiac tissue to optimize electrical signaling between cells.

More recently, the researchers identified spiral-shaped collagen fibers in the extracellular matrix of rat hearts. Seeing the potential for an advance, they set out to recreate them for the first time. After fabricating the spring-like fibers using advanced techniques, they subjected them to a variety of tests.

As the researchers predicted, the spring-like fibers showed better mechanical properties than straight fibers, with especially improved elasticity. And compared to tissue engineered with straight fibers, the tissue engineered with spring-like fibers contracted with greater force and less mechanical resistance.

"These properties are very important, because we want to transplant the tissue into the human heart, which expands and contracts constantly," says Fleischer.

Saving lives

Heart disease is responsible for a third of all deaths in the United States, according to a 2013 American Heart Association report. The researchers in Dr. Dvir's lab hope that tissue engineered with spring-like fibers will help fight this epidemic, improving and prolonging the lives of millions of people.

But additional research is needed first. The researchers say the processes for fabricating the fibers and assembling them into a scaffold need to be refined. Most importantly, they say, the ability of the tissue to improve heart function after a heart attack needs to be tested in humans — something they plan to do in pre-clinical and then clinical trials.


Why Kids Breathe Easier in Summer
9/17/2013

TAU researchers find winter viruses may be behind sleep-disordered breathing spike in children

A good night's sleep is important to our children's development. But with the first day of school just passed, many children are at increased risk for sleep breathing disorders that can impair their mental and physical development and hurt their academic performance.

A study conducted in North America in 2011 showed that the frequency of sleep-disordered breathing increases in the winter and spring. Until now, researchers believed asthma, allergies, and viral respiratory infections like the flu contributed to disorders that affect children's breathing during sleep.

Now, in a new study conducted at the Pediatric Sleep Center at the Tel Aviv Sourasky Medical Center and published in the journal Sleep Medicine, Dr. Riva Tauman and her fellow researchers of the Sackler Faculty of Medicine at Tel Aviv University have shown that asthma and allergies do not contribute to pediatric sleep-disordered breathing. Viruses alone, they say, may be responsible for the seasonal variation seen in children.

The researchers say the study has broad implications for the treatment of sleep-breathing disorders in children, bolstering the idea that the time of year is relevant when treating children for sleep-disordered breathing in borderline cases.

Blowing hot and cold

"We knew from research and clinical practice that sleep-disordered breathing in children gets worse during the colder months," Dr. Tauman says. "What we didn't expect is that the trend has nothing to do with asthma or allergies."

"Sleep-disordered breathing" is a blanket term for a group of disorders. One of the common disorders is obstructive sleep apnea, in which the upper airway becomes blocked, usually by enlarged tonsils or adenoids, causing snoring and, in more severe cases, breathing pauses that lead to poor-quality and fragmented sleep and decreased oxygen and elevated carbon dioxide levels in the bloodstream.

In the long term, sleep-disordered breathing in children can cause stunted growth, heart disease, and neurocognitive problems associated with diminished school performance, impaired language development, and behavioral issues.

In their study, Dr. Tauman and her Sackler Faculty of Medicine colleagues Michal Greenfeld and Yakov Sivan statistically analyzed the cases of more than 2,000 children and adolescents who were referred to the sleep center to be tested for suspected sleep-disordered breathing between 2008 and 2010. Confirming earlier results of a 2011 study of five- to nine-year-olds, the researchers found that pediatric sleep-disordered breathing is worse in the winter — which in Israel they defined as from November to March — than in the summer. The seasonal variability is most apparent in children less than five years old, they found.

The researchers also found that wheezing and asthma do not contribute to the trend.

Based on their findings, the researchers speculate that viral respiratory infections — which are more prevalent in younger children and during colder months — are the major contributor to the seasonal variability seen in pediatric sleep-disordered breathing.

Taking the long view

If the sleep clinic tests had all been conducted in the winter, the researchers estimate that seven percent more children would have been diagnosed with sleep-disordered breathing. Seven percent fewer would have been diagnosed if all the tests had been done in the summer, they estimate.

"Our study suggests that if a child comes into the sleep laboratory in the winter with a mild case, I may consider not treating him. I can assume he will be better in the summer," said Tauman. "But if he has only mild symptoms in the summer, I can assume they are more severe in the winter."


When Good Cells Go Bad
9/16/2013

TAU research could help prevent white blood cells from contributing to colon cancer and lung disease

Researchers at Tel Aviv University have gained new insight into the workings of white blood cells that contribute to several deadly diseases — an insight that offers hope for new and more successful treatments.

Dr. Ariel Munitz and doctoral student Danielle Karo-Atar of TAU's Department of Clinical Microbiology and Immunology at the Sackler Faculty of Medicine found a receptor on the cells — called macrophages — involved in stopping the macrophages from becoming overactive and harmful.

Macrophages serve an essential role in the immune system, "eating" cellular debris and pathogens. But they also contribute to several diseases, including colon cancer and lung disease. In the laboratory, the researchers were able to determine how the receptor suppresses the macrophage behavior that contributes to colon cancer and idiopathic pulmonary fibrosis.

"We identified a cell-surface receptor on the macrophages, paired immunoglobulin-like receptor B, that regulates their response to suppress their wound-healing capacity," Dr. Munitz told the ISRAEL21c news website. He says the receptor could be a good candidate for drugs targeting diseases linked to macrophage activity.

Their preliminary findings were published in the American Journal of Respiratory Cell and Molecular Biology. For more, see the ISRAEL21c story:
http://israel21c.org/health/new-pathway-to-treat-colorectal-cancer-pulmonary-fibrosis/


Meal Timing Can Significantly Improve Fertility in Women with Polycystic Ovaries
8/13/2013

Managing insulin levels through meal timing boosts ovulation and decreases testosterone, says TAU researcher

Polycystic Ovarian Syndrome (PCOS), a common disorder that impairs fertility by impacting menstruation, ovulation, hormones, and more, is closely related to insulin levels. Women with the disorder are typically "insulin resistant" — their bodies produce an overabundance of insulin to deliver glucose from the blood into the muscles. The excess makes its way to the ovaries, where it stimulates the production of testosterone, thereby impairing fertility.

Now Prof. Daniela Jakubowicz of Tel Aviv University's Sackler Faculty of Medicine and the Diabetes Unit at Wolfson Medical Center has found a natural way to help women of normal weight who suffer from PCOS manage their glucose and insulin levels to improve overall fertility. And she says it's all in the timing.

The goal of her maintenance meal plan, based on the body's 24 hour metabolic cycle, is not weight loss but insulin management. Women with PCOS who increased their calorie intake at breakfast, including high protein and carbohydrate content, and reduced their calorie intake through the rest of the day, saw a reduction in insulin resistance. This led to lower levels of testosterone and dramatic increase in the ovulation frequency — measures that have a direct impact on fertility, notes Prof. Jakubowicz.

The research has been published in Clinical Science and was recently presented at the Endocrine Society's annual meeting in June. It was conducted in collaboration with Dr. Julio Wainstein of TAU and Wolfson Medical Center and Dr. Maayan Barnea and Prof. Oren Froy of the Hebrew University of Jerusalem.

Managing insulin to increase ovulation

Many of the treatment options for PCOS are exclusively for obese women, Prof. Jakubowicz explains. Doctors often suggest weight loss to manage insulin levels, or prescribe medications that are used to improve the insulin levels of overweight patients. But many women who suffer from PCOS maintain a normal weight — and they are looking for ways to improve their chances of conceiving and giving birth to a healthy baby.

In a recent study, Prof. Jakubowicz and her fellow researchers confirmed that a low-calorie weight-loss plan focusing on larger breakfasts and smaller dinners also lowers insulin, glucose, and triglycerides levels. This finding inspired them to test whether a similar meal plan could be an effective therapeutic option for women with PCOS.

Sixty women suffering from PCOS with a normal body mass index (BMI) were randomly assigned to one of two 1,800 calorie maintenance diets with identical foods. The first group ate a 983 calorie breakfast, a 645 calorie lunch, and a 190 calorie dinner. The second group had a 190 calorie breakfast, a 645 calorie lunch, and 983 calorie dinner. After 90 days, the researchers tested participants in each group for insulin, glucose, and testosterone levels as well as ovulation and menstruation.

As expected, neither group experienced a change in BMI, but other measures differed dramatically. While participants in the "big dinner" group maintained consistently high levels of insulin and testosterone throughout the study, those in the "big breakfast" group experienced a 56 percent decrease in insulin resistance and a 50 percent decrease in testosterone. This reduction of insulin and testosterone levels led to a 50 percent rise in ovulation rate, indicated by a rise in progesterone, by the end of the study.

A natural therapy

According to Prof. Jakubowicz, these results suggest that meal timing — specifically a meal plan that calls for the majority of daily calories to be consumed at breakfast and a reduction of calories throughout the day — could help women with PCOS manage their condition naturally, providing new hope for those who have found no solutions to their fertility issues, she says. PCOS not only inhibits natural fertilization, but impacts the effectiveness of in vitro fertilization treatments and increases the rate of miscarriage.

And beyond matters of fertility, this method could mitigate other symptoms associated with the disorder, including unwanted body hair, oily hair, hair loss, and acne. Moreover, it could protect against developing type-2 diabetes.


A "GPS System" in the Human Brain
8/8/2013

TAU neurosurgeon and two American colleagues discover the "grid cells" behind the body's navigational system

Neurosurgeon Prof. Itzhak Fried of Tel Aviv University's Sackler School of Medicine and the University of California, Los Angeles, is part of a team of scientists that recently located cells that act like GPS systems in the human brain. Fried discovered the so-called "grid cells" along with Drs. Joshua Jacobs of Drexel University and Michael J. Kahana of the University of Pennsylvania. They reported their findings in the journal Nature Neuroscience.

When scientists found in 2005 that rodents, bats, and nonhuman primates have grid cells that form navigation systems in their brains, it was one of the most important brain-research developments of the past few decades. Grid cells are neurons that emit pulses of electricity in a regular pattern that maps the animal's movement. Although scientists predicted they would find grid cells in humans, until now no one had previously been able to prove they were there.

"Without grid cells, it is likely that humans would frequently get lost or have to navigate based only on landmarks," Jacobs said. "Grid cells are thus critical for maintaining a sense of location in an environment."

The researchers made the discovery using electrodes implanted in the brains of 14 patients scheduled for surgery for severe epilepsy. The patients volunteered to play a video game in which they navigated a virtual environment. As they played, the patterns characteristic of rodent grid cells were found, showing that humans use the same neural mechanism as other mammals.

Understanding grid cells in humans could have important medical applications, the researchers say. "The area where the grid cells are found, the entorhinal cortex, is a key component of the human memory system, and in fact is the first to be affected in Alzheimer's disease," said Fried. "A better understanding of this system in humans may offer potential for the development of therapeutic measures to treat memory disorders in neurological patients." The scientists also located grid cells in another brain area in humans, the cingulate cortex.

For more, see the New York Times story:
http://www.nytimes.com/2013/08/06/science/navigational-cell-systems-located-in-human-brains.html


Micro-Machines for the Human Body
8/7/2013

TAU researchers adapt microscopic technology for bionic body parts and other medical devices

Tiny sensors and motors are everywhere, telling your smartphone screen to rotate and your camera to focus. Now, a team of researchers at Tel Aviv University has found a way to print biocompatible components for these micro-machines, making them ideal for use in medical devices, like bionic arms.

Microelectromechanical systems, better known as MEMS, are usually produced from silicon. The innovation of the TAU researchers — engineering doctoral candidates Leeya Engel and Jenny Shklovsky under the supervision of Prof. Yosi Shacham-Diamand of the School of Electrical Engineering and Slava Krylov of the School of Mechanical Engineering — is creating a novel micro-printing process that works a highly flexible and non-toxic organic polymer. The resulting MEMS components can be more comfortably and safely used in the human body and they expend less energy.

A two-way street

As their name suggests, MEMS bridge the worlds of electricity and mechanics. They have a variety of applications in consumer electronics, automobiles, and medicine. MEMS sensors, like the accelerometer that orients your smartphone screen vertically or horizontally, gather information from their surroundings by converting movement or chemical signals into electrical signals. MEMS actuators, which may focus your next smartphone's camera, work in the other direction, executing commands by converting electrical signals into movement.

Both types of MEMS depend on micro- and nano-sized components, such as membranes, either to measure or produce the necessary movement.

For years, MEMS membranes, like other MEMS components, were primarily fabricated from silicon using a set of processes borrowed from the semiconductor industry. TAU's new printing process, published in Microelectronic Engineering and presented at the AVS 59th International Symposium in Tampa, FL, yields rubbery, paper-thin membranes made of a particular kind of organic polymer. This material has specific properties that make it attractive for micro- and nano-scale sensors and actuators. More importantly, the polymer membranes are more suitable for implantation in the human body than their silicon counterparts, which partially stems from the fact that they are hundreds of times more flexible than conventional materials.

The unique properties of the polymer membranes have unlocked unprecedented possibilities. Their flexibility could help make MEMS sensors more sensitive and MEMS motors more energy efficient. They could be key to better cameras and smartphones with a longer battery life.

Giving patients a hand

But the printing process may deliver the biggest jolt to the field of medicine, where polymer membranes could be used in devices like diagnostic tests and smart prosthetics. There are already bionic limbs that can respond to stimuli from an amputee's nervous system and the external environment, and prosthetic bladders that regulate urination for people paralyzed below the waist. Switching to MEMS made with the polymer membranes could help make such prosthetics more comfortable, efficient, and safer for use on or inside the body.

"The use of new, soft materials in micro devices stretches both the imagination and the limits of technology," Engel says, "but introducing polymer MEMS to industry can only be realized with the development of printing technologies that allow for low cost mass production. The team's new polymer membranes can already be quickly and inexpensively produced."

The next step, she says, is to use the printing process to make functional sensors and actuators almost entirely out of the polymer at the micro- and nano-scales. Such flexible machines could be put to use in things like artificial muscles and screens so flexible that you can roll them up and put them in your pocket.


Eating a Big Breakfast Fights Obesity and Disease
8/5/2013

A high-calorie breakfast protects against diabetes, hypertension, and cardiovascular problems, says TAU researcher

Whether you hope to lose weight or just stay healthy, what you eat is a crucial factor. The right nutrients can not only trim your waistline, but also provide energy, improve your mood, and stave off disease. Now a Tel Aviv University researcher has found that it's not just what you eat — but when.

Metabolism is impacted by the body's circadian rhythm — the biological process that the body follows over a 24 hour cycle. So the time of day we eat can have a big impact on the way our bodies process food, says Prof. Daniela Jakubowicz of TAU's Sackler Faculty of Medicine and the Diabetes Unit at Wolfson Medical Center. In a recent study, she discovered that those who eat their largest daily meal at breakfast are far more likely to lose weight and waist line circumference than those who eat a large dinner.

And the benefits went far beyond pounds and inches. Participants who ate a larger breakfast — which included a dessert item such as a piece of chocolate cake or a cookie — also had significantly lower levels of insulin, glucose, and triglycerides throughout the day, translating into a lower risk of cardiovascular disease, diabetes, hypertension, and high cholesterol. These results, published recently in the journal Obesity, indicate that proper meal timing can make an important contribution towards managing obesity and promoting an overall healthy lifestyle.

The study was done in collaboration with Dr. Julio Wainstein of TAU and the Wolfson Medical Center and Dr. Maayan Barnea and Prof. Oren Froy at the Hebrew University of Jerusalem.

A dramatic difference

To determine the impact of meal timing on weight loss and health, Prof. Jakubowicz and her fellow researchers conducted a study in which 93 obese women were randomly assigned to one of two isocaloric groups. Each consumed a moderate-carbohydrate, moderate-fat diet totalling 1,400 calories daily for a period of 12 weeks. The first group consumed 700 calories at breakfast, 500 at lunch, and 200 at dinner. The second group ate a 200 calorie breakfast, 500 calorie lunch, and 700 calorie dinner. The 700 calorie breakfast and dinner included the same foods.

By the end of the study, participants in the "big breakfast" group had lost an average of 17.8 pounds each and three inches off their waist line, compared to a 7.3 pound and 1.4 inch loss for participants in the "big dinner" group. According to Prof. Jakubowicz, those in the big breakfast group were found to have significantly lower levels of the hunger-regulating hormone ghrelin, an indication that they were more satiated and had less desire for snacking later in the day than their counterparts in the big dinner group.

The big breakfast group also showed a more significant decrease in insulin, glucose, and triglyceride levels than those in the big dinner group. More important, they did not experience the high spikes in blood glucose levels that typically occur after a meal. Peaks in blood sugar levels are considered even more harmful than sustained high blood glucose levels, leading to high blood pressure and greater strain on the heart.

Eliminating late night snacking

These findings suggest that people should adopt a well thought-out meal schedule, in addition to proper nutrition and exercise, to optimize weight loss and general health. Eating the right foods at the wrong times can not only slow down weight loss, it can also be harmful. In their study, the researchers found that those in the big dinner group actually increased their levels of triglycerides — a type of fat found in the body — despite their weight loss, reports Prof. Jakubowicz.

Prof. Jakubowicz suggests an end to late night snacking. Mindless eating in front of the computer or television, especially in the late evening hours, is a huge contributor to the obesity epidemic, she believes. It increases not only poundage, but the risk of cardiovascular disease — making that midnight sugar rush more costly than it appears.


Cell Phones Could Increase Cancer Risk
7/29/2013

Saliva from heavy cell phone users shows increased risk factors for cancer, says a TAU researcher

Scientists have long been worried about the possible harmful effects of regular cellular phone use, but so far no study has managed to produce clear results. Currently, cell phones are classified as carcinogenic category 2b — potentially carcinogenic to humans — by the International Agency for Research on Cancer (IARC). A new Tel Aviv University study, though, may bring bad news.

To further explore the relationship between cancer rates and cell phone use, Dr. Yaniv Hamzany of Tel Aviv University's Sackler Faculty of Medicine and the Otolaryngology Head and Neck Surgery Department at the Rabin Medical Center, looked for clues in the saliva of cell phone users. Since the cell phone is placed close to the salivary gland when in use, he and his fellow researchers, including departmental colleagues Profs. Raphael Feinmesser, Thomas Shpitzer and Dr. Gideon Bahar and Prof. Rafi Nagler and Dr. Moshe Gavish of the Technion in Haifa, hypothesized that salivary content could reveal whether there was a connection to developing cancer.

Comparing heavy mobile phone users to non-users, they found that the saliva of heavy users showed indications of higher oxidative stress — a process that damages all aspects of a human cell, including DNA — through the development of toxic peroxide and free radicals. More importantly, it is considered a major risk factor for cancer.

The findings have been reported in the journal Antioxidants and Redox Signaling.

Putting stress on tissues and glands

For the study, the researchers examined the saliva content of 20 heavy-user patients, defined as speaking on their phones for a minimum of eight hours a month. Most participants speak much more, Dr. Hamzany says, as much as 30 to 40 hours a month. Their salivary content was compared to that of a control group, which consisted of deaf patients who either do not use a cell phone, or use the device exclusively for sending text messages and other non-verbal functions.

Compared to the control group, the heavy cell phone users had a significant increase in all salivary oxidative stress measurements studied.

"This suggests that there is considerable oxidative stress on the tissue and glands which are close to the cell phone when in use," he says. The damage caused by oxidative stress is linked to cellular and genetic mutations which cause the development of tumors.

Making the connection

This field of research reflects longstanding concerns about the impact of cell phone use, specifically the effects of radiofrequency non-ionizing electromagnetic radiation on human tissue located close to the ear, say the researchers. And although these results don't uncover a conclusive "cause and effect" relationship between cellular phone use and cancer, they add to the building evidence that cell phone use may be harmful in the long term, and point to a new direction for further research.

One potential avenue of future research would be to analyze a person's saliva prior to exposure to a cell phone, and then again after several intense minutes of exposure. This will allow researchers to see if there is an immediate response, such as a rise in molecules that indicate oxidative stress, Dr. Hamzany says.


Breastfeeding Could Prevent ADHD
7/22/2013

TAU research finds that breastfed children are less likely to develop ADHD later in life

We know that breastfeeding has a positive impact on child development and health — including protection against illness. Now researchers from Tel Aviv University have shown that breastfeeding could also help protect against Attention Deficit/Hyperactivity Disorder (ADHD), the most commonly diagnosed neurobehavioral disorder in children and adolescents.

Seeking to determine if the development of ADHD was associated with lower rates of breastfeeding, Dr. Aviva Mimouni-Bloch, of Tel Aviv University's Sackler Faculty of Medicine and Head of the Child Neurodevelopmental Center in Loewenstein Hospital, and her fellow researchers completed a retrospective study on the breastfeeding habits of parents of three groups of children: a group that had been diagnosed with ADHD; siblings of those diagnosed with ADHD; and a control group of children without ADHD and lacking any genetic ties to the disorder.

The researchers found a clear link between rates of breastfeeding and the likelihood of developing ADHD, even when typical risk factors were taken into consideration. Children who were bottle-fed at three months of age were found to be three times more likely to have ADHD than those who were breastfed during the same period. These results have been published in Breastfeeding Medicine.

Understanding genetics and environment

In their study, the researchers compared breastfeeding histories of children from six to 12 years of age at Schneider's Children Medical Center in Israel. The ADHD group was comprised of children that had been diagnosed at the hospital, the second group included the siblings of the ADHD patients, and the control group included children without neurobehavioral issues who had been treated at the clinics for unrelated complaints.

In addition to describing their breastfeeding habits during the first year of their child's life, parents answered a detailed questionnaire on medical and demographic data that might also have an impact on the development of ADHD, including marital status and education of the parents, problems during pregnancy such as hypertension or diabetes, birth weight of the child, and genetic links to ADHD.

Taking all risk factors into account, researchers found that children with ADHD were far less likely to be breastfed in their first year of life than the children in the other groups. At three months, only 43 percent of children in the ADHD group were breastfed compared to 69 percent of the sibling group and 73 percent of the control group. At six months, 29 percent of the ADHD group was breastfed, compared to 50 percent of the sibling group and 57 percent of the control group.

One of the unique elements of the study was the inclusion of the sibling group, says Dr. Mimouni-Bloch. Although a mother will often make the same breastfeeding choices for all her children, this is not always the case. Some children's temperaments might be more difficult than their siblings', making it hard for the mother to breastfeed, she suggests.

Added protection

While researchers do not yet know why breastfeeding has an impact on the future development of ADHD — it could be due to the breast milk itself, or the special bond formed between mother and baby during breastfeeding, for example — they believe this research shows that breastfeeding can have a protective effect against the development of the disorder, and can be counted as an additional biological advantage for breastfeeding.

Dr. Mimouni-Bloch hopes to conduct a further study on breastfeeding and ADHD, examining children who are at high risk for ADHD from birth and following up in six-month intervals until six years of age, to obtain more data on the phenomenon.


A Heart of Gold
7/17/2013

Gold nanofibers in engineered heart tissue can enhance electrical signalling, TAU researchers find

Heart tissue sustains irreparable damage in the wake of a heart attack. Because cells in the heart cannot multiply and the cardiac muscle contains few stem cells, the tissue is unable to repair itself — it becomes fibrotic and cannot contract properly.

In their search for innovative methods to restore heart function, scientists have been exploring cardiac "patches" that could be transplanted into the body to replace damaged heart tissue. Now, in his Tissue Engineering and Regenerative Medicine Laboratory, Dr. Tal Dvir and his PhD student Michal Shevach of Tel Aviv University's Department of Molecular Microbiology and Biotechnology and the Center for Nanoscience and Nanotechnology, together with their colleagues, are literally setting a gold standard in cardiac tissue engineering.

To meet one of the biggest challenges in the development of cardiac patches — ensuring that engineered tissue can mimic the heart's coordinated electrical system, which controls heartbeat and rhythm — they integrated cardiac cells with nanofibers made of gold particles to form functional engineered tissues. Their goal is to optimize electrical signalling between cells.

Gold has been found to increase the connectivity of biomaterials, explains Dr. Dvir. With the addition of the gold particles, cardiac tissues contract much faster and stronger as a whole, he reports, making them more viable for transplants. The research was recently published in the Journal of Materials Chemistry B.

Lending nature a helping hand

On their surface, heart cells contain proteins that are responsible for transferring electrical signals. But the process of tissue engineering itself leads to the loss of these proteins. And while the cells will start to produce them again naturally, says Dr. Dvir, they take time to develop — time which a patient may not have. Gold nanofibers can fill the role of electrical connectors until the cells are able to produce their own connectors once more.

New tissues are created by placing cells taken from patients or animals onto a three-dimensional scaffolding made of biomaterials — any matter or surface that interacts with biological systems — which organize the cells into the proper formation as they grow. Dr. Dvir and his team used various chemical and physical processes to integrate gold nanoparticles into their scaffolds. The cells then interacted with each other through these gold nanoparticles.

The researchers used a scanning electron microscope and various measures of electrical activity in order to observe the nanoparticles on the fibers and check conductivity. Cells placed on the gold-embedded scaffolding had significantly stronger contractions compared to those on a scaffolding without gold. Importantly, the cells contracted in unison, demonstrating effective electrical signalling between them.

A golden opportunity

Because 50 percent of heart attack victims die within five years of their initial attack, new treatment options are sorely needed. A functioning, transplantable tissue could not only save lives, but improve a patient's quality of life overall.

Having demonstrated the electrical signalling capability of these gold infused cardiac patches, Dr. Dvir will next evaluate their potential to improve function after heart attack through pre-clinical tests in the lab and, eventually, clinical trials with patients. He says that the ideal method would be to use a patient's own cells when building the new tissue, therefore avoiding the risk of rejection.


Israel Makes Dramatic Advance in Blindness Protection
7/10/2013

Lessons from Israel's healthcare system could optimize eye health around the world, says a TAU researcher

According to the World Health Organization, 80% of blindness is preventable or treatable — but it remains a severe health concern across the globe, even in industrialized countries.

Now hope is on the horizon — especially if countries are willing to emulate Israel's approach to eye health, says Prof.Michael Belkin of the Goldschleger Eye Research Institute at Tel Aviv University's Sackler Faculty of Medicine and Sheba Medical Center in a new study published in the American Journal of Ophthalmology. In the last decade, rates of preventable blindness in Israel have been cut by more than half — from 33.8 cases of blindness per 100,000 residents in 1999 to 14.8 in 2010. This improvement, found across all four main causes of avoidable blindness — age-related deterioration, glaucoma, diabetes, and cataract — is unmatched anywhere else in the world, he says.

The secret is not only the innovative methods of treatment that were added to the Israeli medical system, but their universal availability and accessibility, as well as good patient compliance with treatment regimens, including the correct use of prescribed medications.

Israel also offers community-based programs, such as dedicated diabetes clinics, which promote early prevention and timely treatment for diabetes-related complications that can lead to blindness. Prof. Belkin notes that such programs save public and private health care money in the long term.

Advancing eye care

To evaluate the effectiveness of eye health care in Israel, Prof. Belkin and his fellow researchers Alon Skaat, Angela Chetrit and Ofra Kalter-Leibovici from TAU and Sheba, conducted a statistical study measuring rates of blindness in the Israeli population over twelve years. They discovered that Israel has emerged as a world leader in preventing avoidable blindness, reducing rates by over 56%. The rates of untreatable genetic causes of blindness remained steady over the same period.

Several solutions are employed by Israel, which approaches the problem of blindness from medical, public health, and cultural perspectives. For example, age-related macular degeneration, one of the leading causes of blindness in the industrialized world, is treated with a drug therapy originally approved for colon cancer tumors. By diluting the drug to create smaller doses for the eye — an idea that originated in the United States — it is possible to provide inexpensive therapy to thousands of patients.

From the public policy standpoint, Prof. Belkin notes that the decline in blindness due to cataracts is due to a change in health care policy rather than any technical advance. Since the 1990's, patients have been able to choose their doctors privately for cataract surgery. This practically eliminated wait times for surgery and prevented the condition from growing worse over the long term.

Long term savings

Prof. Belkin believes that it's possible for any country to adopt Israel's strategies for reducing blindness. Although the initial costs can be daunting — such as the price of top-notch medications and setting up clinics — it's a worthwhile investment. Treating blindness as it develops rather than preventing it from the start is much more expensive for the healthcare system in the long term. Diabetes clinics in Israel pay for themselves in about two years' time, he says, factoring in their impact on preventing greater health concerns.

But even the most advanced and widely available treatments can't be effective if patients are not examined by an ophthalmologist and don't adhere to the treatment regimen. In Israel, an exceptionally high rate of adherence to these regimens is a major contributor to the prevention of blindness.


Newly Identified Bone Marrow Stem Cells Reveal Markers for ALS
7/9/2013

Genes could give new direction for diagnostics and therapeutics research, says a TAU researcher

Amyotrophic Lateral Sclerosis (ALS) is a devastating motor neuron disease that rapidly atrophies the muscles, leading to complete paralysis. Despite its high profile — established when it afflicted the New York Yankees' Lou Gehrig — ALS remains a disease that scientists are unable to predict, prevent, or cure.

Although several genetic ALS mutations have been identified, they only apply to a small number of cases. The ongoing challenge is to identify the mechanisms behind the non-genetic form of the disease and draw useful comparisons with the genetic forms.

Now, using samples of stem cells derived from the bone marrow of non-genetic ALS patients, Prof. Miguel Weil of Tel Aviv University's Laboratory for Neurodegenerative Diseases and Personalized Medicine in the Department of Cell Research and Immunology and his team of researchers have uncovered four different biomarkers that characterize the non-genetic form of the disease. Each sample shows similar biological abnormalities to four specific genes, and further research could reveal additional commonalities. "Because these genes and their functions are already known, they give us a specific direction for research into non-genetic ALS diagnostics and therapeutics," Prof. Weil says. His initial findings were reported in the journal Disease Markers.

Giving in to stress

Although several genetic ALS mutations have been identified, they only apply to a small number of cases. The ongoing challenge is to identify the mechanisms behind the non-genetic form of the disease and draw useful comparisons with the genetic forms.

To hunt for these biomarkers, Prof. Weil and his colleagues turned to samples of bone marrow collected from ALS patients. Though more difficult to collect than blood, bone marrow’s stem cells are easy to isolate and grow in a consistent manner. In the lab, he used these cells as cellular models for the disease. He ultimately discovered that cells from different ALS patients shared the same abnormal characteristics of four different genes that may act as biomarkers of the disease. And because the characteristics appear in tissues that are related to ALS — including in muscle, brain, and spinal cord tissues in mouse models of genetic ALS — they may well be connected to the degenerative process of the disease in humans, he believes.

Searching for the biological significance of these abnormalities, Prof. Weil put the cells under stress, applying toxins to induce the cells' defense mechanisms. Healthy cells will try to fight off threats and often prove quite resilient, but ALS cells were found to be overwhelmingly sensitive to stress, with the vast majority choosing to die rather than fight. Because this is such an ingrained response, it can be used as a feature for drug screening for the disease, he adds.

The hunt for therapeutics

Whether these biomarkers are a cause or consequence of ALS is still unknown. However, this finding remains an important step towards uncovering the mechanisms of the disease. Because these genes have already been identified, it gives scientists a clear direction for future research. In addition, these biomarkers could lead to earlier and more accurate diagnostics.

Next, Prof. Weil plans to use his lab's high-throughput screening facility — which can test thousands of compounds' effects on diseased cells every day — to search for drug candidates with the potential to affect the abnormal expression of these genes or the stress response of ALS cells. A compound that has an impact on these indicators of ALS could be meaningful for treating the disease, he says.

Prof. Weil is the director of the new Cell Screening Facility for Personalized Medicine at TAU. The facility is dedicated to finding potential drugs for rare and Jewish hereditary diseases.


Disrupting Memories Could Help Alcoholics Stay on the Wagon
7/2/2013

TAU researcher discovers that manipulating memories associated with addiction can prevent relapse

For alcoholics and other addicts who've gotten clean, avoiding a relapse is a difficult task. According to Dr. Segev Barak of Tel Aviv University's Sagol School of Neuroscience, 70-80% of alcohol and drug addicts return to their substance of choice, even a year after a successful detox. And memory, he says, has a lot to do with it.

"One of the main causes of relapse in alcoholics is memories that link objects and places connected to alcohol consumption, such as shops, liquor bottles, and of course the smell and taste of alcohol," Dr. Barak says. Now he and his fellow researchers from the University of California at San Francisco (UCSF) have discovered that by "disengaging" memories associated with alcohol, it is possible to significantly cut the recidivism rate for alcoholics. In a UCSF lab, researchers were able to identify and deactivate a brain pathway in rats linked to cravings from alcohol, ultimately preventing the animals from seeking alcohol and drinking it.

In the study, researchers offered the rats a choice between water and 40 proof (20 percent) alcohol, which the rats drank in large quantities for two months. At the same time, the researchers trained the rats to press a lever to obtain alcohol. The rats were then put through a 10-day detoxification regimen, tempting them with the smell and taste of alcohol in their food.

Scanning the brains of the rodents, they discovered that memories of alcohol consumption, often prompted by external stimuli, caused activation of mTORC1 — a protein which plays an important role in memory — in specific areas of the brain responsible for memory processing, emotional memories, and emotional symptoms related to withdrawal. The activation of this protein made relapse for the rats far more likely.

However, in rats that were given a drug called rapamycin, administered immediately after exposure to the memory cue, the pathway was deactivated and there was no relapse. The rats' drinking was suppressed until the end of the study.

Dr. Barak is now working on a behavioral treatment to find the best ways to implement memory disruption and end alcohol and drug recidivism, without the need for pharmaceutical intervention. "If we can develop an efficient treatment without the use of drugs, it would be a real revolution," he said.

For the full story on Dr. Barak's study, see the Times of Israel story:
http://www.timesofisrael.com/israeli-researcher-helps-alcoholics-stay-on-the-wagon/


Video Games an Effective Tool for Stroke Rehabilitation
6/27/2013

Video game-based therapy elicits more purposeful movement than traditional therapy, says TAU researcher

In the months following a stroke, patients undergo hours of rehabilitation to restore movement, speech, and overall functionality. But many still return home without the ability to perform daily tasks, such as dressing, cooking or driving.

Now occupational therapist Dr. Debbie Rand of Tel Aviv University's Stanley Steyer School of Health Professions at the Sackler Faculty of Medicine, has turned to common interactive video games as an affordable and effective alternative to traditional therapy. In a recent study, done in collaboration with a team from Sheba Medical Center and funded by the Marie Curie International Reintegration Grant, she found that people recovering from stroke who use video games as a therapeutic method are more physically active during rehabilitation sessions, making more movements overall than those who experience traditional motor therapy.

The results were presented at the 9th International Conference on Disability, Virtual Reality and Associated Technologies (ICDVRAT 2012).

Goal-directed movement

Interactive game consoles require players to move continuously to interact with the virtual games, Dr. Rand explains. In her study, not only did the players perform double the number of arm movements during each session compared to patients in traditional therapy, but all of their movements were purposeful or "goal-directed" and not just repetitive exercises.

When individuals plan their movements and move deliberately in order to accomplish a specific goal, it is likely to have a positive impact on brain plasticity — changes in the brain that are crucial for recovery from brain damage caused by stroke, Dr. Rand notes. Players' movements require precision and balance, and there is a cognitive benefit in that video games require strategy and planning. And because the individuals are motivated and enjoy the activity, it's more likely that they will continue the treatment regime long-term, she believes.

To test the effectiveness of interactive video games compared to traditional therapy, individuals who had experienced a stroke one to seven years before the study began were randomly assigned to one of two groups of 20 participants each — a traditional therapy group, who completed traditional rehabilitation exercises, and a video games group which played video games using Xbox Kinect, Sony PlayStation and Nintendo Wii gaming consoles. Each group received two sessions a week with occupational therapists for a period of three months.

Although both groups showed improvement in functions such as grip strength of their weaker and stronger hands and gait speed, participants in the video games group continued to improve their grip strength for three months following the intervention, while the traditional group did not.

Having fun with therapy

Beyond the physical advantages, Dr. Rand believes that video games could be an excellent alternative to traditional therapy simply because they’re more fun. In the video game group, 92 percent of participants reported enjoying the experience "extremely" or "very much," opposed to 72 percent of the traditional group. If patients are enjoying the therapy experience, it's more likely that they will adhere to the therapy regime long-term, noting that game consoles are now widely available and fairly inexpensive. Participants who were in the video game playing group reported: "It was lots of fun," "it stimulated all of my senses," and "I finished the sessions wet from sweat, which proves that I really worked hard."

The group environment also contributed to the success of the therapy, Dr. Rand says. Often, individuals with stroke are isolated and don't have a very active social life. This program allowed them to connect with people like themselves, and encourage and support one another's efforts.

In future studies, she intends to investigate whether these interactive video games will be as effective if they are used independently by patients at home to keep up activity levels — a crucial element of rehabilitation following a stroke.


Artificial Sweetener a Potential Treatment for Parkinson's Disease
6/17/2013

TAU researcher says mannitol could prevent aggregation of toxic proteins in the brain

Mannitol, a sugar alcohol produced by fungi, bacteria, and algae, is a common component of sugar-free gum and candy. The sweetener is also used in the medical field — it's approved by the FDA as a diuretic to flush out excess fluids and used during surgery as a substance that opens the blood/brain barrier to ease the passage of other drugs.

Now Profs. Ehud Gazit and Daniel Segal of Tel Aviv University's Department of Molecular Microbiology and Biotechnology and the Sagol School of Neuroscience, along with their colleague Dr. Ronit Shaltiel-Karyo and PhD candidate Moran Frenkel-Pinter, have found that mannitol also prevents clumps of the protein α-synuclein from forming in the brain — a process that is characteristic of Parkinson's disease.

These results, published in the Journal of Biological Chemistry and presented at the Drosophila Conference in Washington, DC in April, suggest that this artificial sweetener could be a novel therapy for the treatment of Parkinson's and other neurodegenerative diseases. The research was funded by a grant from the Parkinson's Disease Foundation and supported in part by the Lord Alliance Family Trust.

Seeing a significant difference

After identifying the structural characteristics that facilitate the development of clumps of α-synuclein, the researchers began to hunt for a compound that could inhibit the proteins' ability to bind together. In the lab, they found that mannitol was among the most effective agents in preventing aggregation of the protein in test tubes. The benefit of this substance is that it is already approved for use in a variety of clinical interventions, Prof. Segal says.

Next, to test the capabilities of mannitol in the living brain, the researchers turned to transgenic fruit flies engineered to carry the human gene for α-synuclein. To study fly movement, they used a test called the "climbing assay," in which the ability of flies to climb the walls of a test tube indicates their locomotive capability. In the initial experimental period, 72 percent of normal flies were able to climb up the test tube, compared to only 38 percent of the genetically-altered flies.

The researchers then added mannitol to the food of the genetically-altered flies for a period of 27 days and repeated the experiment. This time, 70 percent of the mutated flies could climb up the test tube. In addition, the researchers observed a 70 percent reduction in aggregates of α-synuclein in mutated flies that had been fed mannitol, compared to those that had not.

These findings were confirmed by a second study which measured the impact of mannitol on mice engineered to produce human α-synuclein, developed by Dr. Eliezer Masliah of the University of San Diego. After four months, the researchers found that the mice injected with mannitol also showed a dramatic reduction of α-synuclein in the brain.

Delivering therapeutic compounds to the brain

The researchers now plan to re-examine the structure of the mannitol compound and introduce modifications to optimize its effectiveness. Further experiments on animal models, including behavioral testing, whose disease development mimics more closely the development of Parkinson's in humans is needed, Prof. Segal says.

For the time being, mannitol may be used in combination with other medications that have been developed to treat Parkinson's but which have proven ineffective in breaking through the blood/brain barrier, says Prof. Segal. These medications may be able to "piggy-back" on mannitol's ability to open this barrier into the brain.

Although the results look promising, it is still not advisable for Parkinson's patients to begin ingesting mannitol in large quantities, Prof. Segal cautions. More testing must be done to determine dosages that would be both effective and safe.


A Peptide to Protect Brain Function
6/13/2013

TAU researcher develops a protein to protect and restore nerve cell communications

A structure called "the microtubule network" is a crucial part of our nervous system. It acts as a transportation system within nerve cells, carrying essential proteins and enabling cell-to-cell communications. But in neurodegenerative diseases like Alzheimer's, ALS, and Parkinson's, this network breaks down, hindering motor abilities and cognitive function.

Now Prof. Illana Gozes of Tel Aviv University's Sackler Faculty of Medicine has developed a new peptide in her lab, called NAP or Davunetide, that has the capacity to both protect and restore microtubule function. The peptide is a compound derived from the protein ADNP, which regulates more than 400 genes and is essential for brain formation, memory, and behavior.

Prof. Gozes and her team of researchers, including Dr. Yan Jouroukhin and graduate student Regin Ostritsky of TAU, observed that in animal models with microtubule damage, NAP was able to maintain or revive the transport of proteins and other materials in cells, ameliorating symptoms associated with neurodegeneration. These findings, which were reported in the journal Neurobiology of Disease, indicate that NAP could be an effective tool in fighting some of the most debilitating effects of neurodegenerative diseases.

Prof. Gozes is the director of TAU's Adams Super Center for Brain Studies and holds the Lily and Avraham Gildor Chair for the Investigation of Growth Factors.

Securing passage through the brain

In their investigation, the researchers used two different animal models with microtubule damage. The first group was made up of normal mice whose microtubule system was broken down through the use of a compound. The second group were genetically-engineered mouse models of ALS, in which the microtubule system was chronically damaged. In both groups, half the mice were given a single NAP injection, while the control half were not.

To determine the impact of NAP on nerve cell communications, the researchers administered the chemical element manganese to all animal models and tracked its movement through the brain using an MRI. In the mice treated with NAP, researchers observed that the manganese was able to travel through the brain normally — the microtubule system had been protected from damage or restored to normal use. Those mice that did not receive the peptide experienced the usual breakdown or continued dysfunction of the microtubule system.

These findings were corroborated by a subsequent study conducted in the UK, published in the journal Molecular Psychiatry, which found that NAP was able to ameliorate damage in fruit fly models of microtubule deficiency, repairing nerve cell dysfunction.

Slowing down cognitive dysfunction

NAP appears to have widespread potential in terms of neuroprotection, says Prof. Gozes, who was recently awarded the Meitner-Humblodt Research Award for her lifelong contribution to the field of brain sciences.

Previous studies on the peptide, conducted through a collaboration between Allon Therapeutics and Ramot, TAU's technology transfer arm, have shown that patients suffering from cognitive dysfunction — a precursor to Alzheimer's Disease — showed significant improvements in their cognitive scores when treated with NAP. Additional studies have also shown that NAP has a positive impact on rectifying microtubule deficiencies in schizophrenia patients.

Prof. Gozes notes that more research must be conducted to discover how to optimize the use of NAP as a treatment, including which patients can benefit most from the intervention.


Understanding the Heart's Rhythm
6/11/2013

TAU research discovers an unknown channel in the heart could illuminate unsolved cases of arrhythmia

The heart's regular rhythm is crucial to the delivery of oxygenated blood and nutrients to all the organs of the body. It is regulated by a bundle of cells called "the pacemaker," which use electrical signals to set the pace of the heart. Dysfunction in this mechanism can lead to an irregular heartbeat, known as arrhythmia, and often necessitates the implantation of an artificial pacemaker.

Previously, scientists found that many cases of inherited arrhythmias originating in the pacemaker could be attributed to functional defects in the channels responsible for the flow of sodium and calcium. Now Prof. Bernard Attali of Tel Aviv University's Sackler Faculty of Medicine and his fellow researchers have discovered a previously unidentified potassium channel in the cardiac pacemaker which helps to regulate the heartbeat. He hypothesizes that some cases of unexplained arrhythmia could be traced back to irregularities in this channel.

Developing therapies to target this potassium channel could be a significant step towards circumventing artificial pacemakers in favor of biological options, says Prof. Attali. This research has been reported in the journal PNAS.

A cellular heart model

To further investigate the workings of the biological pacemaker, Prof. Attali and his fellow researchers turned to embryonic stem cells isolated from human subjects. Once coaxed into differentiating into cardiac tissue, these cells began to beat automatically, like a small human heart.

While observing and recording the cells' electrical activity, researchers discovered the existence of a new channel in the pacemaker. Facilitating the flow of potassium from the pacemaker cells, this channel triggers the repolarization of the cells — returning the cell membrane from a "beating" to a "resting" state — and automatically renews or "restarts" the cycling of the heart.

Since discovering this channel in the embryonic heart, the researchers have shown that the channel exists in the adult heart as well. This finding deepens medicine's understanding of the heart's pacemaker function, which has been the subject of scientific research for over a century.

Screening for mutations

The next step is to conduct screening for mutations in the gene encoding the potassium channel, a process already underway at the TAU-affiliated Sheba Medical Center. "We would like to understand if there are genetic diseases linked to this channel," such as a previously unknown cause of arrhythmia, explains Prof. Attali. If a mutation is found, researchers can begin the hunt for drug compounds, which target this channel. The ultimate goal, he adds, is to be able to treat heart arrhythmias biologically by altering the properties of the pacemaker bundle, rather than relying on a man-made electric pacemaker.

One possible solution could be transplanting healthy pacemaker cells — developed from a patient's own stem cells — to replace dysfunctional cells and restore proper heart rhythm. This method would circumvent a common risk of the body rejecting a mechanical transplant.


Manipulating Memory in the Hippocampus
6/3/2013

Protein modification may help control Alzheimer's and epilepsy, TAU researchers find

In the brain, cell-to-cell communication is dependent on neurotransmitters, chemicals that aid the transfer of information between neurons. Several proteins have the ability to modify the production of these chemicals by either increasing or decreasing their amount, or promoting or preventing their secretion. One example is tomosyn, which hinders the secretion of neurotransmitters in abnormal amounts.

Dr. Boaz Barak of Tel Aviv University's Sagol School of Neuroscience, in collaboration with Prof. Uri Ashery, used a method for modifying the levels of this protein in the mouse hippocampus — the region of the brain associated with learning and memory. It had a significant impact on the brain's activity: Over-production of the protein led to a sharp decline in the ability to learn and memorize information, the researchers reported in the journal NeuroMolecular Medicine.

"This study demonstrates that it is possible to manipulate various processes and neural circuits in the brain," says Dr. Barak, a finding which may aid in the development of therapeutic procedures for epilepsy and neurodegenerative diseases such as Alzheimer's. Slowing the transmission rate of information when the brain is overactive during epileptic seizures could have a beneficial effect, and readjusting the levels of tomosyn in an Alzheimer's patient may help increase cognition and combat memory loss.

A maze of memory loss

The researchers teamed up with a laboratory at the National Institutes of Health (NIH) in Baltimore to create a virus which produces the tomosyn protein. In the lab, the virus was injected into the hippocampus region in mice. Then, in order to test the consequences, they performed a series of behavioral tests designed to measure functions like memory, cognitive ability, and motor skills.

In one experiment, called the Morris Water Maze, mice had to learn to navigate to, and remember, the location of a hidden platform placed inside a pool with opaque water. During the first five days of testing, researchers found that the test group with an over-production of tomosyn had a significant problem in learning and memorizing the location of the platform, compared to a control group that received a placebo injection. And when the platform was removed from the maze, the test group spent less time swimming around the area where the platform once was, indicating that they had no memory of its existence. In comparison, the control group of mice searched for the missing platform in its previous location for two or even three days after its removal, notes Dr. Barak.

These findings were further verified by measuring electrical activity in the brains of both the test group and the control group. In the test group, researchers found decreased levels of transmissions between neurons in the hippocampus, a physiological finding that may explain the results of the behavioral tests.

Correcting neuronal processes

In the future, Dr. Barak believes that the ability to modify proteins directly in the brain will allow for more control over brain activities and the correction of neurodegenerative processes, such as providing stricter regulation in neuronal activity for epileptic patients or stimulating neurotransmitters to help with learning and memory loss in Alzheimer's patients. Indeed, a separate study conducted by the researchers demonstrates that mouse models for Alzheimer's disease do have an over-production of tomosyn in the hippocampus region, so countering the production of this protein could have a beneficial effect.

Now Dr. Barak and Prof. Ashery are working towards a method for artificially decreasing levels of the protein, which they believe will have the opposite effect on the cognitive ability of the mice. "We hypothesize that with an under-production in tomosyn, the mice will show a marked improvement in their performance in behavioral testing," he says.


Low Doses of THC Can Halt Brain Damage
5/30/2013

Extremely low doses of marijuana's psychoactive component protect brain before and after injury, says TAU researcher

Though marijuana is a well-known recreational drug, extensive scientific research has been conducted on the therapeutic properties of marijuana in the last decade. Medical cannabis is often used by sufferers of chronic ailments, including cancer and post-traumatic stress disorder, to combat pain, insomnia, lack of appetite, and other symptoms.

Now Prof. Yosef Sarne of Tel Aviv University's Adelson Center for the Biology of Addictive Diseases at the Sackler Faculty of Medicine says that the drug has neuroprotective qualities as well. He has found that extremely low doses of THC — the psychoactive component of marijuana — protects the brain from long-term cognitive damage in the wake of injury from hypoxia (lack of oxygen), seizures, or toxic drugs. Brain damage can have consequences ranging from mild cognitive deficits to severe neurological damage.

Previous studies focused on injecting high doses of THC within a very short time frame — approximately 30 minutes — before or after injury. Prof. Sarne's current research, published in the journals Behavioural Brain Research and Experimental Brain Research, demonstrates that even extremely low doses of THC — around 1,000 to 10,000 times less than that in a conventional marijuana cigarette — administered over a wide window of 1 to 7 days before or 1 to 3 days after injury can jumpstart biochemical processes which protect brain cells and preserve cognitive function over time.

This treatment, especially in light of the long time frame for administration and the low dosage, could be applicable to many cases of brain injury and be safer over time, Prof. Sarne says.

Conditioning the brain

While performing experiments on the biology of cannabis, Prof. Sarne and his fellow researchers discovered that low doses of the drug had a big impact on cell signalling, preventing cell death and promoting growth factors. This finding led to a series of experiments designed to test the neuroprotective ability of THC in response to various brain injuries.

In the lab, the researchers injected mice with a single low dose of THC either before or after exposing them to brain trauma. A control group of mice sustained brain injury but did not receive the THC treatment. When the mice were examined 3 to 7 weeks after initial injury, recipients of the THC treatment performed better in behavioral tests measuring learning and memory. Additionally, biochemical studies showed heightened amounts of neuroprotective chemicals in the treatment group compared to the control group.

The use of THC can prevent long-term cognitive damage that results from brain injury, the researchers conclude. One explanation for this effect is pre- and post-conditioning, whereby the drug causes minute damage to the brain to build resistance and trigger protective measures in the face of much more severe injury, explains Prof. Sarne. The low dosage of THC is crucial to initiating this process without causing too much initial damage.

Preventative and long-term use

According to Prof. Sarne, there are several practical benefits to this treatment plan. Due to the long therapeutic time window, this treatment can be used not only to treat injury after the fact, but also to prevent injury that might occur in the future. For example, cardiopulmonary heart-lung machines used in open heart surgery carry the risk of interrupting the blood supply to the brain, and the drug can be delivered beforehand as a preventive measure. In addition, the low dosage makes it safe for regular use in patients at constant risk of brain injury, such as epileptics or people at a high risk of heart attack.

Prof. Sarne is now working in collaboration with Prof. Edith Hochhauser of the Rabin Medical Center to test the ability of low doses of THC to prevent damage to the heart. Preliminary results indicate that they will find the same protective phenomenon in relation to cardiac ischemia, in which the heart muscle receives insufficient blood flow.


Common Food Supplement Fights Degenerative Brain Disorders
5/21/2013

Nutritional supplement delays advancement of Parkinson's and Familial Dysautonomia, TAU researchers discover

Widely available in pharmacies and health stores, phosphatidylserine is a natural food supplement produced from beef, oysters, and soy. Proven to improve cognition and slow memory loss, it's a popular treatment for older people experiencing memory impairment. Now a team headed by Prof. Gil Ast and Dr. Ron Bochner of Tel Aviv University's Department of Human Molecular Genetics has discovered that the same supplement improves the functioning of genes involved in degenerative brain disorders, including Parkinson's disease and Familial Dysautonomia (FD).

In FD, a rare genetic disorder that impacts the nervous system and appears almost exclusively in the Ashkenazi Jewish population, a genetic mutation prevents the brain from manufacturing healthy IKAP proteins — which likely have a hand in cell migration and aiding connections between nerves — leading to the early degeneration of neurons. When the supplement was applied to cells taken from FD patients, the gene function improved and an elevation in the level of IKAP protein was observed, reports Prof. Ast. These results were replicated in a second experiment which involved administering the supplement orally to mouse populations with FD.

The findings, which have been published in the journal Human Molecular Genetics, are very encouraging, says Prof. Ast. "That we see such an effect on the brain — the most important organ in relation to this disease — shows that the supplement can pass through the blood-brain barrier even when administered orally, and accumulate in sufficient amounts in the brain."

Slowing the death of nerve cells

Already approved for use as a supplement by the FDA, phosphatidylserine contains a molecule essential for transmitting signals between nerve cells in the brain. Prof. Ast and his fellow researchers decided to test whether the same chemical, which is naturally synthesized in the body and known to boost memory capability, could impact the genetic mutation which leads to FD.

Researchers applied a supplement derived from oysters, provided by the Israeli company Enzymotec, to cells collected from FD patients. Noticing a robust effect on the gene, including a jump in the production of healthy IKAP proteins, they then tested the same supplement on mouse models of FD, engineered with the same genetic mutation that causes the disease in humans.

The mice received the supplement orally, every two days for a period of three months. Researchers then conducted extensive genetic testing to assess the results of the treatment. "We found a significant increase of the protein in all the tissues of the body," reports Prof. Ast, including an eight-fold increase in the liver and 1.5-fold increase in the brain. "While the food supplement does not manufacture new nerve cells, it probably delays the death of existing ones," he adds.

Therapeutic potential for Parkinson's

That the supplement is able to improve conditions in the brain, even when given orally, is a significant finding, notes Prof. Ast. Most medications enter the body through the blood stream, but are incapable of breaking through the barrier between the blood and the brain.

In addition, the researchers say the supplement's positive effects extend beyond the production of IKAP. Not only did phosphatidylserine impact the gene associated with FD, but it also altered the level of a total of 2400 other genes — hundreds of which have been connected to Parkinson's disease in previous studies.

The researchers believe that the supplement may have a beneficial impact on a number of degenerative diseases of the brain, concludes Prof. Ast, including a major potential for the development of new medications which would help tens of millions of people worldwide suffering from these devastating diseases.


Reversing Paralysis with a Restorative Gel
5/13/2013

TAU researchers develop implant to regenerate nerves

Some parts of the body, like the liver, can regenerate themselves after damage. But others, such as our nervous system, are considered either irreparable or slow to recover, leaving thousands with a lifetime of pain, limited mobility, or even paralysis.

Now a team of Tel Aviv University researchers, including Dr. Shimon Rochkind of TAU's Sackler Faculty of Medicine and Tel Aviv Sourasky Medical Center and Prof. Zvi Nevo of TAU's Department of Human Molecular Genetics and Biochemistry, has invented a method for repairing damaged peripheral nerves. Through a biodegradable implant in combination with a newly-developed Guiding Regeneration Gel (GRG) that increases nerve growth and healing, the functionality of a torn or damaged nerve could ultimately be restored.

This innovative project is now gaining international recognition. Its initial successes were reported recently at several renowned scientific congresses, including the World Federation of Neurological Societies and the European Neurological Society. And the therapy, already tested in animal models, is only a few years away from clinical use, says Dr. Rochkind.

Like healing in the womb

A nerve is like an electrical cable. When severed or otherwise damaged, power can no longer be transferred and the cable loses its functionality. Similarly, a damaged nerve loses the ability to transfer signals for movement and feeling through the nervous system.

But Dr. Rochkind and Prof. Nevo found a way to breach the gap. In their method, two severed ends of a damaged nerve are reconnected by implanting a soft, biodegradable tube, which serves as a bridge to help the nerve ends connect. The innovative gel which lines the inside of the tube nurtures nerve fibers' growth, encouraging the nerve to reconnect the severed ends through the tube, even in cases with massive nerve damage, Dr. Rochkind says.

The key lies in the composition of the gel, the researchers say, which has three main components: anti-oxidants, which exhibit high anti-inflammatory activities; synthetic laminin peptides, which act as a railway or track for the nerve fibers to grow along; and hyaluronic acid, commonly found in the human fetus, which serves as a buffer against drying, a major danger for most implants. These components allow the nerve to heal the way a fetus does in the womb — quickly and smoothly.

Keeping cells safe for transplant

The implant has already been tested in animal models, and the gel by itself can be used as a stand-alone product, acting as an aid to cell therapy. GRG is not only able to preserve cells, it can support their survival while being used for therapy and transplantation, says Dr. Rochkind. When grown in the gel, cells show excellent development, as well as intensive fiber growth. This could have implications for the treatment of diseases such as Parkinson's, for which researchers are actively exploring cell therapy as a potential solution.


Positive Social Support at Work Shown to Reduce Risk of Diabetes
5/9/2013

Work conditions can predict development of diabetes in otherwise healthy employees, TAU research finds

Cases of type 2 diabetes continue to rise in the US. And while the development of the disease is more commonly associated with risk factors such as obesity, high blood pressure, and physical inactivity, research has shown that stress can also have a significant impact.

Now Dr. Sharon Toker of Tel Aviv University's Faculty of Management has found that low levels of social support and high levels of stress in the workplace can accurately predict the development of diabetes over the long term — even in employees who appear to be healthy otherwise. Published in the Journal of Occupational Health Psychology, the study contributes to an ongoing body of research linking work conditions to physical and mental health.

The researchers' 3.5-year-long study of male and female employees established that work conditions had a preventative or predictive effect on the development of type 2 diabetes. Participants who reported having a high level of social support at work had a 22 percent lesser chance of developing diabetes over the course of the study. And those who described themselves as either over- or under-worked were 18 percent more likely to develop the disease. The results were controlled for various risk factors including age, family history, activity level, and body mass index.

Dr. Toker says these findings paint a grim picture, with a worrying rise in the rate of diabetes in the researchers' middle-aged study cohort, which had a mean age of 48. "You don't want to see working populations have an increasing rate of diabetes. It's costly to both employees and employers, resulting in absenteeism and triggering expensive medical insurance," she explains.

Assessing work conditions

For the study, conducted in collaboration with Prof. Arie Shirom of TAU, Dr. Galit Armon of the University of Haifa, and Dr. Samuel Melamed of the Tel Aviv Yaffo Academic College, researchers recruited 5,843 individuals who visited a health center in Tel Aviv for a routine physical examination sponsored by their employer. On these initial visits, all participants were healthy and had no indication of diabetes.

To assess whether physical and psychological strain caused by the work environment could predict the development of diabetes, Dr. Toker and her fellow researchers surveyed the participants according to an "expanded job strain model," which takes into account measures of social support, perceived workload, and perceived control over work pace and objectives.

After the initial interview and examination, the health of all participants was followed for a period of 41 months, over which time 182 participants developed diabetes, reports Dr. Toker. When these results were analyzed in relation to reported work conditions, social support emerged as a strong protective factor against the development of the disease, with supported individuals significantly less at risk for diabetes than their unsupported peers. Workload was also correlated with disease development, with employees who felt either overworked or underworked being at increased risk.

Promoting the right balance

The results highlight some of the negative effects of our changing work environment, in which employees are putting in more hours than ever before, says Dr. Toker. Beyond the hours spend in the office, technology now allows us to be constantly connected, heightening expectations that work will be completed in non-working hours, ultimately increasing workloads. This takes a heavy toll on our health, she warns.

One of the most interesting findings of the study — that a too-small workload is as harmful as a too-large workload — shows that dramatically reducing the load of a busy employee may not have the desired effect. Employees will be stressed when overloaded, but they still need to feel challenged to be satisfied in their jobs, notes Dr. Toker.

She suggests that employers focus on finding the right balance in terms of workload and take the initiative to ensure their employees receive the necessary social support, whether that includes a network of emotional support, praising good work performance, or finding ways to improve office communication.


Sniffing Out Schizophrenia
4/29/2013

Neurons in the nose could be the key to early, fast, and accurate diagnosis, says a TAU researcher

A debilitating mental illness, schizophrenia can be difficult to diagnose. Because physiological evidence confirming the disease can only be gathered from the brain during an autopsy, mental health professionals have had to rely on a battery of psychological evaluations to diagnose their patients.

Now, Dr. Noam Shomron and Prof. Ruth Navon of Tel Aviv University's Sackler Faculty of Medicine, together with PhD student Eyal Mor from Dr. Shomron's lab and Prof. Akira Sawa of Johns Hopkins Hospital in Baltimore, Maryland, have discovered a method for physical diagnosis — by collecting tissue from the nose through a simple biopsy. Surprisingly, collecting and sequencing neurons from the nose may lead to "more sure-fire" diagnostic capabilities than ever before, Dr. Shomron says.

This finding, which was reported in the journal Neurobiology of Disease, could not only lead to a more accurate diagnosis, it may also permit the crucial, early detection of the disease, giving rise to vastly improved treatment overall.

From the nose to diagnosis

Until now, biomarkers for schizophrenia had only been found in the neuron cells of the brain, which can't be collected before death. By that point it's obviously too late to do the patient any good, says Dr. Shomron. Instead, psychiatrists depend on psychological evaluations for diagnosis, including interviews with the patient and reports by family and friends.

For a solution to this diagnostic dilemma, the researchers turned to the olfactory system, which includes neurons located on the upper part of the inner nose. Researchers at Johns Hopkins University collected samples of olfactory neurons from patients diagnosed with schizophrenia and a control group of non-affected individuals, then sent them to Dr. Shomron's TAU lab.

Dr. Shomron and his fellow researchers applied a high-throughput technology to these samples, studying the microRNA of the olfactory neurons. Within these molecules, which help to regulate our genetic code, they were able to identify a microRNA which is highly elevated in those with schizophrenia, compared to individuals who do not have the disease.

"We were able to narrow down the microRNA to a differentially expressed set, and from there down to a specific microRNA which is elevated in individuals with the disease compared to healthy individuals," explains Dr. Shomron. Further research revealed that this particular microRNA controls genes associated with the generation of neurons.

In practice, material for biopsy could be collected through a quick and easy outpatient procedure, using a local anesthetic, says Dr. Shomron. And with microRNA profiling results ready in a matter of hours, this method could evolve into a relatively simple and accurate test to diagnose a very complicated illness.

Early detection, early intervention

Though there is much more to investigate, Dr. Shomron has high hopes for this diagnostic method. It's important to determine whether this alteration in microRNA expression begins before schizophrenic symptoms begin to exhibit themselves, or only after the disease fully develops, he says. If this change comes near the beginning of the timeline, it could be invaluable for early diagnostics. This would mean early intervention, better treatment, and possibly even the postponement of symptoms.

If, for example, a person has a family history of schizophrenia, this test could reveal whether they too suffer from the disease. And while such advanced warning doesn't mean a cure is on the horizon, it will help both patient and doctor identify and prepare for the challenges ahead.


Bursts of Brain Activity May Protect Against Alzheimer's Disease
4/18/2013

TAU reveals the missing link between brain patterns and Alzheimer's

Evidence indicates that the accumulation of amyloid-beta proteins, which form the plaques found in the brains of Alzheimer's patients, is critical for the development of Alzheimer's disease, which impacts 5.4 million Americans. And not just the quantity, but also the quality of amyloid-beta peptides is crucial for Alzheimer's initiation. The disease is triggered by an imbalance in two different amyloid species — in Alzheimer's patients, there is a reduction in a relative level of healthy amyloid-beta 40 compared to 42.

Now Dr. Inna Slutsky of Tel Aviv University's Sackler Faculty of Medicine and the Sagol School of Neuroscience, with postdoctoral fellow Dr. Iftach Dolev and PhD student Hilla Fogel, have uncovered two main features of the brain circuits that impact this crucial balance. The researchers have found that patterns of electrical pulses (called "spikes") in the form of high-frequency bursts and the filtering properties of synapses are crucial to the regulation of the amyloid-beta 40/42 ratio. Synapses that transfer information in spike bursts improve the amyloid-beta 40/42 ratio.

This represents a major advance in understanding that brain circuits regulate composition of amyloid-beta proteins, showing that the disease is not just driven by genetic mutations, but by physiological mechanisms as well. Their findings were recently reported in the journal Nature Neuroscience.

Tipping the balance

High-frequency bursts in the brain are critical for brain plasticity, information processing, and memory encoding. To check the connection between spike patterns and the regulation of amyloid-beta 40/42 ratio, Dr. Dolev applied electrical pulses to the hippocampus, a brain region involved in learning and memory.

When increasing the rate of single pulses at low frequencies in rat hippocampal slices, levels of both amyloid-beta 42 and 40 grew, but the 40/42 ratio remained the same. However, when the same number of pulses was distributed in high-frequency bursts, researchers discovered an increased amyloid-beta 40 production. In addition, the researchers found that only synapses optimized to transfer encoded by bursts contributed towards tipping the balance in favor of amyloid-beta 40. Further investigations conducted by Fogel revealed that the connection between spiking patterns and the type of amyloid-beta produced could revolve around a protein called presenilin. "We hypothesize that changes in the temporal patterns of spikes in the hippocampus may trigger structural changes in the presenilin, leading to early memory impairments in people with sporadic Alzheimer's," explains Dr. Slutsky.

Behind the bursts

According to Dr. Slutsky, different kinds of environmental changes and experiences — including sensory and emotional experience — can modify the properties of synapses and change the spiking patterns in the brain. Previous research has suggested that a stimulant-rich environment could be a contributing factor in preventing the development of Alzheimer's disease, much as crossword and similar puzzles appear to stimulate the brain and delay the onset of Alzheimer's. In the recent study, the researchers discovered that changes in sensory experiences also regulate synaptic properties — leading to an increase in amyloid-beta 40.

In the next stage, Dr. Slutsky and her team are aiming to manipulate activity patterns in the specific hippocampal pathways of Alzheimer's models to test if it can prevent the initiation of cognitive impairment. The ability to monitor dynamics of synaptic activity in humans would be a step forward early diagnosis of sporadic Alzheimer's.

Hila Milshtein, Yevgeny Berdichevsky, and Neta Gazit of Dr. Slutsky's lab at TAU, and Noa Lipstein and Nils Brose of the Max-Planck-Institute for Experimental Medicine in Germany, also contributed to this work.


TAU School of Public Health Hosts Second Summer Institute in Collaboration with Johns Hopkins University
4/15/2013

Israeli-US initiative advances international perspective on public health

From July 7 to 26, 2013, Tel Aviv University's School of Public Health at the Sackler Faculty of Medicine will host the second annual Summer Institute of Advanced Epidemiology and Preventative Medicine in collaboration with Johns Hopkins University's Bloomberg School of Public Health. The program comprises five advanced level courses open to students and professionals in the health care field, as well as others interested in developing advanced skills in Epidemiology and Preventive Medicine and gaining insight into Israel's health system and unique public health challenges.

"The Summer Institute of Advanced Epidemiology and Preventative Medicine, open to students from abroad and inside the country, will address topics of global importance," says Prof. Dani Cohen, Director of TAU's School of Public Health and one of the co-directors of the program along with Prof. Tamy Shohat of TAU and Prof. Jonathan Zenilman of Johns Hopkins University. "It's a rare opportunity to take advanced courses while experiencing this unique country and all the benefits that Tel Aviv has to offer."

Some of the topics on this year's calendar include food security and public health, the development and evaluation of vaccines, and cardiovascular epidemiology. The institute offers a limited number of dormitory rooms to the program's international participants. Registration and other information on the program can be found at http://international.tau.ac.il/prospective-students/summer-programs/summer-eapm.html.

A shared vision

Featuring instructors from universities and research institutions in the United States, Europe, and Israel, the Summer Institute represents the vision and dedication of leading experts in the field of public health. This summer's lecturers will be donating their time to a program — and a country — that they believe in, says Prof. Cohen. The institute is the result of many years of co-operation between TAU researchers and their colleagues in the international arena. "With these interactions, you can truly build special programs," he notes.

Last year, more than 80 Israeli and international students participated in TAU's Summer Institute program, which is based on the Johns Hopkins Bloomberg School of Public Health summer institute initiative. This year, Prof. Cohen predicts that new and exciting course offerings will draw an even higher number. "Faculty and researchers from University of Maryland, University of British Colombia, Emory University, Pasteur Institute, other academic institutions and the World Health Organization will be joining TAU and Johns Hopkins researchers," he says. Among the faculty from Johns Hopkins who will teach at TAU this summer are Prof. Moyses Szklo, Director of the Graduate Summer Institute of Epidemiology and Biostatistics and Prof. Lawrence Appel, Director of the Welch Center for Prevention, Epidemiology and Clinical Research.

Breaking boundaries with public health

The Summer Institute represents the next step in the growth of TAU's School of Public Health, which has been gaining in international recognition and prestige since first opening its doors seven years ago. The Summer Institute of Advanced Epidemiology and Preventative Medicine is the second international program run by the school, joining the International Masters in Public Health in Emergency and Disaster Management program, which also draws students from all over the world.

The organizers are seeking funding for scholarships to support participation of students from all over the world including developing countries. The School of Public Health has long worked to break down boundaries through improving public health in the Middle East, and is part of the Middle East Consortium for Infectious Disease Surveillance, which brings together academic and health organizations in Israel, Jordan, and the Palestinian Authority.


Sustained Stress Heightens Risk of Miscarriage
4/8/2013

TAU researcher finds a 59% increased risk of miscarriage for women living under rocket fire

Several studies have examined the impact of stress on a pregnancy — both chronic stress, such as workload, and acute stress associated with traumatic events like the 9/11 terrorist attacks. They conclude that stress can lead to adverse birth outcomes, including miscarriage and premature birth.

Few studies, however, assess the impact of continuous military or political stress throughout a pregnancy, says Prof. Liat Lerner-Geva of Tel Aviv University's Sackler Faculty of Medicine and the Women and Children's Health Research Unit at The Gertner Institute for Epidemiology and Health Policy Research Ltd, Tel Hashomer. Now her new study, conducted with PhD student Tamar Wainstock and Prof. Ilana Shoham-Vardi of Ben Gurion University, Prof. Eyal Anteby of the Barzilai Medical Center, and Saralee Glasser of Gertner Institute, Tel Hashomer, reveals that living under these sustained stresses significantly increases the risk of miscarriage.

Following the pregnancies of women from the Israeli town of Sderot, which is constantly under threat of rocket bombings from Gaza, and women from nearby Kiryat Gat, which is outside of Gaza's rocket range, the researchers demonstrated that those living under rocket fire were 59 percent more likely to miscarry than their neighbors.

These results, published in the Psychosomatic Medicine Journal of Biobehavioural Medicine, should be a call-to-action for practitioners, advises Prof. Lerner-Geva, who suggests making intervention readily available to pregnant women in stressful and threatening situations.

Studying stress under fire

Sderot has been a constant target of rocket fire from the Gaza Strip since 2001. Rocket attacks are preceded by an alarm warning residents to take shelter. The alarms themselves are loud, sudden, and themselves stress-inducing — once they sound, Sderot residents have only seconds before the rocket hits. Between 2001 and 2008, more than 1,000 alarms were sounded in the vicinity of Sderot. Since 2001, rockets exploding in the town have killed at least 13 residents, wounded dozens, and caused extensive property damage.

To study the impact of such sustained stress on pregnancy, researchers turned to the medical records at Barzilai Medical Center, a hospital which serves both Sderot and Kiryat Gat. They followed the pregnancies of 1,345 women from Sderot who were exposed to alarms and subsequent rocket fire, and 2,143 residents of Kiryat Gat who live out of missile range. The medical records were then cross-referenced to local municipal databases that track the number and location of rocket attacks.

In the unexposed group in Kiryat Gat, miscarriage rates were 4.7 percent, which accords with predictions from existing medical research literature. In the exposed group in Sderot, however, 6.9 percent of women miscarried — a statistically significant increase. The results were controlled for other risk factors for miscarriage, such as age and other medical conditions.

Within the exposed group, the researchers also analyzed the intensity of exposure. Not every neighborhood in Sderot was subject to the same number of attacks, notes Prof. Lerner-Geva, and the researchers originally hypothesized that women in higher stress areas would have a higher probability of miscarriage. However, the results indicate that women in both high-intensity and low-intensity areas were at the same risk. One explanation is that the constant fear of attack is as stressful as the attacks themselves, she concludes.

Prevention through intervention

One advantage that healthcare providers have in dealing with populations under constant threat is that they can make use of early intervention, says Prof. Lerner-Geva. "Most of the Sderot pregnant women receive prenatal care through community health clinics. This presents an opportunity to run preventive interventions to reduce stress or even provide one-on-one counseling."

Currently, she and her fellow researchers are conducting further studies on the same population to determine whether sustained stress had an impact on other negative birth outcomes, such as preterm delivery or low birth weights.


President Obama Puts Much-Needed Money Where the Brain Is
4/4/2013

TAU researcher says that BRAIN Initiative is a welcome step forward

When US President Barack Obama announced a $100 million brain mapping initiative this week, he said that the new project will attempt to "crack the code" of what causes degenerative neurological diseases. Prof. Rivka Inzelberg, a leading neurologist at Tel Aviv University's Sackler Faculty of Medicine, told US News & World Report that she welcomed the funding and the attention it will draw.

"A lot of money is needed because [brain mapping] is expensive," Prof. Inzelberg told the magazine. "Of course, any money invested in this area is welcome, but $100 million is not a lot of money for brain research. It's below what is really needed."

Hundreds of millions of dollars are already being spent in neurological research around the world. The National Institutes of Health, which will receive at least $40 million of the initial funds, already spends $5.5 billion annually on neurosciences, according to the report.

Prof. Inzelberg is a member of TAU's Adams Super Center for Brain Studies. The Center brings together lead scientists to spearhead a multidisciplinary approach to brain research, with participants from TAU's faculties of medicine, engineering, life sciences, and the humanities, among others. Its studies and teaching are aimed at deciphering the secrets of the mind and the brain and finding new approaches to the treatment of devastating neurological diseases.

Prof. Inzelberg says incremental advances have been made in neurology over the past few years, notably in her field of Alzheimer's research. This research is increasingly necessary, she says — the number of people with Alzheimer's disease is expected to triple by 2050. "It's a problem with major implications. We'll not only have the cost of treating these people, but it'll also be a burden for the generation of people who will have to take care of them."

For the full story, see the US News & World Report article:
http://www.usnews.com/news/articles/2013/04/02/obamas-100-million-brain-initiative-barely-makes-a-dent-in-neuroresearch-budget

For more about Tel Aviv University's Adams Super Center for Brain Studies, see the Center's Web site:
http://www.brain.tau.ac.il/


New Relief for Gynecological Disorders
4/3/2013

TAU researchers discover injectable protein to reverse symptoms of dangerous conditions

The creation of new blood vessels in the body, called "angiogenesis," is usually discussed in connection with healing wounds and tumors. But it's also an ongoing process in the female reproductive tract, where the growth and breaking of blood vessels is a normal part of the menstrual cycle. But abnormal growth of blood vessels can have painful consequences and resultant pathologies.

Now, Prof. Ruth Shalgi and research associate Dr. Dana Chuderland of Tel Aviv University's Sackler Faculty of Medicine have found a potential treatment for this abnormal growth in a potent physiological anti-angiogentic factor, PEDF. Administered by simple injection, this protein reverses the symptoms of related diseases without compromising fertility, according to pre-clinical studies.

These new findings, which have been reported in the Journal of Clinical Endocrinology and Metabolism, Human Reproduction, and Molecular Human Reproduction, could provide relief for millions of women worldwide. This work was done in collaboration with Prof. Rafael Ron-El and Dr. Ido Ben-Ami from Assaf Harofeh Hospital.

Dangers of angiogenesis

There are two primary pathologies associated with angiogenesis in the female reproductive system. One is endometriosis, characterized by the passage of uterine cells to other locations in the body during menstruation, which causes severe pain and reduced fertility. The other is ovarian hyperstimulation syndrome (OHSS), a possible side effect of IVF treatments. This is a potentially life-threatening disease with symptoms including abdominal pain and swelling.

Approximately 170 million women suffer from endometriosis worldwide, and about 10 percent of women receiving IVF treatment develop OHSS. Because no treatment currently exists for either of these conditions, affected women have no choice but to suffer through the symptoms.

In the past few decades, scientists have conducted extensive research on both pro-angiogenic factors such as VEGF and anti-angiogenic factors including PEDF. The effect of PEDF in decreasing abnormal angiogenesis has been extensively investigated in the eye and in tumors. Prof. Shalgi and Dr. Chuderland hypothesized that the same protein could play a role in diseases of the female reproductive system related to blood vessels growth.

In both OHSS and endometriosis, rampant VEGF levels allow for the abnormal vascularization that characterises both diseases. To counteract this effect and restore a healthy angiogenic balance in the reproductive system, the researchers turned to PEDF as a replacement therapy agent. In the lab, Prof. Shalgi and Dr. Chuderland developed mouse models of both endometriosis and OHSS. After preparing the PEDF protein, they injected the mice with it.

The researchers noted a "perfect reversal" of all symptoms, including reduced abdominal swelling in OHSS-induced mice and eradicated lesions in endometriosis. When evaluating whether this protein might affect fertility, they confirmed that PEDF had no negative impact on ovulation or pregnancy rate. In fact, it increased the number of ovulated eggs in the endometriosis model, suggesting improved fertility.

Easing the pain

The next step is to commercialize the protein for therapeutic use, say the researchers, who were the first to prove that this anti-angiogenic protein is active in the reproductive system. This discovery has been patent protected and is currently undergoing commercialization by Ramot, the technology transfer company of TAU (www.ramot.org).

There are currently no treatment options for women suffering from these diseases, explains Dr. Chunderland, who believes that endometriosis, in particular, is under-diagnosed and usually dismissed as severe menstrual pain. This new treatment could bring long-awaited relief from painful and seemingly uncontrollable symptoms, including severe abdominal pain and infertility issues.

Endometriosis has a negative impact on eggs' quality; 30 percent of women with this disease require fertility treatments in order to conceive, say the researchers. Women who develop OHSS have a lower chance of conception and a higher chance of miscarriage during their IVF treatment cycles. If these diseases could be eradicated, it would ease the sometimes difficult road towards conception, they suggest.


Job Burnout Can Severely Compromise Heart Health
3/12/2013

Top 20% of burnt-out employees have a dramatically increased risk of heart disease, TAU researcher finds

Americans work longer hours, take fewer vacation days, and retire later than employees in other industrialized countries around the globe. With such demanding careers, it's no surprise that many experience job burnout — physical, cognitive, and emotional exhaustion that results from stress at work. Researchers have found that burnout is also associated with obesity, insomnia, and anxiety.

Now Dr. Sharon Toker of Tel Aviv University's Faculty of Management and her fellow researchers — Profs. Samuel Melamed, Shlomo Berliner, David Zeltser and Itzhak Shpira of TAU's Sackler Faculty of Medicine — have found a link between job burnout and coronary heart disease (CHD), the buildup of plaque in the coronary arteries that leads to angina or heart attacks.

Those who were identified as being in the top 20 percent of the burnout scale were found to have a 79 percent increased risk of coronary disease, the researchers reported in the journal Psychosomatic Medicine. Calling the results "alarming," Dr. Toker says that these findings were more extreme than the researchers had expected — and make burnout a stronger predictor of CHD than many other classical risk factors, including smoking, blood lipid levels, and physical activity.

Taking a toll on the heart

Some of the factors that contribute to burnout are common experiences in the workplace, including high stress, heavy workload, a lack of control over job situations, a lack of emotional support, and long work hours. This leads to physical wear and tear, which will eventually weaken the body.

Knowing that burnout has been associated with other cardiovascular risk factors, such as heightened amounts of cholesterol or fat in the bloodstream, the researchers hypothesized that it could also be a risk factor for coronary heart disease.  Over the course of the study, a total of 8,838 apparently healthy employed men and women between the ages of 19 and 67 who presented for routine health examinations were followed for an average of 3.4 years. Each participant was measured for burnout levels and examined for signs of CHD. The researchers controlled for typical risk factors for the disease, such as sex, age, family history of heart disease, and smoking.

During the follow-up period, 93 new cases of CHD were identified. Burnout was associated with a 40% increased risk of developing CHD. But the 20% of participants with the highest burnout scores had a 79% increased risk. Dr. Toker predicts that with a more extended follow-up period, the results would be even more dramatic.

Avoiding long-term damage

These results are valuable for preventative medicine, says Dr. Toker. Healthcare providers who know that their patients are experiencing burnout can closely monitor for signs of coronary heart disease as well.

Once burnout begins to develop, it sparks a downwards spiral and ultimately becomes a chronic condition, she warns. Employers need to prioritize prevention by promoting healthy and supportive work environments and keeping watch for early warning signs of the condition. Simple diagnostic questionnaires that identify burnout are already available online. Workers can contribute to prevention by making healthy lifestyle choices, such as exercising more regularly, getting seven to eight hours sleep per night, and seeking psychological therapy if required.


Study Finds Fat and Bone Mass Are Genetically Linked
3/11/2013

Obesity and osteoporosis should not be treated separately, TAU researcher counsels

When it comes to body shape, diet and exercise can only take us so far. Our body shape and geometry are largely determined by genetic factors. Genetics also have an impact on our body composition — including soft fat tissue and hard bone tissue — and can lead to excess fat or osteoporosis.

Now Prof. Gregory Livshits of Tel Aviv University's Department of Anatomy and Anthropology at the Sackler Faculty of Medicine, working alongside Dr. Michael Korostishevsky, has uncovered a clear genetic link between fat and bone mass. These factors, which contribute to bone metabolism, also affect Body Mass Index (BMI), which often serves as an indicator of overall health.

Reported in the journal Bone, this finding is a step towards understanding how these tissues are inter-related on a biological level, and will help doctors develop better treatment plans for patients dealing with fat or bone related pathologies. "When a patient is prescribed a medication, it is always important to know the potential side effects," says Prof. Livshits. As a result of this genetic connection, "a medication that is prescribed to treat obesity might have a negative impact on skeletal health," he says.

Connections forged in fat and bone

Previous studies revealed that osteocalcin, a protein produced by bone cells, has an impact not only on bone but also on fat tissue metabolism. The protein's function is associated with bone formation and bone mineralization. But recent data suggest that osteocalcin is also involved in the regulation of glucose and fat metabolism and that osteocalcin levels are lower in obese and overweight individuals. Prof. Livshits and Dr. Korostishevsky set out to determine the underlying mechanism of this osteocalcin link — whether it was purely environmental or had a genetic basis.

The researchers conducted their study on a European population called the Chuvasha — descendants of Bulgarian tribes that have lived along the Volga River for more than a thousand years. As a relatively isolated and ethnically homogeneous population, they are highly appropriate for the study of genetic effects. 1,112 participants over the age of 20 hailing from a total of 230 families were tested for variants in the osteocalcin gene. Genetic information was analyzed in connection with measurements that reflect body mass, including BMI, thickness of skin folds, reflecting the amount of fat beneath the skin and others.

"We discovered a statistically significant association between osteocalcin gene variants and measures of body mass, suggesting the involvement of this gene in body mass regulation," says Prof. Livshits. To check the reliability of their findings, they asked researchers at Tulane University in Louisiana to test the same association between genetic variants of the osteocalcin gene and body mass measurements in an extensive sample of 2,244 Americans of European background. The results revealed a very similar pattern.

Balancing treatment

Because the connection between fat and bone mass has been shown to be genetic rather than environmental, related issues can't be addressed separately, Prof. Livshits says. Bisphosphonates, for example, are effective agents for the treatment of bone mineral density loss and are therefore commonly used to treat osteoporosis. However, it is also important to know how this therapy impacts fat tissue. "After a few years of treatment that improves the bones, we don't want to discover that we have harmed the fat tissue in the process," he adds.

In parallel studies, the researchers are also investigating the FTO (fat mass and obesity-associated) gene, which has been shown to impact fat and lean body mass and is suspected to impact bone mineral density too. Their future research will explore the extent to which osteocalcin, FTO, and several other genes impact muscle mass in addition to fat and bone mass. It is important to understand the extent to which these genes contribute to interdependence of all major body composition components, says Prof. Livshits.


Star-Shaped Glial Cells Act as the Brain's "Motherboard"
3/6/2013

New framework for brain communications offers insight into brain disease, says TAU researcher

The transistors and wires that power our electronic devices need to be mounted on a base material known as a "motherboard." Our human brain is not so different — neurons, the cells that transmit electrical and chemical signals, are connected to one another through synapses, similar to transistors and wires, and they need a base material too.

But the cells serving that function in the brain may have other functions as well. PhD student Maurizio De Pittà of Tel Aviv University's Schools of Physics and Astronomy and Electrical Engineering says that astrocytes, the star-shaped glial cells that are predominant in the brain, not only control the flow of information between neurons but also connect different neuronal circuits in various regions of the brain.

Using models designed to mimic brain signalling, De Pittà's research, led by his TAU supervisor Prof. Eshel Ben-Jacob, determined that astrocytes are actually "smart" in addition to practical. They integrate all the different messages being transferred through the neurons and multiplexing them to the brain's circuitry. Published in the journal Frontiers in Computational Neuroscience and sponsored by the Italy-Israel Joint Neuroscience Lab, this research introduces a new framework for making sense of brain communications — aiding our understanding of the diseases and disorders that impact the brain.

Transcending boundaries

"Many pathologies are related to malfunctions in brain connectivity," explains Prof. Ben-Jacob, citing epilepsy as one example. "Diagnosis and the development of therapies rely on understanding the network of the brain and the source of undesirable activity."

Connectivity in the brain has traditionally been defined as point-to-point connections between neurons, facilitated by synapses. Astrocytes serve a protective function by encasing neurons and forming borders between different areas of the brain. These cells also transfer information more slowly, says Prof. Ben-Jacob — one-tenth of a second compared to one-thousandth of a second in neurons — producing signals that carry larger amounts of information over longer distances. Aastrocytes can transfer information regionally or spread it to different areas throughout the brain — connecting neurons in a different manner than conventional synapses.

De Pittà and his fellow researchers developed computational models to look at the different aspects of brain signalling, such as neural network electrical activity and signal transfer by synapses. In the course of their research, they discovered that astrocytes actually take an active role in the way these signals are distributed, confirming theories put forth by leading experimental scientists.

Astrocytes form additional networks to those of the neurons and synapses, operating simultaneously to co-ordinate information from different regions of the brain — much like an electrical motherboard functions in a computer, or a conductor ensuring that the entire orchestra is working in harmony, explains De Pittà.

These findings should encourage neuroscientists to think beyond neuron-based networks and adopt a more holistic view of the brain, he suggests, noting that the two communication systems are actually interconnected, and the breakdown of one can certainly impact the other. And what may seem like damage in one small area could actually be carried to larger regions.

A break in communication

According to Prof. Ben-Jacob, a full understanding of the way the brain sends messages is significant beyond satisfying pure scientific curiosity. Many diseases and disorders are caused by an irregularity in the brain's communication system or by damage to the glial cells, so more precise information on how the network functions can help scientists identify the cause or location of a breakdown and develop treatments to overcome the damage.

In the case of epilepsy, for example, the networks frequently become overexcited. Alzheimer's disease and other memory disorders are characterized by a loss of cell-to-cell connection. Further understanding brain connectivity can greatly aid research into these and other brain-based pathologies.

To read the article, see:
http://www.frontiersin.org/computational_neuroscience/10.3389/fncom.2012.00098/abstract

To learn more about De Pittà's research, visit his home page:
https://sites.google.com/site/mauriziodepitta/home


Walking Away from Back Pain
3/5/2013

Home aerobic program as effective as clinical therapy in treating lower back pain, finds TAU researcher

Lower back pain is a common complaint, and treatment often requires many hours of physical therapy over multiple weekly clinic visits — a costly commitment. Now Dr. Michal Katz-Leurer of Tel Aviv University's Stanley Steyer School of Health Professions at the Sackler Faculty of Medicine says that a simple aerobic walking program is as effective in alleviating lower back pain as muscle strengthening programs that require specialized equipment in rehabilitation clinics. The program includes walking two to three times a week for a period of 20 to 40 minutes.

Dr. Katz-Leurer and her colleague Ilana Shnayderman, a graduate student at the Department of Physical Therapy and a practicing physiotherapist at Maccabi Health Care, say that their treatment option fits easily into a daily routine and allows those with back pain to be more responsible for their own health.

Their study was published in the journal Clinical Rehabilitation.

A simple solution

According to Dr. Katz-Leurer, research has shown that when people walk actively, abdominal and back muscles work in much the same way as when they complete exercises that target these areas. And unlike muscle strengthening programs, which often call for specific equipment and can involve exercises that require expert supervision, walking is a simple activity that can be done alone.

For the study, the researchers recruited 52 patients with lower back pain to participate in a randomized control trial. Through questionnaires, they were initially assessed for pain levels, feelings of disability, and avoidance of daily activities, as well as muscle and walking endurance.

Then, half of the participants completed a typical clinic-based muscle strengthening program, with two to three exercise sessions a week for six weeks. The other half completed a six-week aerobic walking program, walking two to three times weekly. Participants started with 20 minutes of walking, then progressed to 40 minutes as their endurance improved.

Results showed that both groups improved significantly in all areas of assessment, demonstrating that the walking program was "as effective as treatment that could have been received in the clinic," says Dr. Katz-Leurer.

The path to a healthier lifestyle

Dr. Katz-Leurer says that the walking program has the additional advantage of encouraging patients to follow a healthier lifestyle overall. In terms of physical fitness, those in the walking group were able to walk an average of 0.05 miles farther during a six-minute walking test at the end of the program compared to the pre-program assessments.

She also notes that that regularly active people are less likely to suffer typical aches and pains over their lifetime. Walking, a low-impact activity, also lowers blood pressure, boosts brain and immune system functioning, and reduces stress, she says.


Crowd-Sourced Funding Provides Missing Help for Rare Genetic Diseases
2/27/2013

TAU researcher heads first international branch of the Rare Genomics Institute

For the estimated 250 million people worldwide who suffer from rare diseases, there is little hope for diagnosis or treatment. Because each individual disease impacts so few people, hardly any funding is allocated to research, leaving many without medical options. The US-based non-profit organization Rare Genomics Institute (RGI) is working to address this problem by "crowd-funding" — allowing people to donate on the Internet towards genetic testing for individual children who are struggling with a rare disease.

Now, thanks to Dr. Noam Shomron of Tel Aviv University's Sackler Faculty of Medicine, RGI's vital mission has come to Israel — the first international branch of the organization. Its online home is http://raregenomics.org/world_Israel.php, and it has launched its first appeal for two Israeli children at http://raregenomics.org/donors.php.

Based at the TAU-affiliated Sourasky Medical Center and Rabin Medical Center, RGI-Israel will help families with children impacted by rare genetic diseases find support and care through advanced genetic testing. The Israeli branch is run in collaboration with three of Israel's top geneticists, Drs. Lina Basel, Shay Ben-Shachar, and Hagit Baris.

The services that the organization provides are sorely needed in Israel, says Dr. Shomron, who is the director of Israel’s RGI. Both Jewish and Arabic populations in Israel are plagued by a unique pool of genetic diseases. "There are decades of genetic puzzles in the Israeli population, and we are hoping to solve a few of them," he says, hoping that RGI-Israel will help provide the funding to support these families in need.

A community effort

A decade ago, the human genome was sequenced for the first time. The process cost over a billion dollars and took more than ten years to complete. But now a more advanced technology, deep sequencing, can sequence the entire human genome in a matter of days and at a less prohibitive cost. Dr. Shomron's TAU lab is a world leader in this field of research.

RGI's approach is straight-forward. It maintains online donation pages with pictures and personal stories of children in need of genetic testing for mutations as the first step toward treatment or a cure. Donors can then contribute to the cost of DNA testing for each individual child. "Deep sequencing costs around $1,500 per person now, and the fundraising goal for each child is less than $8,000, which is used for sequencing and confirmation of the genomes of the affected child and their relatives, depending on the family's genetic history and the genetics of the disease," says Dr. Shomron, who notes that Israeli families are already reaching out to RGI Israel for help. This allows families to avoid the difficult and expensive process of testing for mutations gene by gene.

One family, for example, has been plagued for generations by what appears to be mental retardation — but the medical cause of this condition remains a mystery. "They have been living for many years without knowing what causes this problem in their family. They don't know whether their DNA is the cause — and if it is, what mutation causes it," he says.

Once the genetic testing has been completed, RGI-Israel's doctors will meet with each family to discuss the results. And the support won't end there. The next phase is to link each family with researchers who study the genes in question, building a network of researchers and patients who work together to investigate these rare diseases. Ultimately, this process assures each patient that they are not facing their disease alone.

Family planning

For many families, simply knowing the cause of their child's disease gives a sense of relief and hope. It also helps doctors to develop better treatment plans, and in a few "miracle" cases, RGI's work has even led to a successful therapeutic management. With the very first child whose genome was sequenced, doctors discovered that he had a mutation in a haematological-related gene, says Dr. Shomron. With a stem cell related transplant, they were able to completely eradicate his disease.

Genetic knowledge can also be invaluable in terms of future family planning. Many affected parents want more children but are afraid of similar complications with subsequent births. Once the genetic mutation is identified, these couples can use IVF and advanced scanning methods such as Preimplantation Genetic Diagnosis (PGD) to ensure that their future children are healthy.

For more information on RGI-Israel or to donate, please visit the website at:
http://raregenomics.org/world_Israel.php


Backs Bear a Heavy Burden
2/21/2013

TAU research finds that heavy loads on the shoulders can cause nerve damage in the hands and fingers

Trudging from place to place with heavy weights on our backs is an everyday reality, from schoolchildren toting textbooks in backpacks to firefighters and soldiers carrying occupational gear. Muscle and skeletal damage are very real concerns. Now Tel Aviv University researchers say that nerve damage, specifically to the nerves that travel through the neck and shoulders to animate our hands and fingers, is also a serious risk.

Prof. Amit Gefen of TAU's Department of Biomedical Engineering and Prof. Yoram Epstein of TAU’s Sackler Faculty of Medicine, along with PhD student Amir Hadid and Dr. Nogah Shabshin of the Imaging Institute of the Assuta Medical Center, have determined that the pressure of heavy loads carried on the back have the potential to damage the soft tissues of the shoulder, causing microstructural damage to the nerves.

The result could be anything from simple irritation to diminished nerve capacity, ultimately limiting the muscles' ability to respond to the brain's signals, inhibiting movement of the hand and the dexterity of the fingers. In practice, this could impact functionality, reducing a worker's ability to operate machinery, compromise a soldiers' shooting response time, or limiting a child's writing or drawing capacity.

The research was published in the Journal of Applied Physiology and partially supported by a grant from TAU's Nicholas and Elizabeth Slezak Super Center for Cardiac Research and Biomedical Engineering.

Modeling impaired nerve function

Focusing their study on combat units in which soldiers must carry heavy backpacks, the researchers discovered that, in addition to complaining of discomfort or pain in their shoulders, soldiers also reported tickling sensations or numbness in the fingers.

Exploring this issue in a non-invasive manner, they used biomechanical analysis methods originally developed for investigating chronic wounds. The analyses show how mechanical loads, defined as the amount of force or deformation placed on a particular area of the body, were transferred beneath the skin to cause damage to tissue and internal organs.

Based on data collected by MRI, Profs. Gefen and Epstein developed anatomical computer models of the shoulders. These showed how pressure generated by the weight of a backpack load is distributed beneath the skin and transferred to the brachial plexus nerves. The models also account for mechanical properties, such as the stiffness of shoulder tissues and the location of blood vessels and nerves in the sensitive areas which are prone to damage.

Extensive mechanical loading was seen to have a high physiological impact. "The backpack load applies tension to these nerves," explains Prof. Gefen. He notes that the resulting damage "leads to a reduction in the conduction velocity — that is, the speed by which electrical signals are transferred through the nerves." With a delay or reduction in the amplitude or the intensity of signals, nerve communication cannot properly function, he says.

A danger to adults and children

These results apply to people from all walks of life, says Prof. Gefen. Many professions and leisure activities, such as hiking or travelling, involve carrying heavy equipment on the back. The researchers plan to extend this study in two directions: first, to study the effects of load on nerve conductivity, and second, to examine the impact of these heavy loads on a child's anatomy.

School bags are a major concern, he warns. It cannot be assumed that children's bodies react to shoulder stress in exactly the same way as adults. Differences in physiology could lead to different consequences, tolerance, and damage levels.


Medicine Gets More Personal
2/12/2013

High-content drug screening could be the key for treatment of rare Jewish diseases, says a TAU researcher

Personalized medicine — tailoring diagnostics and treatment according to individual genetics — is a rapidly growing field. Using advanced screening technologies, the dream of offering customized care to each patient is slowly becoming a reality, offering hope to sufferers of rare diseases, who are often left without medical support. But because each disease impacts only a handful of people worldwide, there is no commercial incentive for pharmaceutical companies to fund drug research and development.

Now Tel Aviv University is bridging the gap. The laboratory of Prof. Miguel Weil of TAU's Department of Cell Research and Immunology is home to a new state-of-the-art high-throughput drug screening facility which can apply thousands of drug compounds a day on diseased cells. This enhances the chance of finding a "hit" — when a compound has a positive impact on a sick cell.

The method could dramatically shorten drug development time, Prof. Weil explains, adding that a compound being tested for viability is simultaneously checked for toxicity. Considering the critical nature of many of these cases, the quicker an effective treatment can be identified, the better.

Finding a needle in a haystack

Prof. Weil was inspired to pursue this field of research after his own son Nir was born with Familial Dysautonomia (FD), a rare genetic disorder of the autonomic nervous system that is prevalent in Ashkenazi Jews. In their research and with the permission of hospital ethics committees, Prof. Weil and his team use live cells isolated from tissue samples of patients with FD and Amyotrophic Lateral Sclerosis. First, they compare the diseased cells with healthy ones to identify the biological differences, including various molecular features or markers of disease. Then, they use the drug screening facility to screen thousands of drug compounds against patient cells, searching for a compound that will affect the cellular markers of the disease.

There are two candidate groups of compounds used in screening, explains Prof. Weil. One category comprises FDA-approved drugs, which can be used for treatment not long after they are discovered to be effective at the cellular level. The other category includes libraries of unknown compounds deemed potentially viable as drug therapies due to their chemical structure.

But even when scientists have identified the genetic mutation that causes a disease, it doesn't necessarily mean that they understand why. Drug development is like searching for a needle in a haystack, Prof. Weil says. "This technology allows you to develop drugs without knowing exactly what you are aiming for, using an unbiased approach to drug screening," he explains.

Drug development for one

Rare diseases are an ideal starting point for personalized medicine development, Prof. Weil believes. Because sufferers make up such a tiny percentage of the population, a compound can be statistically beneficial – even if there are only 10 patients. "Using rare diseases as a proof-of-concept will help us to develop useful technologies for personalized medicine in cancer and other more common diseases," he says.

This research is especially critical for Jewish Ashkenazi population, which is at high risk for a total of 19 rare diseases, including FD, Tay-Sachs, and Cystic Fibrosis. One in five Ashkenazi Jews is a carrier of a disease. TAU's Cell Screening Facility for Personalized Medicine, established by the Mexican Friends of Tel Aviv University, is the first worldwide to deal with drug screening for rare Jewish diseases.

Prof. Weil and his team are currently seeking long-term funding in order to continue their lifesaving work, with the goal of establishing a workable platform for developing individualized therapies. The large range of testing that the screening facility allows will eventually help them to tweak compounds to meet a patient's specific biological needs, uncovering much needed treatment options for people like his son Nir, who too often fall by the wayside of mainstream medicine, says Prof. Weil.


A Privacy Risk in Your DNA
2/7/2013

New policies are needed to safeguard participants' identity in genetic studies, cautions TAU researcher

The growing ease of DNA sequencing has led to enormous advancements in the scientific field. Through extensive networked databases, researchers can access genetic information to gain valuable knowledge about causative and preventative factors for disease, and identify new targets for future treatments. But the wider availability of such information also has a significant downside — the risk of revealing personal information.

Researchers from Tel Aviv University and the Whitehead Institute of Biomedical Research in Cambridge, MA, have developed an algorithm that can identify last names using information gathered from the Y chromosome, which passes from father to son. This finding shows how genetic data can be used to compromise an individual's privacy, says Prof. Eran Halperin of TAU's Blavatnik School of Computer Science and Department of Molecular Microbiology and Biotechnology, who worked on the project with PhD student David Golan of TAU's Department of Statistics and Operations Research and Dr. Yaniv Ehrlich of the Whitehead Institute.

Using chromosomal data drawn from genetic databases, the researchers were able to identify the surname of one in every eight people from a sample of 911 American men. Sometimes other private information could even be discovered, including their geographic locations or the identities of their relatives. Published in the journal Science, this result should serve as a call to action for safeguards, the researchers note.

Weighing science and privacy

"Having such data is critical to scientific research, so we must look for ways to minimize the risk, including better techniques for encrypting genetic data, education for study participants and researchers, and new legislation to protect such information and prevent its misuse," Prof. Helperin says.

Although information about a person's entire genome is often available, this project sought to determine how much can be discovered about an individual using only a small amount of chromosomal data. The researchers chose to focus on the Y chromosome, which is passed down through the male lineage, because of its connection to surnames, which are commonly passed down through the male lineage as well.

Data relating to the Y chromosome of the sample of 911 American men — whose genetic information was collected through a private company — was used to search for their corresponding surnames in public databases. The researchers' algorithm was able to identify the family name of 12 percent of the participants.

Because they were only looking for near-precise matches, this is a very conservative return, notes Prof. Halperin. A broader search would reveal a short-list of possibilities that could reveal even more identities. And with some additional details that are commonly included in study databases, such as age group or geographic location, there is a much higher chance of tracing a person's identity, explains Golan. Those with rarer surnames were also easier to identify accurately than those with more common names.

Mitigating risk

While Prof. Halperin believes there are some positive applications of these findings, such as searching for lost relatives or identifying bodies in mass disasters, there are also serious security issues to consider. Even if the genomic data is originally anonymous, it can still be used to invade an individual's privacy — and that of their family as well. Insurance companies could use this genetic information to determine if you are at higher risk for a particular illness and ultimately deny coverage, suggests Golan.

Steps must be taken to ensure that identities are secure while allowing scientists to access valuable genomic information, the researchers say. As credit cards and other forms of ID are encrypted to extract required information while safeguarding personal details, researchers must find a way to publish genetic data in a way that it maintains individuals' privacy but still has scientific value. Those who publish their genomic information, or participate in such studies, should be made aware of the implications. And new legislation concerning the maintenance of private and public databases, as well as anti-genetic-discrimination laws, should be drafted, conclude Prof. Halperin and Golan.


Can Cancer Be Turned Against Itself?
2/4/2013

Immune system can use melanoma's own proteins to kill off cancer cells, TAU researchers find

Though a small group of proteins, the family called Ras controls a large number of cellular functions, including cell growth, differentiation, and survival. And because the protein has a hand in cellular division, mutated Ras, which can be detected in one-third of all tumors, contributes to many human cancers by allowing for the rapid growth of diseased cells.

Now Prof. Yoel Kloog of Tel Aviv University's Department of Neurobiology, along with Dr. Itamar Goldstein of TAU's Sackler Faculty of Medicine and the Sheba Medical Center and their students Helly Vernitsky and Dr. Oded Rechavi, has found that oncogenic Ras, which promotes cancer development, can also alert the immune system to the presence of cancer cells.

For the first time, the researchers have shown the transfer of oncogenic Ras in human cells from melanoma cells to T cells, which belong to a group of white blood cells that are part of the immune system. This transfer allows the immune cells to gather crucial intelligence on what they are fighting and develop the necessary cytokines, or signalling molecules, to kill the melanoma cells.

Prof. Kloog suggests that a drug that enhances the transfer of the oncogene from the tumor to the immune cells is a potential therapy to augment the anti-cancer immune response. This research has been published in the Journal of Immunology.

Finding the tipping point

Although they found that immune cells often exchange proteins among themselves, the discovery that melanoma cells transfer mutated Ras is an intriguing first. And it's this initial transfer that begins what the researchers call a positive feedback loop.

In the lab, researchers incubated T-cells from patients with human melanoma cells that had originated from tumors to track the process of handing-off various proteins. They uncovered a circuit that runs between the cancer and immune cells. Once the melanoma cells pass oncogenic Ras to the T-cells, the T-cells are activated and begin to produce cytokines, which enhances their capacity to kill cancer cells.

As these melanoma cells pass along the mutated Ras, the immune cells become increasingly active. Eventually, enough oncogenic material is transferred across the immune cells' threshold, causing the T-cells to act on the melanoma cells from which the oncogenic Ras was derived. Ultimately, this transfer tips the scales in favor of the immune cells, the researchers say.

Exploiting the information transfer

The next step is to develop a therapy that can enhance the transfer in patients with cancers linked to oncogenic Ras, says Prof. Kloog. And although their research has so far focused on melanoma, which is known to elicit the response of the immune system, he believes that this finding could be applicable to other types of cancers.

There is a constant balancing act between cancer cells and the immune system, says Dr. Goldstein. Under normal circumstances, the immune system will kill some cancerous cells on a daily basis. The disease becomes critical when the immune system can no longer keep cancer cells in check. Although there are many theories as to how cancer cells break free of this cycle, scientists are still attempting to discover why this occurs.

Prof. Kloog and Dr. Goldstein hope that this research leads to a better understanding of how the immune system fights tumors. "It's a part of the interaction between cancer and the immune system that is not well known," says Dr. Goldstein. "We are trying to gather more comprehensive data on all the proteins that are being passed around, and how this information impacts the immune system's response to cancer."


Discovering the Missing "LINC" to Deafness
1/28/2013

Mutation in a genetic protein prevents hearing, reports a TAU researcher

Because half of all instances of hearing loss are linked to genetic mutations, advanced gene research is an invaluable tool for uncovering causes of deafness — and one of the biggest hopes for the development of new therapies. Now Prof. Karen Avraham of the Sackler Faculty of Medicine at Tel Aviv University has discovered a significant mutation in a LINC family protein — part of the cells of the inner ear — that could lead to new treatments for hearing disorders.

Her team of researchers, including Dr. Henning Horn and Profs. Colin Stewart and Brian Burke of the Institute of Medical Biology at A*STAR in Singapore, discovered that the mutation causes chaos in a cell's anatomy. The cell nucleus, which contains our entire DNA, moves to the top of the cell rather than being anchored to the bottom, its normal place. Though this has little impact on the functioning of most of the body's cells, it's devastating for the cells responsible for hearing, explains Prof. Avraham. "The position of the nucleus is important for receiving the electrical signals that determine proper hearing," she explains. "Without the ability to receive these signals correctly, the entire cascade of hearing fails."

This discovery, recently reported in the Journal of Clinical Investigation, may be a starting point for the development of new therapies. In the meantime, the research could lead towards work on a drug that is able to mimic the mutated protein's anchoring function, and restore hearing in some cases, she suggests.

From human to lab to mouse

Prof. Avraham originally uncovered the genetic mutation while attempting to explain the cause of deafness in two families of Iraqi Jewish descent. For generations, members of these families had been suffering from hearing loss, but the medical cause remained a mystery. Using deep genetic sequencing, a technology used to sequence the entire human genome, she discovered that the hearing impaired members of both families had a mutated version of the protein Nesprin4, a part of the LINC group of proteins that links the cell's nucleus to the inner wall of the cell.

In the lab, Prof. Avraham recreated this phenomenon by engineering the mutation in single cells. With the mutation in place, Nesprin4 was not found in the area around the cell nucleus, as in healthy cells, but was spread throughout the entire cell. Investigating further, she studied lab mice that were engineered to be completely devoid of the protein.

Created in Singapore, the mice were originally engineered to study the biology of LINC proteins. The fact that they were deaf came as a complete surprise to researchers. Without this protein serving as an anchor, the cell nucleus is not located in the correct position within inner ear cells, but seems to float throughout. This causes the cells' other components to reorient as well, ultimately harming the polarity of the cells and hindering electrical signals. It's a mutation that took a heavy toll on the cells' ability to transfer sound signals, explains Prof. Avraham, rendering the mice deaf.

Given the similarity between mouse and human inner ear cells, researchers predict that the same phenomenon is occurring in human patients with a mutation in the Nesprin4 gene.

Looking for a wider impact

Prof. Avraham says that she and her collaborators are the first to reveal this mutation as a cause of deafness. "Now that we have reported it, scientists around the world can test for mutations in this gene," she notes. The mutation could indeed be a more common genetic cause of deafness in a number of populations. And because Nesprin4 belongs to a family of proteins that have been linked to other diseases, such as muscular coordination and degeneration disorders, this could prove a ripe area for further research.

At TAU, the research was supported by the National Institutes of Health — NIDCD and Israeli Center of Research Excellence, I-CORE.


It's True: Medical Cannabis Provides Dramatic Relief for Sufferers of Chronic Ailments
1/24/2013

Treatment can improve appetite, ease chronic pain, and more, say TAU researchers

Though controversial, medical cannabis has been gaining ground as a valid therapy, offering relief to suffers of diseases such as cancer, Post-Traumatic Stress Disorder, ALS and more. The substance is known to soothe severe pain, increase the appetite, and ease insomnia where other common medications fail.

In 2009, Zach Klein, a graduate of Tel Aviv University's Department of Film and Television Studies, directed the documentary Prescribed Grass. Through the process, he developed an interest in the scientific research behind medical marijuana, and now, as a specialist in policy-making surrounding medical cannabis and an MA student at TAU's Porter School of Environmental Studies, he is conducting his own research into the benefits of medical cannabis.

Using marijuana from a farm called Tikkun Olam — a reference to the Jewish concept of healing the world — Klein and his fellow researchers tested the impact of the treatment on 19 residents of the Hadarim nursing home in Israel. The results, Klein says, have been outstanding. Not only did participants experience dramatic physical results, including healthy weight gain and the reduction of pain and tremors, but Hadarim staff saw an immediate improvement in the participants' moods and communication skills. The use of chronic medications was also significantly reduced, he reports.

Klein's research team includes Dr. Dror Avisar of TAU's Hydrochemistry Laboratory at the Department of Geography and Human Environment; Prof. Naama Friedmann and Rakefet Keider of TAU's Jaime and Joan Constantiner School of Education; Dr. Yehuda Baruch of TAU's Sackler Faculty of Medicine and director of the Abarbanel Mental Health Center; and Dr. Moshe Geitzen and Inbal Sikorin of Hadarim.

Cutting down on chronic medications

Israel is a world leader in medical cannabis research, Klein says. The active ingredient in marijuana, THC, was first discovered there by Profs. Raphael Mechoulam and Yechiel Gaoni. Prof. Mechoulam is also credited for having defined the endocannabinoid system, which mimics the effects of cannabis and plays a role in appetite, pain sensation, mood and memory.

In the Hadarim nursing home, 19 patients between the ages of 69 and 101 were treated with medical cannabis in the form of powder, oil, vapor, or smoke three times daily over the course of a year for conditions such as pain, lack of appetite, and muscle spasms and tremors. Researchers and nursing home staff monitored participants for signs of improvement, as well as improvement in overall life quality, such as mood and ease in completing daily living activities.

During the study, 17 patients achieved a healthy weight, gaining or losing pounds as needed. Muscle spasms, stiffness, tremors and pain reduced significantly. Almost all patients reported an increase in sleeping hours and a decrease in nightmares and PTSD-related flashbacks.

There was a notable decline in the amount of prescribed medications taken by patients, such as antipsychotics, Parkinson's treatment, mood stabilizers, and pain relievers, Klein found, noting that these drugs have severe side effects. By the end of the study, 72 percent of participants were able to reduce their drug intake by an average of 1.7 medications a day.

Connecting cannabis and swallowing

This year, Klein is beginning a new study at Israel's Reuth Medical Center with Drs. Jean-Jacques Vatine and Aviah Gvion, in which he hopes to establish a connection between medical cannabis and improved swallowing. One of the biggest concerns with chronically ill patients is food intake, says Klein. Dysphagia, or difficulty in swallowing, can lead to a decline in nutrition and even death. He believes that cannabis, which has been found to stimulate regions of the brain associated with swallowing reflexes, will have a positive impact.

Overall, Klein believes that the healing powers of cannabis are close to miraculous, and has long supported an overhaul in governmental policy surrounding the drug. Since his film was released in 2009, the number of permits for medical cannabis in Israel has increased from 400 to 11,000. His research is about improving the quality of life, he concludes, especially for those who have no other hope.


Oxygen Chamber Can Boost Brain Repair
1/23/2013

Hyperbaric treatment has significantly resuscitated activity in damaged brains, TAU researchers find

Stroke, traumatic injury, and metabolic disorder are major causes of brain damage and permanent disabilities, including motor dysfunction, psychological disorders, memory loss, and more. Current therapy and rehab programs aim to help patients heal, but they often have limited success.

Now Dr. Shai Efrati of Tel Aviv University's Sackler Faculty of Medicine has found a way to restore a significant amount of neurological function in brain tissue thought to be chronically damaged — even years after initial injury. Theorizing that high levels of oxygen could reinvigorate dormant neurons, Dr. Efrati and his fellow researchers, including Prof. Eshel Ben-Jacob of TAU's School of Physics and Astronomy and the Sagol School of Neuroscience, recruited post-stroke patients for hyperbaric oxygen therapy (HBOT) — sessions in high pressure chambers that contain oxygen-rich air — which increases oxygen levels in the body tenfold.

Analysis of brain imaging showed significantly increased neuronal activity after a two-month period of HBOT treatment compared to control periods of non-treatment, reported Dr. Efrati in PLoS ONE. Patients experienced improvements such as a reversal of paralysis, increased sensation, and renewed use of language. These changes can make a world of difference in daily life, helping patients recover their independence and complete tasks such as bathing, cooking, climbing stairs, or reading a book.

Oxygen breathes new life into neurons

According to Dr. Efrati, there are several degrees of brain injury. Neurons impacted by metabolic dysfunction have the energy to stay alive, but not enough to fire electric signals, he explains. HBOT aims to increase the supply of energy to these cells.

The brain consumes 20 percent of the body's oxygen, but that is only enough oxygen to operate five to ten percent of neurons at any one time. The regeneration process requires much more energy. The tenfold increase in oxygen levels during HBOT treatment supplies the necessary energy for rebuilding neuronal connections and stimulating inactive neurons to facilitate the healing process, explains Dr. Efrati.

For their study, the researchers sought post stroke patients whose condition was no longer improving. To assess the potential impact of HBOT treatment, the anatomical features and functionality of the brain were evaluated using a combination of CT scans to identify necrotic tissue, and SPECT scans to determine the metabolic activity level of the neurons surrounding damaged areas.

Seventy-four participants spanning 6 to 36 months post-stroke were divided into two groups. The first treatment group received HBOT from the beginning of the study, and the second received no treatment for two months, then received a two-month period of HBOT treatment. Treatment consisted of 40 two-hour sessions five times weekly in high pressure chambers containing oxygen-rich air. The results indicate that HBOT treatment can lead to significant improvement in brain function in post stroke patients even at chronically late stages, helping neurons strengthen and build new connections in damaged regions.

A potential avenue for prevention

Although the study focuses on patients only through three years post-stroke, Dr. Efrati has seen similar improvement in patients whose brain injuries occurred up to 20 years before, belying the concept that the brain has a limited window for growth and change. "The findings challenge the leading paradigm since they demonstrate beyond any doubt that neuroplasticity can still be activated for months and years after acute brain injury, thus revealing that many aspects of the brain remain plastic into adulthood," says Prof. Ben-Jacob.

This study also "opens the gate into a new territory of treatment," adds Dr. Efrati. The researchers are currently conducting a study on the benefits of HBOT for those with traumatic brain injury. This treatment also has potential as an anti-aging therapy, applicable in other disorders such as Alzheimer's disease and vascular dementia at their early stages.

"It is now understood that many brain disorders are related to inefficient energy supply to the brain," explains Dr. Efrati. "HBOT treatment could right such metabolic abnormalities before the onset of full dementia, where there is still potential for recovery."


"Marisol's Mice" Guide Scientists to New Hope for a Rare Genetic Disorder
1/22/2013

One child's battle with Vanishing White Matter Disease inspires breakthrough research at a TAU lab

Vanishing White Matter (VWM) disease is a devastating condition that destroys the brain's white matter. This white matter protects the axons of neurons, and leads to seizures and the progressive loss of motor function, eyesight, and speech. Also known as Childhood Ataxia with Central Nervous System Hypomyelination (CACH), the disease has no cure, and victims do not typically live longer than the early teens.

It's a heartbreaking diagnosis that the O'Brien family of Boston, Massachusetts, knows well. Their daughter Marisol — "a very energetic, funny, beautiful girl who could light up a room," says her father Tom O'Brien — was diagnosed with the disease at the age of three in 2003, sparking a long journey that led to the finest Boston doctors, Lourdes, Bethesda's National Institutes of Health, and finally Tel Aviv University.

For Prof. Orna Elroy-Stein, whose lab at TAU's Department of Cell Research and Immunology is focused on research surrounding VWM disease, Marisol is a daily source of inspiration. She was first alerted to Marisol's condition through Dr. Rafi Schiffman of the National Institutes of Health, one of her research collaborators. Dr. Schiffman took some hair, skin, and blood samples from Marisol at his Maryland clinic and asked Marisol's father for permission to send them along to Prof. Elroy-Stein's lab; he agreed.

Developing "Marisol's mice"

Marisol passed away from the disease in 2008, but her DNA pattern and specific genetic mutation were the basis for Prof. Elroy-Stein's breakthrough development of the first population of laboratory mice — called "Marisol's mice" — with a VWM disease mutation. With this invaluable biological tool in place, researchers have been able to make important progress into understanding how the disease functions.

Through these mice, the researchers were able to discover that VWM disease was in essence a developmental disorder — the mutation causes delayed development of the myelin that forms after birth, they reported in the journal Brain. The researchers' most recent findings, published in the journal PLoS One, add to this understanding.

"Because of these mutations, the brain's response to physiological stress, such as fever or blunt trauma, is not normal. Following damage, the proteins can't be synthesized quickly enough to make a repair," explains Prof. Elroy-Stein, who keeps a photograph of Marisol on her desk to motivate her in this challenging research. "Every morning, she smiles at me and it keeps me going," she said.

What Marisol's mice revealed

In VWM disease, the systematic loss of the brain's myelin is due to a mutation in the translation factor eIF2B, which translates genetic information from our DNA for the use of proteins, explains Prof. Elroy-Stein. But with this mutation, the protein responsible for the production of white matter is faulty.

That's why patients with VWM disease have an impaired ability to cope with physiological stresses that damage the brain. The brain usually responds to such injuries by triggering elevated protein synthesis to make the proteins necessary for repair, says Prof. Elroy-Stein. But the mutated version of elF2B cannot keep up with such acute demand.

"As long as there is no stress, protein production rate is slower but still sufficient," Prof. Elroy-Stein says. The crisis begins when protein production is needed critically and on a large-scale. Because the developmental delay renders immediate response impossible, it leads to more severe and permanent brain damage, findings suggest.

The personal touch

Four years after Marisol's death, Tom O'Brien visited Prof. Elroy-Stein's lab, and what he found had a powerful effect. "I felt Marisol's strong presence in the lab," he said. "And then Orna took me down to where the mice were — there were thousands and thousands of them! It was amazing!

"Prof. Elroy-Stein is a very kind, wonderful person and a beautiful human being," O'Brien recalls. "There were a lot of researchers we met who were specialists and very smart. But she also understands how this research is very personal for us."

In the future, Prof. Elroy-Stein hopes that she and her team will be able to unravel one of the mysteries connected to VWM disease. Unlike patients of other genetic diseases, the severity of a VWM patient's mutation is not necessarily correlated to disease onset and deterioration. The researchers hypothesize that this could be a simple matter of timing. Myelin forms at a specific stage of development, when the brain is the most sensitive. Early trauma may impact the trajectory of the disease.

These discoveries — and the promise of future findings — are only a part of Marisol's legacy, says Prof. Elroy-Stein. "Though they weren't able to save their daughter, the O'Brien family continues to help others through their Foundation for Marisol's Journey. Their courage and unbelievable effort inspires me to continue on in this challenging research, hoping to help patients in the future. Marisol is the spirit that drives us all forward," she says.


Remembering Marisol
1/22/2013

A family tragedy inspires breakthrough research at TAU

Marisol O'Brien, the youngest of four children Patricia and Tom O'Brien of Boston adopted from Latin American countries, "could light up a room," her father remembers with a smile. But at the age of three she started to lose her ability to walk, and the O'Briens were not prepared for the devastating diagnosis of a very rare disorder that has no cure. Victims of Vanishing White Matter (VWM) disease, they were told, rarely live longer than their early teens. "It was every parent's worst nightmare," he says.

"Most families would feel that they couldn't let this happen to their child," O'Brien says, and they were no different, doing whatever was necessary to help Marisol. "We took her everywhere, even though Boston is a very strong place for medical research and has wonderful doctors. We even took her to Lourdes — a long and difficult trip for us, as you can imagine."

One Boston doctor suggested that the O'Briens contact Dr. Rafi Shiffman, a researcher with the National Institutes for Health in Bethesda, MD. "I wrote Dr. Schiffman a long email about VWM, about where Marisol was in the progression of the disease and her symptoms, and at the end I asked, 'Can I come and visit you?' He sent me a one-word reply — 'Yes.'" Although Dr. Schiffman was not able to offer much hope in 2003, he did take some hair, blood, and skin samples and asked the O'Briens if he could share them with a collaborator.

A call from Tel Aviv

A year later, Tom O'Brien was contacted by Schiffman's collaborator, Prof. Orna Elroy-Stein of Tel Aviv University's Department of Cell Research and Immunology, whose research focuses on VWM disease. In Boston for a conference, Prof. Elroy-Stein, a mother herself, sat down with O'Brien to talk about the disease.

"We talked for a number of hours about Marisol and her condition," O'Brien remembers. "Prof. Elroy-Stein had just begun to create these laboratory mice based on Marisol's very unique DNA pattern. She's a very kind, wonderful person — a beautiful human being. There are a lot of researchers you meet in this process who are specialists and very smart, but don't always have the best bedside manner."

Unfortunately, Marisol O'Brien died on December 20, 2008.

Meeting Marisol's many mice

The family continued to support Prof. Elroy-Stein's work through the nonprofit Foundation for Marisol's Journey, which they started within days of Marisol's death. But it wasn't until 2011 that O'Brien met with Prof. Elroy-Stein a second time, when he came to the Tel Aviv University campus as part of a group of Boston businessmen led by Massachusetts Gov. Deval Patrick.

"Tel Aviv University has a beautiful campus, and I visited Prof. Elroy-Stein's lab there on a beautiful sunny day," O'Brien remembers, his voice breaking slightly. "I felt Marisol's presence with me as I walked into her terrific lab, filled with kind and energetic young people. She took me down to a room where the mice were — there were thousands and thousands of them! It was amazing! She's conducting dozens of experiments with these mice, and she's on a path to truly understanding what happens with this disease."

The Foundation for Marisol's Journey remains committed to raise funds to support Prof. Elroy-Stein's research at Tel Aviv University — and Marisol's spirit continues to animate not only the O'Briens, but also all of the researchers at the TAU lab. "Marisol plays a role in our daily lives — she's done so ever since she came to us in 2000," O'Brien says. "Orna Elroy-Stein understands that. She's a superb research doctor, but she also gets the personal side — why this work is so wonderful for us."

More information about the Foundation can be found at its Web site:
http://www.marisolfoundation.org

 

 

Paging Dr. Charles Dickens!
1/16/2013

Author used literature to showcase discrimination against the disabled, says a TAU researcher

Charles Dickens' tales are filled with immortal characters — think of A Christmas Carol's Scrooge and Great Expectations' Miss Havisham. But more than whims of literary invention, his characters and plots often deal with the difficult social realities of Victorian England. His portrayal of the disabled — both in terms of medicine and the social discrimination they faced — is no exception.

"Social attitudes towards the disabled can often be traced through art, from ancient times through today," explains Prof. Avi Ohry of Tel Aviv University's Sackler Faculty of Medicine, a specialist in rehabilitation medicine and a scholar of the medical humanities. In Dickens' works, he says, readers are confronted with the stark realities of the 19th century, including poor medical care and social discrimination against the physically disabled and the mentally ill.

In a recent article for the journal Orthopedia, Traumatologia and Rehabilitacja, Prof. Ohry argues that literature was a way for Dickens to express his ideas for reform and advocate for better treatment of the disabled. Extremely influential, Dickens’ opinions may have gone a long way towards influencing social attitudes — the first step towards improved care and non-discriminatory legislation, he says.

Putting disability in a new light

During Dickens' time, disabled people were still commonly feared and seen as monstrous, explains Prof. Ohry. In the literature of the 19th century, physical deformities were often interpreted as "outward manifestations of inner depravity" or "punishment for moral failings," he says.

And while Dickens does portray some of his disabled characters in this way, such as the greedy and ruthless Smallweed in Bleak House, many of his disabled characters are uniquely sympathetic and inspirational — a surprisingly progressive attitude, considering the era’s social prejudices towards the disabled. Examples include the heart-tugging Tiny Tim from A Christmas Carol and Phil Squod, a loyal and good-hearted servant in Bleak House, both of whom are "crippled." Dickens also took care to differentiate between physical handicaps and mental disabilities or illness, another distinguishing feature of his work.

This kind of advanced thinking was shaped by Dickens' real life experiences, Prof. Ohry explains. The author's own experience of illness and poverty, especially in early adulthood, bred a lifelong interest in medical and social conditions. Deeply committed to alleviating the plight of the poor and a frequent visitor at both hospitals and asylums, Dickens maintained close friendships with some of the most notable reformers and doctors of his time.

Learning from the past

Although attitudes towards the disabled have shifted throughout the centuries, there are still lessons to be learned from Dickens' message. Today's sociologists and anthropologists who have studied reactions to disabled communities can attest that prejudice remains common, says Prof. Ohry. Ask a healthy individual to sit in a disabled person's wheelchair, for instance, and often he will refuse, as though the disability is contagious, he adds.

In many arenas, advocates for the sick and infirm are still fighting the battle for greater acceptance of those who are different. Dickens' passion for social reform and support for those in need resonates even in our modern society, he concludes.


Parkinson's Treatment Can Trigger Creativity
1/14/2013

Patients treated with dopamine-enhancing drugs are developing artistic talents, reports a TAU researcher

Parkinson's experts across the world have been reporting a remarkable phenomenon — many patients treated with drugs to increase the activity of dopamine in the brain as a therapy for motor symptoms such as tremors and muscle rigidity are developing new creative talents, including painting, sculpting, writing, and more.

Prof. Rivka Inzelberg of Tel Aviv University's Sackler Faculty of Medicine first noticed the trend in her own Sheba Medical Center clinic when the usual holiday presents from patients — typically chocolates or similar gifts — took a surprising turn. "Instead, patients starting bringing us art they had made themselves," she says.

Inspired by the discovery, Prof. Inzelberg sought out evidence of this rise in creativity in current medical literature. Bringing together case studies from around the world, she examined the details of each patient to uncover a common underlying factor — all were being treated with either synthetic precursors of dopamine or dopamine receptor agonists, which increase the amount of dopamine activity in the brain by stimulating receptors. Her report will be published in the journal Behavioral Neuroscience.

Giving in to artistic impulse

Dopamine is involved in several neurological systems, explains Prof. Inzelberg. Its main purpose is to aid in the transmission of motor commands, which is why a lack of dopamine in Parkinson's patients is associated with tremors and a difficulty in coordinating their movements.

But it's also involved in the brain's "reward system" — the satisfaction or happiness we experience from an accomplishment. This is the system which Prof. Inzelberg predicts is associated with increasing creativity. Dopamine and artistry have long been connected, she points out, citing the example of the Vincent Van Gogh, who suffered from psychosis. It's possible that his creativity was the result of this psychosis, thought to be caused by a spontaneous spiking of dopamine levels in the brain.

There are seemingly no limits to the types of artistic work for which patients develop talents, observes Prof. Inzelberg. Cases include an architect who began to draw and paint human figures after treatment, and a patient who, after treatment, became a prize-winning poet though he had never been involved in the arts before.

It's possible that these patients are expressing latent talents they never had the courage to demonstrate before, she suggests. Dopamine-inducing therapies are also connected to a loss of impulse control, and sometimes result in behaviors like excessive gambling or obsessional hobbies. An increase in artistic drive could be linked to this lowering of inhibitions, allowing patients to embrace their creativity. Some patients have even reported a connection between their artistic sensibilities and medication dose, noting that they feel they can create more freely when the dose is higher.

Therapeutic value

Prof. Inzelberg believes that such artistic expressions have promising therapeutic potential, both psychologically and physiologically. Her patients report being happier when they are busy with their art, and have noted that motor handicaps can lessen significantly. One such patient is usually wheelchair-bound or dependent on a walker, but creates intricate wooden sculptures that have been displayed in galleries. External stimuli can sometimes bypass motor issues and foster normal movement, she explains. Similar types of art therapy are already used for dementia and stroke patients to help mitigate the loss of verbal communication skills, for example.

The next step is to try to characterize those patients who become more creative through treatment through comparing them to patients who do not experience a growth in artistic output. "We want to screen patients under treatment for creativity and impulsivity to see if we can identify what is unique in those who do become more creative," says Prof. Inzelberg. She also believes that such research could provide valuable insights into creativity in healthy populations, too.


Promising Stem Cell Therapy for Children with Renal Cancer
1/2/2013

TAU researchers discover potential alternative to dangerous chemotherapy treatment

Conventional chemotherapy, which is toxic to the body, can have a particularly devastating impact on children — and even lead to secondary cancers.

Now a team of Tel Aviv University researchers, led by Prof. Benjamin Dekel of TAU's Sackler Faculty of Medicine and the head of the Pediatric Stem Cell Research Institute at Sheba Medical Center, has isolated cancer stem cells that lead to the growth of a tumor usually found in the kidneys of young children. His research may lead to an alternative therapy that circumvents such negative side effects.

A small group of cancer stem cells (CSCs) are responsible for the creation and spread of tumors. The researchers' study, published in EMBO Molecular Medicine, details the identification of CSCs in children suffering from Wilms' tumors, which are the most common form of pediatric kidney tumors and known to spread aggressively.

To specifically target these cells, the team took tissue from pediatric patients and grafted it into genetically engineered mice.  They were then able to identify the CSC's in these tumors, and, after identifying the molecules on the cells' surface, develop an antibody drug that targets one of the molecules.

"The targeted elimination of the CSCs fuelling the tumor led to shrinkage and, in some cases, the complete eradication of the tumors we induced in mice — without causing any toxic side effects," explains Prof. Dexel. He notes that this discovery may make the use of chemotherapy in pediatric renal cancer patients redundant in the very near future. The antibody is currently being tested in clinical trials with adult patients, and if approved, may also be tested on children.

For the full story on this alternative stem cell therapy, see the December 24, 2012, Ha'aretz story:
"Israeli researchers developing stem-cell therapy for children with renal cancer"


Helmsley Charitable Trust Awards $3.3 Million Matching Grant to TAU for Nanomedicine Initiative
12/19/2012

Research will design "theranostic" drugs personalized for individual cancer, cardiovascular, and inflammatory disease patients

The Leona M. and Harry B. Helmsley Charitable Trust has awarded a three-year $3,304,400 grant to the Tel Aviv University Leona M. and Harry B. Helmsley Nanotechnology Research Fund to launch research on personalized "theranostic" nanomedicines for cancer, cardiovascular, and inflammatory diseases. Theranostics, combining diagnostics and therapeutics, are a key component of the rapidly growing field of personalized medicine.

The Helmsley Charitable Trust grant provides matching funds for monies received from the government-supported Israel National Nanotechnology Initiative (INNI). In March 2012, the INNI selected Tel Aviv University from among 30 applicants to launch and lead a research consortium to work on a combined system of diagnostic and therapeutic treatments. The goal of the "Nanomedicines for Personalized Theranostics" team is to design a new class of drugs that can destroy faulty proteins and to deliver these drugs in a way that is safe for each individual patient.

Comprised of 11 laboratories, the consortium is dedicated to accelerating breakthroughs in the field of personalized medicine by developing nano-sized drug delivery systems for detection and treatment. Eight of the labs are TAU-led, with additional participation from Hebrew University Jerusalem, Bar-Ilan University and Ben Gurion University of the Negev.

Prof. Dan Peer, recruited by TAU from Harvard Medical School in 2008, initiated the project, organized the consortium, and has been appointed director of the initiative. INNI awarded him a $5.75 million grant over five years based on a Tel Aviv University commitment to provide one-to-one matching funds from its own operating budget and donor funds, for a total of $11.5 million at $2.3 million per year. Additional funds have already been secured from the National Institutes of Health and the Oakland, CA-based Kenneth Rainin Foundation.

A humanitarian partnership

President of Tel Aviv University Prof. Yossi Klafter has been personally involved in the initiative throughout. "Together, the INNI and Helmsley Charitable Trust awards put the spotlight on the pioneering work being done by Tel Aviv University scientists, and provide greater access to collaborations with similarly talented international communities. That means more progress in the very promising field of nanotechnology — and at a much faster rate."

Prof. Peer, who also heads the Laboratory of NanoMedicine at TAU, adds that "the addition of the Helmsley Charitable Trust grant puts us in a position to translate laboratory research into clinical practice within 10 years at the outside. For patients, that means minimally invasive, extremely efficient and safe nano-based delivery strategies that will specifically target diseased cells while leaving healthy cells untouched."

Prof. Peer has long been at the forefront of research in the field. His work was among the first to demonstrate systemic delivery of RNAi using targeted nanocarriers to the immune system and the first to demonstrate in vivo validation of new drug targets using RNAi in the immune system. With Prof. Rimona Margalit, he developed a nano-sized vehicle with the ability to deliver chemotherapy drugs directly into cancer cells while avoiding interaction with healthy cells — a stealth "submarine" — increasing the efficiency of chemotherapeutic treatment while reducing its side effects.

This is the first gift to Tel Aviv University from the Leona M. and Harry B. Helmsley Charitable Trust, which aspires to improve lives by supporting effective nonprofits in a variety of selected areas. Since 2008, when the Trust began its active grant-making, it has committed over $700 million to a wide range of charitable organizations.

For more information on the Leona M. and Harry B. Helmsley Charitable Trust and its programs, see
www.helmsleytrust.org

For more on the "Nanomedicines for Personalized Theranostics" consortium, see
http://www.aftau.org/site/News2?page=NewsArticle&id=17301

For more on Prof. Peer's work, see
http://www.aftau.org/site/News2?page=NewsArticle&id=8465


Speaking Skills Crucial for Hearing Impaired Children in the Classroom
12/17/2012

Intelligible speech closes the gap between hearing-impaired children and their normal-hearing peers, TAU researcher says

Current special education laws are geared towards integrating special-needs children into the general classroom environment from a young age, starting as early as preschool. Prof. Tova Most of Tel Aviv University's Jaime and Joan Constantiner School of Education and the Department of Communications Disorders at the Stanley Steyer School of Health Professions says that these laws present a unique set of challenges for children with hearing loss, and that a sense of isolation may inhibit a successful education.

While studies show that many children with hearing loss are academically comparable to their peers with normal hearing, active participation in classroom and group activities, as well as social integration, is more complex. Even with advanced sensory devices such as hearing aids and cochear implants, it can be difficult for children to pick up on all the necessary information in a busy atmosphere, leaving them with a sense that they’re being "left out" by hearing classmates.

In a study designed to explore the social competence and the perceived sense of loneliness of children with hearing loss in a regular classroom with normal hearing children, Prof. Most and her fellow researchers discovered that successful integration is dependent on a child's level of speech intelligibility. The results have been reported in the Journal of Deaf Studies and Deaf Education.

Closing the gap

Modern technology has allowed children with hearing loss to access more auditory information and develop better spoken language than ever before. And because advanced screening for hearing loss is now performed at birth, children can receive intervention from a young age. "In the regular classroom, the more they are intelligible, the more their social skills and competence rise, and it’s easier for them to make hearing friends," Prof. Most reports.

In their study, the researchers measured social competence and perceived sense of loneliness in children with hearing loss in two educational settings: individual inclusion where one child with hearing loss joined a regular classroom, and group inclusion, where a number of children with hearing loss joined a regular classroom. Sixty-four children between the ages of 4-7 participated, 22 in the individual inclusion and 42 in the group inclusion. All results were analyzed in light of the child's speech intelligibility.

Researchers discovered that individually integrated children had a higher social competence with the children with normal hearing than those in the group inclusion scenario. Speaking abilities played an important role in both groups, and had specific importance for children who were individually integrated. The poorer their speech intelligibility, the more likely they were to feel lonely in the classroom, something that the group inclusion children did not experience as part of an hearing loss enclave.

These findings suggest that development of intelligible spoken language has the power to close the gap between children with hearing loss and their hearing peers, resulting in increased social interaction, an improvement in group work, and a change in the teachers' and students' perception of the child with hearing loss, adds Prof. Most.

Meeting the needs of each child

Taking her years of research and in-field experience into account, Prof. Most says that there is an advantage to integrating children with hearing loss with hearing children, provided that their special needs are met.  Each child must be assessed on whether to be integrated individually or in a group, she counsels, noting that a "one size fits all" strategy could be harmful for some students.

"I prefer to see kids integrated into the regular school system, allowing them to be closer to home and interact with children in their neighborhood. They would then have access to broader programming and activities," she says. But if a child's spoken language and cognitive abilities indicate that a regular classroom would be difficult for him or her, pushing integration could result in failure.

Children with hearing loss, parents and specialists can aid successful integration by focusing on speech development, advises Prof. Most. And teachers can also do their part to create a more welcoming environment by creating small work groups and setting up meeting points in advance so the child won't be left out. The more children with normal hearing are exposed to those with hearing loss, the more understanding and accepting they will become, she says.


Embracing the Art of Science
12/5/2012

TAU scientists find beauty and win top prize in "genetic art" competition

The fine arts and the exact sciences may appear an unlikely pair, but creativity is a crucial element in both. Prof. Karen Avraham and PhD candidate Shaked Shivatzki of Tel Aviv University's Sackler Faculty of Medicine embraced this truth when creating Hearing and Deafness: Structure and Sequence, their winning submission to the recent American Society of Human Genetics art competition. Their work was awarded first place and graces the cover of the society's most recent journal.

Their creation uses modern techniques in genetic diagnostics. An image of a mouse cochlea, with cells stained with antibodies to denote the different types of cells and their function in the ear, makes up the background. In the foreground are DNA sequences of a gene that, when mutated, causes deafness, which symbolizes deep sequencing, an advanced technique used to reveal variances in cellular DNA or RNA.

The contest rules were simple, explains Prof. Avraham — create a piece that combines genetics and art to reveal the aesthetic beauty in scientific research. "It's very important to teach the public about science, and one of the ways to do this is to show them the beauty of the field. But a picture is worth a thousand words, and can explain scientific concepts in a clearer way," she said.

Essentially, the image is a tribute to deep sequencing, a technology used to describe the major components of the human genome, DNA. It's one of the most important tools in genetic diagnostics today, says Prof. Avraham, revolutionizing the hunt for genetic mutations. By finding the mutations responsible for human disease, scientists can diagnose disorders in a way that was impossible before. Israel has been one of the pioneering countries in the use of this technology.

Before deep sequencing, it would take a number of years and millions of dollars to sequence a genome. Now, it takes a matter of weeks, and can be done for the comparatively low cost of about $1,000. Not only does this mean greater access to genetic diagnosis, family planning, and medical management of disorders caused by genetic mutations, it also puts researchers on the right path in terms of developing therapeutic treatment.

The gene featured in the image is called Connexin 26. It is now known that mutations in this gene are the most common cause for deafness, found in about 30 percent of the hearing impaired population in Israel, says Prof. Avraham. Much of the early work in terms of diagnosing this mutation was done in Israel and at TAU, she adds. The study was supported by the National Institutes of Health NIDCD and I-CORE Gene Regulation in Complex Human Disease.


Fish Oil Helps Heal Bed Sores of the Critically Ill
12/4/2012

TAU research finds a 20-25 percent reduction in pressure ulcers with a fish oil enriched diet

Chock-full of Omega-3 fatty acids and antioxidants, fish oil can help lower blood pressure, reduce inflammation in the skin and joints, and promote healthy fetal development. Now a Tel Aviv University researcher has found that it has a positive effect on bedsores, too.

A common problem in critically ill patients, bedsores result from constant pressure on the skin and underlying tissue due to prolonged sitting or lying down. Painful and prone to infection, the pressure ulcers need to be healed, says Prof. Pierre Singer of the Sackler Faculty of Medicine. With Ph.D. candidate Miriam Theilla at the Rabin Medical Center, he designed a randomized experiment to determine the impact of dietary fish oil supplements on the bedsores of critically ill patients.

After a three week period of adding eight grams of fish oil to their patients' daily diet, the researchers found not only a significant lessening of pain and discomfort from bedsores — a 20 to 25 percent improvement, according to the Pressure Ulcer Scale for Healing — but also a more efficient immune system and a reduction to inflammation throughout the body. The results were reported in the British Journal of Nutrition and the American Journal of Critical Care.

Boosting the immune system

Inspired by the results of a previous study showing that dietary fish oil supplements for critically ill patients raised oxygen levels in body tissues, Prof. Singer and his fellow researchers sought to determine whether the supplement could also help heal bedsores, which are also formed by a lack of oxygen, reduced blood flow, and skin wetness.

To test this theory, the researchers developed a randomized study with 40 critically ill patients. Half the patients were given standard hospital diets, and the rest had a daily addition of eight grams of fish oil added in their food. After a three-week period, the patients in the fish oil group had an average of 20 to 25 percent improvement in the healing of their bedsores compared to the control group.

Beyond the size of the bedsores, the researchers also measured different immune parameters and found that the patients in the fish oil group had experienced a boost in their immune system and a reduction in swelling. "We saw a modification in the expression of a group of molecules associated with directing leukocytes, or white blood cells, in the direction of the wound, which could explain the improved healing," explains Prof. Singer. In addition, researchers noted a significant decrease in the amount of C-reactive protein in the blood, which is associated with inflammation and linked to viral and bacterial infections, rheumatic diseases, tissue injury, and necrosis.

Natural pain management?

Next, Prof. Singer and his fellow researchers plan to explore the use of fish oil as a method of natural pain management. By measuring the intensity of pain experience in post-surgical patients who have undergone either knee or hip replacements and comparing it to the amount of fish oil the patient has received, they hope to determine whether the nutrient-rich oil can also reduce their patients' suffering.


Can't Stop? Smoking Less Helps
11/19/2012

Forty-year study shows benefit from reduction, say TAU researchers

Countless studies demonstrate the virtues of complete smoking cessation, including a lowered risk of disease, increased life expectancy, and an improved quality of life. But health professionals acknowledge that quitting altogether can be a long and difficult road, and only a small percentage succeed.

Every day, doctors are confronted with patients who either cannot or will not quit, says Vicki Myers, a researcher at Tel Aviv University's Sackler Faculty of Medicine. To address this reality, Myers and her fellow researchers, Dr. Yariv Gerber and Prof. Uri Goldbourt of TAU's School of Public Health, examined survival and life expectancy rates of smokers who reduced their cigarette consumption instead of quitting entirely. Their data covered an unusually long period of over 40 years.

While quitters were found to have the biggest improvement in mortality rates — a 22 percent reduced risk of an early death, compared to smokers who maintained their smoking intensity — reducers also saw significant benefits, with a 15 percent reduced risk. These results show that smoking less is a valid risk reduction strategy, Myers says, adding that formerly heavy smokers had the most to gain from smoking reduction.

This research has been published in the American Journal of Epidemiology.

Cutting down for a longer life

To examine the impact of changes in smoking intensity over time, the researchers drew on a sub-cohort of the Israeli Ischemic Heart Disease Study, comprising a database of 4,633 Israeli working males, all smokers at baseline, with a median age of 51 at recruitment. Interviews regarding their smoking habits took place in 1963 and again in 1965, and participants' mortality status was followed for a period of up to 40 years.

During their first interview, participants were placed in categories by daily cigarette consumption — no cigarettes, 1-10 cigarettes, 11-20 cigarettes, and more than 21. In the second interview, researchers noted whether an individual had increased, maintained, reduced, or ceased smoking during the intervening two years, with "increasing" or "reducing" defined as moving up or down at least one category of cigarette consumption within this range.

Unsurprisingly, quitters were the best-off in the long term, with a 22 percent reduction in overall mortality. Those who reduced their smoking by one category or more were seen to have a 15 percent decrease in overall mortality risk and a 23% reduced risk of cardiovascular mortality. In addition, the researchers measured the participants' survival to the age of 80. Quitters saw a 33 percent increased chance of survival to 80 years of age, and reducers a 22 percent increased chance.

Myers says that their study, one of the few to take smoking reduction into account, shows that reduction is certainly better than doing nothing at all. She credits the long-term follow-up period for demonstrating the effect of smoking reduction where other studies have not, because damage done by smoking, and subsequently the recovery process, has a long timeline.

Never too late

One of the important lessons of their study, says Myers, is that it is never too late to tackle your smoking habit. Participants of this study, who were on average fifty years old when the study began, were still able to quit or reduce their smoking, and see long-term benefits from their efforts. Though reduction is a controversial policy — some health professionals believe it dilutes the message of cessation — smokers should take any steps possible to improve their long term health, she counsels.


Measuring Metabolism Can Predict the Progress of Alzheimer's with 90% Accuracy
11/7/2012

Metabolic studies could lead to new therapies, says a TAU researcher

When it comes to Alzheimer's disease, scientists usually — and understandably — look to the brain as their first center of attention. Now researchers at Tel Aviv University say that early clues regarding the progression of the disease can be found in the brain's metabolism.

In very early stages of the disease, before any symptoms appear, metabolic processes are already beginning to change in the brain, says PhD candidate Shiri Stempler of TAU's Sackler Faculty of Medicine. Working with Profs. Eytan Ruppin and Lior Wolf of TAU's Blavatnik School of Computer Science, Stempler has developed predictor models that use metabolic information to pinpoint the progression of Alzheimer's. These models were 90 percent accurate in predicting the stage of the disease.

Published in the journal Neurobiology of Aging, the research is the first step towards identifying biomarkers that may ensure better detection and analysis of the disease at an early stage, all with a simple blood test. It could also lead to novel therapies. "We hope that by studying metabolism, and the alterations to metabolism that occur in the very early stages of the disease, we can find new therapeutic strategies," adds Stempler.

Interrupting a regulated process

Metabolism describes a set of chemical reactions in cells which sustain life by controlling processes such as growth and reproduction. It is also responsible for providing energy to the body. To delve deeper into the connection between metabolism, brain functioning, and Alzheimer's disease, the researchers used data collected from the hippocampus region of the brain. Controlling memory and learning, this region of the brain is damaged as Alzheimer's progresses.

Based on the number of metabolic genes found in the neurons and surrounding tissue, they built a predictive model which relates abnormalities in these genes to the progression of the disease. Out of almost 1500 genes, the researchers were able to select 50 genes that were the most predictive of Alzheimer's, says Stempler, noting that in Alzheimer's patients these genes are either over or under expressed, meaning that there are either too many or too few.

When they compared the findings from these 50 genes among Alzheimer's patients, healthy patients, and primates (including chimpanzees and rhesus monkeys), the researchers discovered that in all but the Alzheimer's group, the number of the specific genes was tightly limited, with little difference in their number between individuals among each of the species, she explains. This implies that these genes are significant to normal brain functioning, and their strict regulation in healthy patients is compromised by Alzheimer's disease.

Exploring new pathways

Whether metabolic changes are a cause of the disease or merely a symptom remains a topic for future study. But the discovery of this connection is encouraging. "The correlation between metabolic gene expression and cognitive score in Alzheimer's patients is even higher than the correlation we see in medical literature between beta amyloid plaques – found in deposits in the brains of Alzheimer's patients — and cognitive score, pointing to a strong association between cognitive decline and an altered metabolism," Stempler says.

Next the researchers will try to identify biomarkers in the blood that are associated with these metabolic changes. They may lead to detection and information about the disease's progression with an easy and non-invasive blood test. And as their work advances, Stempler hopes to develop therapeutic strategies that are based around these alterations in the metabolic network to help Alzheimer's patients, such as medications that can re-introduce strict regulation over gene expression. They believe that the research is a promising direction for Alzheimer's research.


Nicotine Dependency Puts the Brakes on Parkinson's Development
10/22/2012

TAU researchers explain why smoking slows down Parkinson's

Over a decade ago, scientists discovered that smokers were 60 percent less likely to develop Parkinson's disease, a degenerative disorder of the central nervous system, and that this protective effect continued for 25 years even after the person stopped smoking. Now a team of Israeli researchers, including scientists at Tel Aviv University, have uncovered the genetic mechanism that protects smokers from the disease.

To understand this surprising connection, the researchers conducted genetic testing on blood samples from 677 Parkinson's patients, 438 of whom were never smokers and 239 who currently are or had been smokers. Initial results indicated a link between nicotine dependence and a protective mechanism against the disease. Studying a cluster of genes known as CHRNB5, CHRNB4 and CHRNB3, the researchers discovered that as these genes became more dependent on nicotine, they also held back the development of Parkinson's.

This discovery contributes to the understanding of the mechanism in nicotine that protects against damage to the brain chemical dopamine, which is linked to the disease. While there is no doubt that smoking is bad for your health, and researchers are not advocating smoking as a method of prevention, the finding allows for the identification of new approaches for Parkinson's therapies, such as medications that mimic the chemical impact of nicotine without the additional health risks.

This research is a collaboration between TAU, Hadassah University Hospital, the Hebrew University of Jerusalem, Beilinson Hospital and research institutes in Milan, Italy.

For the full story on the link between nicotine and Parkinson's, see the Ha'aretz story: "Israeli discovery explains why smoking slows down development of Parkinson's"


TAU Named to Spearhead Groundbreaking Nanotechnology Consortium
10/18/2012

Group of eleven laboratories to target personalized treatment for cancer, infections and heart diseases

Tel Aviv University has been appointed by the Israel National Nanotechnology Initiative (INNI) to lead a consortium on "Nanomedicines for Personalized Theranostics," a combined system of diagnostics and therapeutic treatments. This consortium of 11 laboratories will be dedicated to developing nano-sized drug delivery systems for the detection and treatment of various diseases. Eight of the labs are TAU-led, with additional participation from Hebrew University Jerusalem, Bar-Ilan University and Ben Gurion University of the Negev.

The $11.5 million project, designated a Focal Theology Area (FTA) within the INNI and scheduled to last five years, is poised to create a center of excellence in nanotechnology in Israel, says Scientific Director Prof. Dan Peer of TAU's Department of Cell Research and Immunology and Center for Nano Science and Nano Technology. The FTA will be supported by an international scientific advisory board, headed by internationally renowned Prof. Robert Langer of MIT.

The ultimate goal is to design a new class of drugs that can destroy faulty proteins in angiogenesis-dependent diseases that involve the growth of new blood vessels from existing vessels — including cancer, infectious diseases and heart diseases — and deliver these drugs safely into the body. Beyond the academic realm, the group aims to create spin-off companies based on licensed technologies they develop, creating the basis for a thriving biotechnology industry within Israel.

Building a successful industry

Although considered a beacon of research and development, the field of biotechnology in Israel has suffered drawbacks, both in academia and industry. Higher salaries lure the best minds abroad, and international companies have more private capital with which to sustain businesses.

"Israel has amazing intellectual resources, but we are constantly combating budget constraints. With this project, the idea is to create future technologies built on Israeli creativity that also allow us to bring in the brightest people and better funding," says Prof. Peer. While many great biotechnology ideas were born in Israel, the economic situation stymied the establishment of many more successful companies within the country, he observes. "We want to maintain the advantages that we have in the life sciences while boosting this lagging industry. Our research as part of the FTA will be a starting engine."

Prof. Peer hopes that in two years, researchers will be able to start translating their research into practical applications.

The INNI is also working to combat "brain drain" in the academic world by giving TAU and other institutions the means to attract outstanding young researchers back home to Israel, both with funding and with the prestige of the project. New faculty positions at TAU are already being filled, and will continue to be created as part of FTA.

A personalized theranostics approach

This research project is poised to answer a crucial need in modern medicine, advancing the fields of theranostics and personalized medicine.

The major goal of the project is to design a new class of drugs based on genomic information taken from each patient, and then use nano carriers to deliver appropriate drug therapy into specific cell types. Because each patient is biologically different, a one-size-fits-all medical solution doesn't always give the best therapeutic results. "Each person reacts differently to medications," explains Prof. Peer. "In the long term, the idea is to tailor-make not only the drug carrier, but the drug itself for a personalized approach."

For more information, visit the project’s Web site at http://nano.tau.ac.il/fta/.


RNA-Based Therapy Brings New Hope for an Incurable Blood Cancer
10/10/2012

TAU researchers develop interference therapies to knock down gene that drives Mantle Cell Lymphoma

Three thousand new cases of Mantle Cell Lymphoma (MCL), a form of blood cancer, appear in the United States each year. With a median survival span of only five to seven years, according to the Leukemia and Lymphoma Society, this disease is devastating, and new therapies are sorely needed.

One of the characteristics that defines MCL is heightened activity in the gene CCND1, which leads to the aggressive over-production of Cyclin D1, a protein that controls the proliferation of cells, explains Prof. Dan Peer of Tel Aviv University's Department of Cell Research and Immunology. In this disease, Cyclin D1 production spins out of control, producing a 3,000 to 5,000 fold increase.

Now, in an international collaboration between academia and industry, Prof. Peer has developed a new class of drugs based on RNA interference, which can repair or destroy faulty proteins and reprogram cells to act in normal ways. The drugs have the ability to kill off the mutated protein and stop the over-proliferation of cells. Their method, proven in experiments with human cells and published in the journal PLoS One, was generously supported by the Lewis Trust and the Israeli Science Foundation.

Academia and industry work for a cure

In the past, scientists have attempted and failed to knock out this protein in the quest to develop a cure for MCL. But despite the prevalent belief that Cyclin D1 is not an effective target for therapies, Prof. Peer and his fellow researchers, including his PhD student Shiri Weinstein and Dr. Rafi Emmanuel and the Sheba Medical Center's Prof. Arnon Nagler and Dr. Avigdor Abraham, knew there was cause for hope.

To prove their theory that Cyclin D1 was indeed an appropriate target for the treatment of MCL, the researchers turned to two companies considered world-experts in RNA, Alnylam Pharmaceuticals in Cambridge, Massachusetts and Integrated DNA Technologies in Iowa, both of which donated their time and resources to the project. Working in parallel, they were able to design potent RNA interference sequences to stop the production of Cyclin D1.

In MCL, Cyclin D1 is the exclusive cause of the over-production of B Lymphocytes, cells responsible for generating antibodies, explains Prof. Peer. This makes the protein a perfect target for RNA interference — because normal, healthy cells don't express the gene, therapies that destroy the gene will only attack cancer cells. The RNA interference that the researchers have developed targets the faulty Cyclin D1 within the cancerous cells. And when the cells are inhibited from proliferating, they sense they are being targeted and begin to "commit suicide," he says.

In the lab, the researchers have successfully used their RNA interference in human cells, a crucial step towards proving that Cyclin D1 can be targeted through the right interventions. "Ultimately, we want to be able to cure this disease, and I think we are on the way," says Prof. Peer. He hopes that their results might cause scientists to reconsider previous and unproductive results on the effectiveness of treating MCL by addressing aberrations of this protein.

Pairing with nano-delivery methods

The researchers are working to develop a mouse population with MCL to test their newly-developed therapies in vivo. Typically, new therapies for any disease are tested on human cells as well as mouse models in the lab before being taken to clinical trials in humans. But there has never before been a test using mice with this disease, says Prof. Peer, a deficiency that has limited the quality of research. The animal test will allow researchers to conduct a more cautious and in-depth investigation of this new class of drugs before moving to the clinical stage.

As for strategies for delivering the new therapy into the body, the researchers will make use of Prof. Peer's extensive work with nano-sized medical "submarines" which are designed to travel to the source of disease or disorder in the human body, and offload drugs inside specific cells or proteins as needed.


A Spoonful of Honey to Ease Night Time Coughing
10/5/2012

TAU researchers find honey soothes coughs in sleeping children

Researchers at Tel Aviv University have discovered a sweet remedy for children's night time coughs.

A spoonful of honey a half-hour before bedtime was found to temper the frequency and severity of a cough in small children, says Dr. Herman Avner Cohen of TAU's Sackler Faculty of Medicine in a recent study published in the journal Pediatrics.

Because many over-the-counter cough medications cannot be given to children under the age of four, safe and effective ways to soothe a small child's cough are important. And unlike medication, this natural remedy does not have any dangerous side effects.

Approximately 300 children from one through five were randomly assigned to one of four different natural cough remedies — three different kinds of honey or a sweet syrup made from dates that did not include any honey. The researchers then followed up with parents, who were asked to rate their children's cough symptoms, how well their children slept the night before the treatment, then how well their children slept the night of the honey treatment.

On average, parents rated the severity and frequency of their children's coughing and their sleep disruption a "three" or "four" on a seven-point scale without the honey. But on the night that the children took a spoonful of honey before bed, the numbers dropped by two points. For those who had received the date syrup treatment, numbers dropped by only one point. The success of this honey treatment could be related to the antioxidants commonly found in honey, especially darker varieties.

There was a bonus for parents, too: they themselves slept better thanks to their children's more peaceful slumbers, say the researchers, who recommend this treatment for children one year and older.

For the full story on how honey can ease your child's cough, see the Chicago Tribune story:

http://articles.chicagotribune.com/2012-08-05/lifestyle/sns-rt-us-honey-coughingbre87505g-20120805_1_cough-symptoms-honey-board-darker-honey


Two Bionic Ears Are Better Than the Sum of Their Parts
9/20/2012

Bilateral cochlear implants may restore binaural sound processing in the brain, says a TAU researcher

Cochlear implants — electronic devices surgically implanted in the ear to help provide a sense of sound — have been successfully used since the late 1980's. But questions remain as to whether bilateral cochlear implants, placed in each ear rather than the traditional single-ear implant, are truly able to facilitate binaural hearing. Now, Tel Aviv University researchers have proof that under certain conditions, this practice has the ability to salvage binaural sound processing for the deaf and hard-of-hearing.

According to Dr. Yael Henkin of TAU's Department of Communication Disorders at the Stanley Steyer School of Health Professions and Head of The Hearing, Speech, and Language Center at Sheba Medical Center, and her colleagues Prof. Minka Hildesheimer, Yifat Yaar-Soffer, and Lihi Givon, the brain unites incoming sound from each ear at the brainstem through what is called "binaural processing." "When we hear with both ears, we have an efficient auditory system," she explains. Binaural processing provides improved ease of listening, sound localization, and the ability to understand speech in noisy surroundings.

In their study, the researchers looked at children who had lost their hearing at a young age and were not born deaf. Those who were provided with bilateral cochlear implants exhibited true binaural processing, similar to that of their normal hearing peers. In contrast, deaf-at-birth children who received their first cochlear implant at young age and their second after long delay, did not exhibit binaural processing.

The research was recently reported in the journal Cochlear Implants International.

Pairing up

More than a matter of symmetry, our two ears function together to create a whole picture of the sound that surrounds us. The integration of information from both ears not only saves neuronal energy, it is the key to different aspects of hearing, such as locating the source of individual sounds and being able to differentiate between different sounds in a noisy room.

Dr. Henkin and her fellow researchers set out to determine if bilateral cochlear implants were able to restore some binaural processing in the brain. Their study included three groups: children who had lost their hearing as toddlers due to illness and received bilateral cochlear implants soon afterwards; children who had been born deaf and received their first implant at around the age of four and a second approximately six years later; and a control group with normal hearing.

The researchers measured the brainwave P300, associated with auditory discrimination, while participants were asked to listen for the syllables "ta" and "ka" and were told to press a button when they heard the syllable "ta". The sounds were delivered in turn to the left ear, the right ear, and both ears at once. By comparing the P300 brainwaves identified when both ears were stimulated to the sum of brainwaves identified when each ear was stimulated separately a binaural interaction component was identified.

The researchers found a binaural interaction component in participants who had not been born deaf and had received bilateral implants at a young age. This suggested that “auditory experience prior to cochlear implantation is critical for binaural processing," says Dr. Henkin. But in the children who had only one implant for many years, the researchers found no evidence of binaural processing. It appears that the auditory deprivation that results from a long delay between implants may render the system incapable of restoring itself, explain the researchers.

Synchronized technology?

This study adds to the body of literature on how brain function is impacted by both deafness and rehabilitation, says Dr. Henkin. Currently it is not possible to coordinate the operation of separate bilateral implants, but in the future these implants may be designed to synchronize with each other, providing the hearing-impaired patient with the cues required for binaural processing, she says.


Fighting Melanoma's Attraction to the Brain
9/19/2012

TAU researcher discovers homing device that draws cancer

The process of metastasis, by which cancer cells travel from a tumor site and proliferate at other sites in the body, is a serious threat to cancer patients. According to the National Cancer Institute, most recurrences of cancer are metastases rather than "new" cancers.

Virtually all types of cancer can spread to other parts of the body, including the brain. Once metastatic melanoma cells are entrenched in the brain, patients typically have only a few months to live.

Now Prof. Isaac Witz and his team at Tel Aviv University's Department of Cell Research and Immunology are delving deeper into what attracts metastatic melanoma cells to the brain, and how they survive and prosper in this environment. Their experiments have discovered that melanoma cells produce receptors for two chemokines — a family of small proteins secreted by cells — present in the brain tissue. These receptors may act as a homing device, drawing the cancerous cells to the brain.

"These interactions between the chemokines in the brain and the melanoma cell receptors could be potential targets for new therapies," Prof. Witz says. "With medications that suppress these molecules, you could hope to interfere with this specific migration." Published in the International Journal of Cancer, this research is supported by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation.

A dangerous attraction

Although metastasis is a well-understood process, researchers are still trying to uncover the underlying mechanisms of why cancer cells begin to migrate in the first place. It is also crucial to understand what allows them to sustain themselves, divide, and propagate once they have arrived at their new location.

To better understand metastacized melanoma cells in the brain, the researchers cultured brain tissue in the lab, then analyzed all of the materials that were expressed by the cells. They identified certain chemokine receptors in brain-metastasizing melanoma cells and corresponding chemokines in the brain tissue which could ultimately be responsible for the cancer cells' being "attracted" to the brain. If a certain chemokine is released from the brain, and the melanoma cells have the appropriate receptors, a chemical attraction will take place where the melanoma cells would be drawn to wherever the chemokine is.

Duplicating nature

The researchers have also developed a method to compare metastatic and non-metastatic cells with identical genetic backgrounds. Though they are derived from the same cancer, some of these cells become metastatic, while others do not. "This is a good way for us to concentrate on the genes that are specific to metastatic cells. Because we have these two types of cellular variants, where only one goes to the brain and metastasizes, it's an important tool" for future research, explains Prof. Witz.

The researchers have found that mice that are inoculated with non-metastatic cells do end up with melanoma cells in the brain, but they are dormant and do not generate overt metastasis. The key is to discover why these originally identical cells differ — why the non-metastatic cells don't develop in the same way.

Understanding the process will help scientists to "duplicate what nature does, and prevent these cells from becoming metastatic," says Prof. Witz. "If there already is metastasis, it is too late — so what we want to do is to prevent development by understanding the mechanism that keeps the non-metastatic cells dormant."


A GPS in Your DNA
8/16/2012

TAU research says genetics can reveal your geographic ancestral origin

While your DNA is unique, it also tells the tale of your family line. It carries the genetic history of your ancestors down through the generations. Now, says a Tel Aviv University researcher, it's also possible to use it as a map to your family's past.

Prof. Eran Halperin of TAU's Blavatnik School of Computer Science and Department of Molecular Microbiology and Biotechnology, along with a group of researchers from University of California, Los Angeles, are giving new meaning to the term "genetic mapping." Using a probabilistic model of genetic traits for every coordinate on the globe, the researchers have developed a method for determining more precisely the geographical location of a person's ancestral origins.

The new method is able to pinpoint more specific locations for an individual's ancestors, for example placing an individual's father in Paris and mother in Barcelona. Previous methods would "split the difference" and place this origin inaccurately at a site between those two cities, such as Lyon.

Published in the journal Nature Genetics, this method has the potential to reveal the ancestry, origins, and migration patterns of many different human and animal populations. It could also be a new model for learning about the genome.

Points of origin

There are points in the human genome called SNPs that are manifested differently in each individual, explains Prof. Halperin. These points mutated sometime in the past and the mutation was then passed to a large part of the population in a particular geographic region. The probability of a person possessing these mutations today varies depending on the geographical location of those early ancestors.

"We wanted to ask, for example, about the probability of having the genetic mutation 'A' in a particular position on the genome based on geographical coordinates," he says. When you look at many of these positions together in a bigger picture, it's possible to group populations with the same mutation by point of origin.

To test their method, Prof. Halperin and his fellow researchers studied DNA samples from 1,157 people from across Europe. Using a probabilistic mathematical algorithm based on mutations in the genome, they were able to accurately determine their ancestral point or points of origin using only DNA data and the new mathematical model, unravelling genetic information to ascertain two separate points on the map for the mother and father. The researchers hope to extend this model to identify the origins of grandparents, great-grandparents, and so on.

The new method could provide information that has applications in population genetic studies — to study a disease that impacts a particular group, for example. Researchers can track changes in different genomic traits across a map, such as the tendency for southern Europeans to have a mutation in a gene that causes lactose intolerance, a mutation missing from that gene in northern Europeans.

A closer look at migration

The researchers believe that their model could have also relevance for the animal kingdom, tracking the movement of animal populations. "In principle, you could figure out where the animals have migrated from, and as a result learn about habitat changes due to historical climate change or other factors," says Prof. Halperin.

For more information, visit the project's website at: http://genetics.cs.ucla.edu/spa/demo.html.


Launching a "Social Networking War" Against Cancer
8/14/2012

Like bacteria, cancer cells rely on communication and cooperation, says TAU research

Experts agree that, more than ever before, modern wars will be fought in the cyber zone, targeting an enemy's communications technology to cause untold damage. Now a Tel Aviv University researcher is suggesting that the same tactics should be employed in the battle against one of the body's deadliest enemies — cancer.

In an article published in Trends in Microbiology, Prof. Eshel Ben-Jacob of TAU's School of Physics and Astronomy andProf. Herbert Levine of Rice University, long-time bacteria researchers, and Prof. Donald Coffey of Johns Hopkins University, a renowned cancer researcher, examine the shared traits of cancer cells and bacteria. Like bacteria, cancer cells rely on communication and "social networking" to become powerful entities within the body. Inspired by the social and survival tactics of bacteria, the team presents a new picture of cancer as a meta-community of smart communicating cells possessing special traits for cooperative behavior.

Knowing the enemy

For many years, scientists ignored the complex social interactions of bacteria, now the number three killer in hospitals in the Western world. The researchers believe that medical professionals are similarly "underestimating the enemy" when it comes to cancer cells that exhibit many similar behaviors.

The parallels that can be drawn between the two types of cells are astounding. While healthy cells are highly disciplined, responding to chemical and physical cues telling them how to behave, bacteria and cancer cells override this control by using different chemical and genetic pathways. They proliferate quickly to make rapid genetic changes, avoiding the body's immune system and developing drug resistance.

Using intricate communication, cancer cells can distribute tasks, share resources, differentiate, and make decisions. Before sending cells to colonize organs and tissues throughout the body (metastasis), "spying cells" explore the body and return the cancer's origin. Only then do metastatic cells leave the primary tumor and navigate to new posts.

Also like bacteria, cancer cells change their own environment. They induce genetic changes and enslave surrounding normal cells, forcing them to do the disease's bidding — providing physical support, protecting them from the immune system, and more. Cancer cells can also become dormant when they sense danger, such as chemotherapy chemicals, then reactivate at will.

A new therapeutic direction

Prof. Ben-Jacob suggests that studying the social behavior of cancer cells can inspire new research directions and pave the way for the development of novel therapeutic approaches — for example, a new class of drugs to target cell-to-cell communication or send misleading messages.

With the ability to become immune to chemotherapy and lay dormant until it determines the time is right to reawaken, cancer often relapses undetected until it's too late to treat, says Prof. Levine. Breaking the communication code for awakening dormant cells could help researchers learn how to reactivate them on purpose — and be ready to kill them as soon as they "awaken."

The team also suggests further research into cancer "cannibalism," when cancer cells may consume their peers when they run out of resources. The idea is to send signals which trigger cancer cells to kill each other, which can be done with bacteria.

Other researchers have demonstrated that injected bacteria can "outsmart cancer." Bacteria can be used to induce gap junctions between the cancer cells and immune cells, "teaching" the immune system to recognize and kill the tumor cells. We might be entering a new era of biological cyber-warfare, in which scientists can enlist bacterial intelligence to defeat cancer, Prof. Ben-Jacob concludes.


What Sets Allergies in Motion?
8/2/2012

TAU research identifies a protein group that may kick-start allergic reactions

Allergies, or hypersensitivities of the immune system, are more common than ever before. According to the Asthma and Allergies Foundation of America, one in five Americans suffers from an allergy — from milder forms like hay fever to more severe instances, like peanut allergies which can lead to anaphylactic shock.

While medications like antihistamines can treat the symptoms of an allergic reaction, the treatment is too limited, says Prof. Ronit Sagi-Eisenberg, a cell biologist at Tel Aviv University's Sackler Faculty of Medicine. Cells release dozens of molecules during an allergic reaction, and available medications address only a small subset. Now she and her fellow researchers are working to identify what triggers allergic reactions in the body, with the goal of stopping an allergic reaction before it starts.

The answer may lie within the Rab family, a group of 60 proteins that are known to regulate the distribution of proteins throughout the body. Along with her Ph.D. student Nurit Pereg-Azouz, Prof. Sagi-Eisenberg found that 30 of these proteins determined how cells react to an allergen, and two of these have been identified for further research as instruments of preventative medication. When the chain of events leading up to an allergic reaction can be understood, drugs can be developed to inhibit the initial reaction, explains Prof. Sagi-Eisenberg.

This research has been published in The Journal of Immunology.

Getting to the root

Allergic reactions can appear as rashes, respiratory difficulties, or swelling, but they're all caused by the same mechanism. When exposed to an allergen, the body activates the immune system. But mast cells, located throughout the body, sense that the immune system has mistakenly been activated against something that is not bacterial or viral, and they release biologically active molecules to create an inflammatory response.

So what causes mast cells to react? Prof. Sagi-Eisenberg and her team work to identify the exact chain of events in an allergic reaction. They looked to the Rab family of proteins as a potential source for answers, screening for the proteins' involvement in initiating allergic reaction.

"We genetically manipulated mast cells so that they contained mutated versions of these proteins, which were already active without an allergen," explains Prof. Sagi-Eisenberg. If a protein was relevant, it would cause an allergic reaction. "This new methodology allowed us to screen for the functional impact of each member of this family, determining if they either inhibited or activated the allergic process."

In the end, the researchers flagged 30 proteins that were relevant to the process of creating an allergic reaction in the body, and have identified two that appear to be the most involved. Further research will use these two proteins as tools to gain more understanding of allergic reactions.

Targeted drugs could prevent allergic reaction

An allergic reaction is not only a function of two proteins interacting — it's the result of a chain of events. By identifying crucial links in such a chain, researchers can create targeted drugs that break the chain. New medications that target tumor cells, for example, are directed at halting the tumor's ability to function and grow, starving it of crucial blood and oxygen supplies. Prof. Sagi-Eisenberg envisions similar medications for allergies, with medications that address the source of the allergic reaction instead of the symptoms.

The need for such medications is pressing. Steroids, the only available type of drug that effectively prevents mast cells from secreting biologically active agents, also cause harm to kidneys, bones, and the immune system. Patients may suffer more from the treatment than they do from the allergy itself. Alternative medications that are as effective as steroids but will be devoid of their adverse side effects are desperately needed. Prof. Sagi-Eisenberg's work will help to identify proteins that can be targeted by medications without impacting the function of other cells, she hopes.


Protein-Based Coating Could Help Rehabilitate Long-Term Brain Function
7/31/2012

TAU researchers develop bioactive coating to "camouflage" neutral electrodes

Brain-computer interfaces are at the cutting edge for treatment of neurological and psychological disorder, including Parkinson's, epilepsy, and depression. Among the most promising advance is deep brain stimulation (DBS) — a method in which a silicon chip implanted under the skin ejects high frequency currents that are transferred to the brain through implanted electrodes that transmit and receive the signals. These technologies require a seamless interaction between the brain and the hardware.

But there's a catch. Identified as foreign bodies by the immune system, the brain attacks the electrodes and forms a barrier to the brain tissue, making it impossible for the electrodes to communicate with brain activity. So while the initial implantation can diminish symptoms, after a few short years or even months, the efficacy of this therapy begins to wane.

Now Aryeh Taub of Tel Aviv University's School of Psychological Sciences, along with Prof. Matti Mintz, Roni Hogri and Ari Magal of TAU's School of Psychological Sciences and Prof. Yosi Shacham-Diamand of TAU's School of Electrical Engineering, has developed a bioactive coating which not only "camouflages" the electrodes in the brain tissue, but actively suppresses the brain's immune response. By using a protein called an "interleukin (IL)-1 receptor antagonist" to coat the electrodes, the multi-disciplinary team of researchers has found a potential resolution to turn a method for short-term relief into a long-term solution. This development was reported in the Journal of Biomedical Materials Research.

Limiting the immune response

To overcome the creation of the barrier between the tissue and the electrode, the researchers sought to develop a method for placing the electrode in the brain tissue while hiding the electrode from the brain's immune defenses. Previous research groups have coated the electrodes with various proteins, says Taub, but the TAU team decided to take a different approach by using a protein that is active within the brain itself, thereby suppressing the immune reaction against the electrodes.

In the brain, the IL-1 receptor antagonist is crucial for maintaining physical stability by localizing brain damage, Taub explains. For example, if a person is hit on the head, this protein works to create scarring in specific areas instead of allowing global brain scarring. In other words, it stops the immune system from overreacting. The team's coating, the first to be developed from this particular protein, not only integrates the electrodes into the brain tissue, but allows them to contribute to normal brain functioning.

In pre-clinical studies with animal models, the researchers found that their coated electrodes perform better than both non-coated and "naïve protein"-coated electrodes that had previously been examined. Measuring the number of damaged cells at the site of implantation, researchers found no apparent difference between the site of electrode implantation and healthy brain tissue elsewhere, Taub says. In addition, evidence suggests that the coated electrodes will be able to function for long periods of time, providing a more stable and long-term treatment option.

Restoring brain function

Approximately 30,000 people worldwide are currently using deep brain stimulation (DBS) to treat neurological or psychological conditions. And DBS is only the beginning. Taub believes that, in the future, an interface with the ability to restore behavioral or motor function lost due to tissue damage is achievable — especially with the help of their new electrode coating.

"We duplicate the function of brain tissue onto a silicon chip and transfer it back to the brain," Taub says, explaining that the electrodes will pick up brain waves and transfer these directly to the chip. "The chip then does the computation that would have been done in the damaged tissue, and feeds the information back into the brain — prompting functions that would have otherwise gotten lost."


Pediatric Regime of Chemotherapy Proves More Effective for Young Adults
6/18/2012

Leukemia patients 16 to 39 have higher long-term survival rates, finds TAU researcher

Acute lymphoblastic leukemia (ALL), usually found in pediatric patients, is far more rare and deadly in adolescent and adult patients. According to the National Marrow Donor Program, child ALL patients have a higher than 80 percent remission rate, while the recovery rate for adults stands at only 40 percent.

In current practice, pediatric and young adult ALL patients undergo different treatment regimes. Children aged 0-15 years are typically given more aggressive chemotherapy, while young adults, defined as people between 16 and 39 years of age, are treated with a round of chemotherapy followed by a bone marrow transplant. But a new study has revealed that it may be time to rethink this strategy, says Dr. Ron Ram of Tel Aviv University's Sackler Faculty of Medicine and the Davidoff Cancer Center at the Rabin Medical Center.

Dr. Ram and his fellow researchers have determined that a pediatric treatment regime for young adult patients with ALL improves their chance of long-term survival, and decreases the mortality rate itself by 40% — all without the additional complications of a bone marrow transplant. Their findings have been published in the American Journal of Hematology.

Avoiding the transplant list

There are a number of reasons for the differing treatment regimes, including physical stress, psychological preparedness, and prevalence of the disease. Pediatric oncologists, who see dozens of cases of ALL a month, treat their patients with aggressive chemotherapy because there is a consensus that young children can better cope with the treatment — their heart, liver, and lungs are better able to repair themselves after exposure to the toxic cancer-fighting drugs, and they have better psychological support systems to deal with their situation.

Adult oncologists, on the other hand, proceed with more caution, believing that the older body has less ability to heal itself and that adults are not as psychologically well-adapted for the hardships of intensive chemotherapy. In addition, the smaller number of young and mature adult ALL patients means that fewer studies and clinical trials have been done on adolescents and adults with the disease, so less information is available.

For their study, Dr. Ram and his fellow researchers conducted a systematic review of 11 comparative studies comparing the outcomes of 2,489 individuals aged 16-39. They completed an analysis to determine how the young adult regime compared to the pediatric treatment for this age group. They discovered that at three years, mortality was significantly lower when the patient was treated with the pediatric regime than with the adult chemotherapy/transplant combination, with a remission rate closer to that in children. Relapse rates were also significantly lower.

"The long-term survival of these young adults increased significantly when following the pediatric treatment," concludes Dr. Ram. The results disproved the assumption that with the more aggressive chemotherapy, young adult patients would have higher toxicity rates. "There was a worry that the patients might suffer or even die from the toxicity of the treatment, but toxicity rates remained the same. With the pediatric treatment, patients were more frequently in remission and had prolonged survival without bone marrow transplantation — which itself is hard on the body."

More trials needed

Though the comparative studies have pointed researchers in the right direction, Dr. Ram says that this study is limited by a lack of randomized controlled trials, which could give more insight into whether the pediatric regime should be adopted as standard for young adult patients.

Still, the results are persuasive, leading to the conclusion that patients in this age group can be treated as pediatric patients in terms of the level of chemotherapy they can handle. "For a 16-20 year old, I would push them towards a pediatric regime," Dr. Ram says.

This study was conducted in collaboration with Profs. Ofer Shpilberg and Pia Raanani and Drs. Ofir Wolach, Liat Vidal and Anat Gafter-Gvili.


Air Pollution Linked to Chronic Heart Disease
6/5/2012

High pollution increases risk of repeated heart attacks by over 40 percent, says TAU researcher

Air pollution, a serious danger to the environment, is also a major health risk, associated with respiratory infections, lung cancer and heart disease. Now a Tel Aviv University researcher has concluded that not only does air pollution impact cardiac events such as heart attack and stroke, but it also causes repeated episodes over the long term.

Cardiac patients living in high pollution areas were found to be over 40 percent more likely to have a second heart attack when compared to patients living in low pollution areas, according to Dr. Yariv Gerber of TAU's School of Public Health at the Sackler Faculty of Medicine. "We know that like smoking cigarettes, pollution itself provokes the inflammatory system. If you are talking about long-term exposure and an inflammatory system that is irritated chronically, pollution may well be involved in the progression of atrial sclerosis that manifests in cardiac events," explains Dr. Gerber.

Done in collaboration with Prof. Yaacov Drory and funded by the Environmental and Health Fund in Jerusalem, the research was presented at the San Diego Epidemiological Meeting of the American Heart Association in March and the Annual Meeting of the Israeli Heart Society in April.

Risking recurrence

Air pollution has previously been acknowledged as a factor in heart attack risk, as well as other health risks. The goal of this study, says Dr. Gerber, was to quantify that association and determine the long-term effects of air pollution on myocardial infarction (MI) patients. Their study followed 1,120 first-time MI patients who had been admitted to one of eight hospitals in central Israel between 1992 and 1993, all of whom were under the age of 65 at the time of admittance. The patients were followed up until 2011, a period of 19 years.

Air quality was measured at 21 monitoring stations inareas where the patients lived, and analyzed by a group of researchers at the Technion in Haifa. After adjusting for other factors such as socio-economic status and disease severity, the researchers identified an association between pollution and negative clinical outcomes, including mortality and recurrent vascular events such as heart attack, stroke and heart failure.

Compared to patients who lived in areas with the lowest recorded levels of pollution, those in the most polluted environment were 43 percent more likely to have a second heart attack or suffer congestive heart failure and 46 percent more likely to suffer a stroke. The study also found that patients exposed to air pollution were 35 percent more likely to die in the almost 20 year period following their first heart attack than those who were exposed to lower levels of pollution.

According to Dr. Gerber, the true impact of air pollution might be even stronger than this study shows. "Our method of assessing exposure does have limitations. Because we are using data from monitoring stations, it's a crude estimate of exposure, which most likely leads to an underestimation of the association," he warns. He estimates that air pollution could have double the negative impact with more precise measurement.

Identifying vulnerable groups

The results of the study not only indicate a health benefit for a public policy that curtails air pollution caused by industrial emissions and second hand smoke, but also call for heightened awareness by clinicians. Doctors should be making their patients aware of the risks of remaining in high pollution areas, suggesting that they work to limit their exposure, Dr. Gerber suggests.

Another purpose of this study was to begin identifying populations that are vulnerable to MI and re-occurring MI. Establishing the connection between air pollution and long-term risk for patients with cardiovascular diseases was an important step towards that goal.


A Better Delivery System for Chemotherapy Drugs
5/30/2012

TAU researcher develops new antibodies to target and destroy cancer cells

Because cancer cells grow very quickly, chemotherapy is designed to target cells whose numbers grow rapidly. But this treatment comes with a heavy price — many healthy cells essential for body functions are also targeted and killed by the toxin. This dangerous side-effect has prompted researchers to seek better and more selective ways to kill cancer cells inside the body.

Prof. Daniel Wreschner of Tel Aviv University's Department of Cell Research and Immunology is now developing new antibodies — proteins produced by the immune system to fight infection — that bind to and kill off cancer cells exclusively. These antibodies, which target the cancer cells by binding to a protein called MUC1, can be used as an efficient drug delivery method, depositing a parcel of toxins directly into the belly of the diseased cells.

Prof. Wreschner's goal is to improve current methods of using antibodies to induce cancer cell death by utilizing different sub-regions in the MUC1 protein itself, which he believes are a superior target. His method has been shown to produce antibodies with a better ability to bind to cancer cells, which may heighten the efficacy of the antibodies and the toxins attached to them in treating cancer.

Recently reported in the journal Cancer Research, this research was carried out in collaboration with Ph.D. student Edward Pichinuk and undergraduate student Lotem Weiss in Prof. Wreschner's lab; Dr. Nechama I. Smorodinsky and Prof. Itai Benhar of the Department of Molecular Microbiology and Biotechnology; and Dr. Daniel B. Rubinstein of the National Institutes of Health in the US.

Producing a stronger bond

In the transition from normal to cancerous, cells go through specific changes, including differences in make-up of the proteins on the cell surface or membrane. MUC1 is one of the proteins that are overproduced in many types of cancer, including breast and pancreatic cancers and leukemia. Labs around the world are working on methods to use this protein in order to accurately identify, access, and destroy cancer cells.

Currently, researchers are developing antibodies that target the "tandem repeat" of the protein, a section that repeats itself many times and therefore acts as a large bull's eye for antibodies. But targeting this section has a crucial flaw. "The tandem repeat is in the alpha section of the protein," explains Prof. Wreschner. "This alpha section can detach from the cell and be ejected into the bloodstream. At that point, the antibodies will bind to the alpha section in the blood, diminishing their ability to bind to the cancer cell."

But Prof. Wreschner is looking at MUC1 from a fresh perspective. His team's objective is to produce antibodies that have a much higher ability to bind to the proteins on the cell membrane. To do so, he is targeting the SEA domain of the protein, the "junction" which attaches it to the cell membrane. In the lab, this antibody has proven to have a high ability to bind to, enter, and then kill the diseased cell with its attached parcel of chemotherapy toxins. It is superior to antibodies already in use.

Addressing more cancer varieties

Prof. Wreschner says that there is much more research and development to be done before the antibody is available as a treatment option. He is looking for funding partners in order to bring it to a clinical stage.

While there are other FDA-approved medications on the market that use these principles, including Herceptin, used to treat breast cancer, and Erbitux, a treatment for colorectal and head and neck cancer, the advantage to the new antibody is that MUC1 is produced in a higher percentage of cancers. "People who are not eligible to be treated by antibodies already on the market could, following more research and development, likely be eligible for this one," Prof. Wreschner adds.


Diabetes Drug Could Be a Promising Therapy for Traumatic Brain Injury
5/29/2012

Although the death toll is relatively low for people who suffer from traumatic brain injury (TBI), it can have severe, life-long consequences for brain function. TBI can impair a patient's mental abilities, impact memory and behavior, and lead to dramatic personality changes. And long-term medical treatment carries a high economic cost.

Now, in research commissioned by the United States Air Force, Prof. Chaim Pick of Tel Aviv University's Sackler Faculty of Medicine and Dr. Nigel Greig of the National Institute of Aging in the US have discovered that Exendin-4, an FDA-approved diabetes drug, significantly minimizes damage in TBI animal models when administered shortly after the initial incident. Originally designed to control sugar levels in the body, the drug has recently been found effective in protecting neurons in disorders such as Alzheimer's disease.

Prof. Pick's collaborators include his TAU colleagues Dr. Vardit Rubovitch, Lital Rachmany-Raber, and Prof. Shaul Schreiber, and Dr. David Tweedie of the National Institute of Aging in the US. Detailed in the journal Experimental Neurology, this breakthrough is the first step towards developing a cocktail of medications to prevent as much brain damage as possible following injury.

Diabetes medication to halt trauma

Prof. Pick has been researching TBI for many years, beginning with the effects of everyday injuries such as hitting the windshield in a car accident. As a result of his work for the Air Force, he has expanded his research to include trauma sustained when a person is exposed to an explosion, such as during a terrorist attack.

TBI causes long-term damage by changing the chemistry of the brain. During an explosion, increased pressure followed by an intense vacuum shakes the fluid inside the brain and damages the brain's structure. This damage cannot be reversed, but mapping the injury through behavioral and physical tests is crucial to understanding and quantifying the damage and forming a treatment plan through therapy or medication.

Prof. Pick and his colleagues designed a pre-clinical experiment that exposed mice to controlled explosions from 23 and 33 feet away, and then analyzed the resulting injuries. They also studied the effect of Exendin-4 as an additional parameter in minimizing brain damage.

The researchers divided their mice into four groups: a control group; a second group that was exposed to the blast without medication; a third group that received the medication but was not exposed to the blast; and a fourth group, exposed to the explosion but given the medication within an hour after the blast and continuing for seven days afterwards. The mice were placed under anaesthesia before the explosion.

Behavioral and physical tests showed that the mice that had been exposed to the blast had severely impaired brain function compared to the control group. However, the mice that had also received the Exendin-4 treatment were almost on a par with the control group in terms of brain function, proving that Exendin-4 significantly reduced the long-term damage done by an explosion. In separate experiments, the drug was also associated with an improved outcome in mice who sustained TBI by blunt force.

Finding the ideal drug cocktail

Prof. Pick says this promising discovery can help researchers find the ideal combination of medications to minimize the lasting impact of TBI. "We are moving in the right direction. Now we need to find the right dosage and delivery system, then build a cocktail of drugs that will increase the therapeutic value of this concept," he explains. He adds that in treating such traumatic injuries, one drug is unlikely to be sufficient.

This work was also done in collaboration with Dr. Bruce Citron from the American Veterans Association and Dr. Barry Hoffer from the National Institute of Drug Abuse at the National Institute of Health.


Common Acne Medication Doubles Risk of Eye Infections
5/23/2012

Combine acne pills with eyedrops to avoid damage, TAU researcher suggests

Millions of teenagers suffer from acne, and they deal with the embarrassing skin blemishes by taking popular prescription medications such as Accutane or Roaccutane. Now, however, research from Tel Aviv University shows that these pills can also cause eye infections such as conjunctivitis (pink eye) or sties.

According to Dr. Gabriel Chodick of TAU's School of Public Health at the Sackler Faculty of Medicine, clinicians have long theorized a connection between acne and eye infections, but there was little available statistical research on the subject. "Acne itself can increase the risk of ocular diseases," he explains. "There is a greater tendency towards inflammation, and sometimes this leads to irritation." His research revealed that patients who took these oral medications doubled the risk of developing an eye infection, compared to acne sufferers who did not.

Published in Archives of Dermatology, the work was done in collaboration with Drs. Meira Neudorfer, Orna Shamai-Lubovitz and Varda Shalev from the Sackler Faculty of Medicine and Inbal Goldshtein from Maccabi Health Care Services.

Drying those tears

The researchers looked at records of almost 15,000 adolescents from the Maccabi Health Care Services database, one of Israel's largest health funds. They were divided into three groups: those who were acne-free; those who had acne but did not take oral medication; and those who had acne and were prescribed a medication such as Accutane or Roaccutane.

Out of the 15,000 subjects, 1,791 people developed inflammatory ocular diseases, including 991 in the medicated group, 446 in the acne group, and 354 in the acne-free group. The most common infection was conjunctivitis, commonly called pink eye. Four percent of patients who were on acne medication contracted pink eye, compared to 2 percent for the normal population.

"A very common side effect of Accutane and Roaccutane is dryness of skin and lips, so it's only natural that these medications would also effect the lubrication of the eyelids — specifically the oil glands along the rim of the eyelid," explains Dr. Chodick. Tears are crucial because they lubricate the surface of the eye and they wash away debris, including bacteria and viruses, that can lie on the eye or its lid. Infection of the gland itself can lead to sties, and more serious bacterial infections might lead to the swelling of the entire eyelid.

A simple solution

Though not a serious medical condition, acne is still worth treating, says Dr. Chodick. But dermatologists and patients should be aware of these side effects, because there is the potential for long-term damage. According to some studies, including one published in Clinical and Experimental Optometry, irritation and eye rubbing can lead to structural eye problems such as keratoconus, a degeneration of the cornea.

Dr. Chodick advises that patients on oral acne medication ask their doctors how to minimize eye damage. One simple step is to use artificial tears, or eye drops, to keep the eyes lubricated. Local pharmacies can offer several inexpensive over-the-counter options, he says.


Doing the Tooth Implant Two-Step
5/22/2012

Two-step tooth implantation and built-up bone can be longer lasting, TAU researcher discovers

Periodontists routinely grow bone in the mouth to guarantee a stable environment for teeth and tooth implants. But whether it's better to build up bone before placing the implant, or to simply place the implant and allow bone to grow around it, has been a subject of considerable medical debate.

Now Prof. Zvi Artzi of Tel Aviv University's Maurice and Gabriela Goldschleger School of Dentistry at the Sackler Faculty of Medicine has completed a study that concludes the two-step method is the more effective alternative — building bone first, then implanting and allowing further bone growth. Currently, many dental professionals prefer a one-step process to save their patients from an additional surgical procedure.

Published in the Journal of Clinical Periodontology, Prof. Artzi's study shows that a one-step implant will show more wear and tear over time than one implanted through the more cautious two-step procedure. While both are clinically effective methods, he concludes, implant placement procedures done with the one-step method show greater bone resorption around the implant neck — a process by which the bone is broken down. Bonding of the bone around the implant was also shown to be inferior.

Testing proven procedures

The successful placement of a tooth implant is based on the biocompatibility of titanium, the main component of most dental and orthopedic implants. Both animal and human tissues readily accept the implant and grow around it. But in many cases, the amount of bone is also crucial to the success of the implant. Building bone to stabilize a titanium fixture is a long-standing procedure in dentistry.

Periodontists typically choose either the one-step or two-step procedure based on their preference alone. So Prof. Artzi and his fellow researchers set out to determine which procedure was scientifically superior in the long-term, well past the time when periodontists would typically monitor a patient's progress. In their study, they compared both methods of implantation in lab animals, and followed the progress of the implants over a course of two years.

The one-step procedure is based on the idea that a bone graft will simply attract the surrounding tissue to build up bone around the titanium implant — a process called conduction. The benefit of this procedure is that patients are only subjected to one surgery. But the study shows a difference in long-term efficacy, Prof. Artzi says. Ultimately, the bone recedes less in the more cautious two-step procedure. The quality of the resulting bone itself is similar.

A judgement call

Though the study proves that the two-step method is more advantageous in most cases, each case is different, says Prof. Artzi. For example, dental professionals also take into account the already existing bone – which determines how stable a future implant will be – before deciding which route to take with each individual patient. Clinically, both methods remain sound, and periodontists should still rely on their own judgement as to what is best for the patient.


Unique Gold Earring Found in Intriguing Collection of Ancient Jewelry at Tel Megiddo
5/21/2012

Hoard of gold and silver jewelry hidden for thousands of years could have Egyptian origin, say TAU researchers

Researchers from Tel Aviv University have recently discovered a collection of gold and silver jewelry, dated from around 1100 B.C., hidden in a vessel at the archaeological site of Tel Megiddo in the Jezreel Valley in northern Israel. One piece — a gold earring decorated with molded ibexes, or wild goats — is "without parallel," they believe.

According to Prof. Israel Finkelstein of TAU's Department of Archaeology and Near Eastern Cultures, the vessel was found in 2010, but remained uncleaned while awaiting a molecular analysis of its content. When they were finally able to wash out the dirt, pieces of jewelry, including a ring, earrings, and beads, flooded from the vessel. Prof. Finkelstein is the co-director of the excavation of Tel Megiddo along with Professor Emeritus David Ussishkin of Tel Aviv University and Associate Director Prof. Eric Cline of George Washington University in Washington, D.C.

The researchers believe that the collection, which was discovered in the remains of a private home in the northern part of Megiddo, belongs to a time period called "Iron I," and that at least some of the pieces could have originated in nearby Egypt. Some of the materials and designs featured in the jewelry, including beads made from carnelian stone, are consistent with Egyptian designs from the same period, notes Ph.D. candidate Eran Arie, who supervises the area where the hoard was found.

A treasure trove with mysterious origins

When the researchers removed the ceramic jug from the excavation site, they had no idea there was jewelry hidden within. The jewelry was well preserved and wrapped in textiles, but the circumstances surrounding it are mysterious. According to Prof. Finkelstein, it is likely that the jug was not the jewelry's normal storage place. "It's clear that people tried to hide the collection, and for some reason they were unable to come back to pick it up." The owners could have perished or been forced to flee, he says. Prof. Ussishkin believes that it was the jewelry collection of the Canaanite woman who lived in the house.

The assortment of jewelry is also out of the ordinary, notes Arie. Though the collection includes a number of lunette (moon-shaped) earrings of common Canaanite origin, researchers found an abundance of gold items in the collection and a number of beads made from carnelian, which was frequently used in the making of Egyptian jewellery in the same period. This points to a strong Egyptian connection, whether in influence or origin. Such a connection would not be surprising, according to Prof. Cline, who stated that interactions between Egypt and Megiddo are known to have taken place during both the Bronze Age and the Iron Age.

The most notable piece, the researchers agree, is a gold earring with a pattern of molded wild goats. "For unique items, we work to find parallels to help place the items in their correct cultural and chronological settings, but in this case we still haven't found anything," say the researchers.

Adding dimension to a multi-layer dig

It's another fascinating find from a unique archaeological site. Tel Megiddo was an important Canaanite city-state until the early 10th century B.C.E. and a pivotal center of the Northern Kingdom of Israel in the 9th and 8th centuries B.C.E. It is a multi-layered site with various time periods clearly differentiated, and in this time period there are 10 to 11 strata well-dated through radiocarbon analysis. "Such a sequence of radiocarbon dates doesn't exist anywhere else in the region," says Prof. Finkelstein.

The layer in which the jewelry was found has already been dated to the 11th century B.C., just after the end of Egyptian rule in the 12th century B.C., Arie says. Either the jewelry was left behind in the Egyptian withdrawal or the people who owned the jewelry were influenced by Egyptian culture.

The researchers hope that analysis of both the textiles in which the jewelry was wrapped and the jewelry itself will tell them more about the origins of the collection. If the gold is pure rather than a mixture of gold and silver, for example, the metal most likely will have come from Egypt itself, a region that was poor in silver resources but rich in gold.


Freezing Parkinson's in its Tracks
5/2/2012

Parkinson's disease, a disorder which affects movement and cognition, affects over a million Americans, including actor Michael J. Fox, who first brought it to the attention of many TV-watching Americans. It's characterized by a gradual loss of neurons that produce dopamine. Mutations in the gene known as DJ-1 lead to accelerated loss of dopaminergic neurons and result in the onset of Parkinson's symptoms at a young age.

The ability to modify the activity of DJ-1 could change the progress of the disease, says Dr. Nirit Lev, a researcher at Tel Aviv University's Sackler Faculty of Medicine and a movement disorders specialist at Rabin Medical Center. Working in collaboration with Profs. Dani Offen and Eldad Melamed, Dr. Lev has now developed a peptide which mimics DJ-1's normal function, thereby protecting dopamine- producing neurons. What's more, the peptide can be easily delivered by daily injections or absorbed into the skin through an adhesive patch.

Based on a short protein derived from DJ-1 itself, the peptide has been shown to freeze neurodegeneration in its tracks, reducing problems with mobility and leading to greater protection of neurons and higher dopamine levels in the brain. Dr. Lev says that this method, which has been published in a number of journals including the Journal of Neural Transmission, could be developed as a preventative therapy.

Guarding dopamine levels

As we age, we naturally lose dopamine-producing neurons. Parkinson's patients experience a rapid loss of these neurons from the onset of the disease, leading to much more drastic deficiencies in dopamine than the average person. Preserving dopamine-producing neurons can mean the difference between living life as a Parkinson's patient or aging normally, says Dr. Lev.

The researchers set out to develop a therapy based on the protective effects of DJ-1, using a short peptide based on the healthy version of DJ-1 itself as a vehicle. "We attached the DJ-1-related peptide to another peptide that would allow it to enter the cells, and be carried to the brain," explains Dr. Lev.

In pre-clinical trials, the treatment was tested on mice utilizing well-established toxic and genetic models for Parkinson's disease. From both a behavioral and biochemical standpoint, the mice that received the peptide treatment showed remarkable improvement. Symptoms such as mobility dysfunctions were reduced significantly, and researchers noted the preservation of dopamine-producing neurons and higher dopamine levels in the brain.

Preliminary tests indicate that the peptide is a viable treatment option. Though many peptides have a short life span and degrade quickly, this peptide does not. Additionally, it provides a safe treatment option because peptides are organic to the body itself.

Filling an urgent need

According to Dr. Lev, this peptide could fill a gap in the treatment of Parkinson's disease. "Current treatments are lacking because they can only address symptoms — there is nothing that can change or halt the disease," she says. "Until now, we have lacked tools for neuroprotection."

The researchers also note the potential for the peptides to be used preventatively. In some cases, Parkinson's can be diagnosed before motor symptoms begin with the help of brain scans, explains Dr. Lev, and patients who have a genetic link to the disease might opt for early testing. A preventative therapy could help many potential Parkinson's patients live a normal life.


A New Drug to Manage Resistant Chronic Pain
4/30/2012

Neuropathic pain, caused by nerve or tissue damage, is the culprit behind many cases of chronic pain. It can be the result of an accident or caused by a variety of medical conditions and diseases such as tumors, lupus, and diabetes. Typically resistant to common types of pain management including ibuprofen and even morphine, neuropathic pain can lead to lifelong disability for many sufferers.

Now a drug developed by Tel Aviv University researchers, known as BL-7050, is offering new hope to patients with neuropathic pain. Developed by Prof. Bernard Attali and Dr. Asher Peretz of TAU's Department of Physiology and Pharmacology at the Sackler Faculty of Medicine, the medication inhibits the transmission of pain signals throughout the body. In both in-vitro and in-vivo experiments measuring electrical activity of neurons, the compound has been shown to prevent the hyper-excitability of neurons — protecting not only against neuropathic pain, but epileptic seizures as well.

The medication has been licensed by Ramot, TAU's technology transfer company, for development and commercialization by BioLineRx, an Israeli biopharmaceutical development company.

Targeting potassium for pain control

According to Prof. Attali, the medication works by targeting a group of proteins which act as a channel for potassium. Potassium has a crucial role in the excitability of cells, specifically those in the nervous system and the heart. When potassium channels don't function properly, cells are prone to hyper-excitability, leading to neurological and cardiovascular disorders such as epilepsy and arrhythmias. These are also the channels that convey pain signals caused by nerve or tissue damage, known as neuropathic pain.

With few treatment options available for neuropathic pain, Prof. Attali set out to develop a medication that could bind to and stabilize the body's potassium channels, controlling their hyper-excitability and preventing the occurrence of pain by keeping the channels open for the outflow of potassium. This novel targeting approach has been recently reported in the journal PNAS.

Inducing calm in the neurons

Understanding the mechanism that controls these channels has been crucial to the development of the drug. By successfully controlling the excitability of the neurons, Prof. Attali believes that BL-7050 could bring relief to hundreds of millions of patients around the world who suffer from neuropathic pain. The medication will reach the first phase of clinical trials in the near future.

In pre-clinical trials, BL-7050 was tested in rats experiencing both epilepsy and neuropathic pain and was found to be efficient in protecting against both when taken as a pill. While on the medication, rats were no longer affected by stimuli that had previously caused pain. Measures in the electrical activities of neurons also revealed that the medication was able to induce "calm" in the neurons, inhibiting pain pathways.


New Lab Mice Cut Search for Genetic Links to Disease by More Than a Decade
4/5/2012

TAU breeds population of lab mice with genetic diversity closer to humans

With a 95 percent genomic similarity to humans, mice have long been used to learn about the genetic causes of human disease. Once researchers can shine a light on the genetic factors that cause disease in mice, they can start to develop prevention and treatment options to protect the human population.

But this process, called genetic mapping, is a long and difficult road, made more challenging by the 5% difference between the humans and lab mice. Now Prof. Fuad Iraqi of Tel Aviv University's Sackler Faculty of Medicine is closing the gap with an international project called Collaborative Cross. The project is developing lab mice with increased genetic diversity, making them more advantageous for genetic research related to human health.

The new population will offer 1,000 genetic strains within a fixed genotype — the composite of the entire genetic makeup of an organism. This is a marked improvement on the previously existing 450 genetic strains of lab mice with varying genotypes, making Prof. Iraqi’s new strain ideal for genetic mapping. And with these mice, researchers will be able to identify a gene associated with a particular disease within two to three years instead of the 10 to 15 years it takes now, says Prof. Iraqi.

The research has been published in the journals Nature, Nature Genetics, and Genome Research, and receives its primary funding from the Wellcome Trust in the UK. The project itself is a collaboration among Tel Aviv University, Oxford University in the UK, North Carolina State University in the US, and Perth University in Australia.

Expanding the family tree

Genetic determinants play an important role in a variety of conditions from diabetes and obesity to different types of cancers. For example, mutated forms of the genes BRCA1 and BRCA2, which can be genetically inherited, are associated with higher rates of breast and ovarian cancers. This kind of genetic diversity in humans influences diseases and helps researchers track their genetic causes. According to Prof. Iraqi, the fact that humans have many genetic variances for the same gene means that they are “outbred” among individuals from different families. To best identify the genes that cause a disease, scientists require a test population with these same variances.

But standard strains of lab mice are inbred. Their genetic similarities make it difficult to identify the connection between particular traits and the specific genes responsible. The Collaborative Cross project answers this deficiency in lab mice by increasing genetic variation as much as possible — a powerful and unique resource for research.

In order to develop a genetically enriched population of lab mice, the researchers took five classic inbred strains of mice and mixed them with three wild-derived strains, mating brothers and sisters for generations in order to reshuffle the genetic deck but keep the genotype consistent. With an increased range of traits, including differences in appearance such as fur color and tail length, this new mouse population more closely mimics the genetic diversity of humans, says Prof. Iraqi.

Building a better mouse

The various genetic strains are housed within participating universities across the world, notes Prof. Iraqi, and are already available for order by researchers. Within Tel Aviv University's laboratories, there are currently genetic mapping projects for a variety of diseases, including diabetes, various types of cancers, dental infections, bacterial infections, and fungal infections — all making use of these genetically enriched mice.

Prof. Iraqi has already used the new mouse population to identify a group of genes that are crucial to susceptibility to infection when exposed to Aspergillus fumigatus, a soil fungus that causes respiratory infections in humans. Getting to this point took only a year — compared to the 15 years it might have taken using standard lab mice, he calculates.


Can a Ray of Sunshine Help the Critically Ill?
4/3/2012

Scientists have long believed that vitamin D, which is naturally absorbed from sunlight, has an important role in the functioning of the body's autoimmune system. Now Prof. Howard Amital of Tel Aviv University's Sackler Faculty of Medicine and Sheba Medical Center has discovered that the vitamin may also affect the outcomes of patients in intensive care.

In a six-month study, Prof. Amital and his colleagues found that patients who had a vitamin D deficiency lived an average of 8.9 days less than those who were found to have sufficient vitamin D. Vitamin D levels also correlated with the level of white blood cells which fight disease.

The study, which was published in the journal QJM: An International Journal of Medicine, demonstrates further research into giving patients vitamin D could confirm that it will improve their survival outcomes.

Adding days of life

To measure the impact of vitamin D levels on the survival of critically ill patients, the researchers designed an observational study. Over the course of six months, 130 patients over the age of 18 admitted to an intensive care unit of a TAU-affiliated hospital and requiring mechanical ventilation were admitted to the study. Patients who had taken vitamin D supplements prior to admittance were excluded from the study population.

Upon admittance, patients were divided into two groups based on vitamin D concentration: those who had 20 nanograms or more of the vitamin — the amount defined as the National Institute of Health as sufficient — and those who were vitamin D deficient based on the same criteria. In total, 107 patients suffered from vitamin D deficiency.

Survival curves indicate that while patients with sufficient vitamin D survived an average of 24.2 days, those who were deemed to be deficient in vitamin D survived an average of only 15.3 days — patients with sufficient vitamin D levels survived an average of 8.9 days longer. They were also found to have a better WBC count.

Seek out sun — or supplements

These findings merit further investigation, Prof. Amital says. He suggests that the effects of vitamin D supplementation in critically ill patients be further assessed in future studies. The initial results indicate only that vitamin D concentration may be an indicator of survival, he says.

But don't wait until you're in poor health to start taking vitamin D, suggests Prof. Amital. Vitamin D appears to enhance the function of the immune system in numerous ways, and it’s becoming clear that it does have an impact on overall health and well-being.

According to research, including an article in the New England Journal of Medicine, the majority of those who live in North America and other Western countries are known to be vitamin D deficient due to limited exposure to the sun. But even if the springtime skies are gray, supplements from the pharmacy shelf will have the same benefits, Prof. Amital says.


A 24-karat Gold Key to Unlock the Immune System
3/26/2012

Innovative TAU tool for immune system activation could lead to better drug delivery

Developing a drug or vaccine requires a delicate balancing act with the immune system. On one hand, medications need to escape detection by the immune system in order to perform their function. But vaccinations — de-activated versions of a disease or virus — need to do the reverse. They prompt the immune system to create protective antibodies. But scientists are still stumped by how the immune system recognizes different particles, and how it chooses whether or not to react against them.

Using nanoparticles made of pure gold, Dr. Dan Peer, head of Tel Aviv University's Laboratory of Nanomedicine at the Department of Cell Research and Immunology and the Center for Nanoscience and Nanotechnology, with a team including Drs. Meir Goldsmith and Dalit Landesman-Milo and in collaboration with Prof. Vincent Rotello and Dr. Daniel Moyano from the University of Massachusetts at Amherst, has developed a new method of introducing chemical residues into the immune system, allowing them to note the properties that incur the wrath of immune cells. Because the gold flecks are too small to be detected by the immune system, the immune system only responds when they are coated with different chemical residues.

This breakthrough could lead to an increased understanding of the properties of viruses and bacteria, better drug delivery systems, and more effective medications and vaccinations. Their study was published in the Journal of the American Chemical Society.

A tool for exploration

To begin probing the immune system, researchers used particles of gold, approximately two nanometers in diameter, and covered them with various chemical residues. Only when water-resistant residues were introduced did the immune system respond to their presence. That established a demonstrable link between hydrophobicity — the degree to which a molecule repels water — and the reaction of the immune system.

This idea has a basis in the normal functioning of the immune system, Dr. Peer explains. During cell death, the hydrophobic areas of the cell membrane become exposed. The immune system then realizes that damage has occurred and begins to alert neighboring cells.

The researchers discovered that the same principle held true for the chemicals added to the gold particles' surface. The more "water-hating" the particle is, the more actively the immune system will mobilize against it, he says.

Dr. Peer observes that this is only the first step in a long line of experiments. "We are using these gold particles to tackle the question of how the immune system recognizes different particles, which might include features such as geometry, charge, curvature, and so much more. Now that we know the tool works, we can build on it," he says.

Testing the "Danger Model"

Until now, scientists have developed theories about how the immune system functions, but have lacked the machinery to test these ideas. One such theory is the "Danger Model" by Prof. Polly Matzinger, which hypothesizes that cellular damage interacts with immune cells at the membrane level. Once they identify the foreign molecule as a "danger," the immune cells send signals throughout the immune system. Their initial experiment with hydrophobicity was designed to generate a toolbox for probing this theory, says Dr. Peer, whose investigations included both in vitro and in vivo experiments using mouse immune cells.

In the future, researchers will study various bacterial, viral, or damaged cells and to make the gold nanoparticles even more similar, thereby discovering which elements of dangerous particles are calling the body's immune system to arms. "We now have the capability of using nanomaterials to probe the immune system in a very accurate manner," says Dr. Peer, a breakthrough that could revolutionize the way we understand the immune system.


Pain Relievers Could be Spiking Your Blood Pressure
3/20/2012

Diseases such as kidney failure and endocrine tumors are among the suspects causing high blood pressure — but could the common pain relievers in your medicine cabinet be the culprit?

According to Prof. Ehud Grossman of Tel Aviv University's Sackler Faculty of Medicine and the Sheba Medical Center, many common over-the-counter and prescription medications are underlying causes of hypertension, which is a major risk factor for stroke, heart attack, and aneurisms. The chemical components of the drugs can raise blood pressure or interfere with anti-hypertensive medications, he explains. And while many medications can cause this drug-induced hypertension, both patients and doctors remain dangerously uninformed.

His recent research was published in the American Journal of Medicine.

Weighing the treatment options

"In diagnosing the causes of hypertension, over-the-counter drugs like ibuprofen are often overlooked," says Prof. Grossman. Patients often assume that because a medication can be obtained without a prescription, it's relatively harmless. But that's not always the case.

Many of the medications that are linked with a rise in blood pressure are quite widely used, says Prof. Grossman, whose research provides an overview of which medications are related to high blood pressure. Examples include contraceptive pills, various anti-depressants, anti-inflammatory pills to control pain. and bacterial antibiotics.

Though high blood pressure is a known side effect of many of these medications, doctors do not always account for them in their treatment plans, and they don't inform patients of the potential risks associated with these medications. It's ultimately the doctor's responsibility to weigh treatment options and present the best course for their patient should issues of hypertension arise, Prof. Grossman says.

Doctors may be advised to decrease the dosage of the drug, or add an anti-hypertensive drug to the treatment regime, he says. In any case, awareness on the part of both doctors and patients needs to be raised. "Many physicians don't account for this, and some don't even know about it. It's their responsibility to be informed and make sure that their patients are aware that this is a possibility."

Cost and benefit

Though much of the time a course of treatment can be altered to account for the dangers of hypertension, that isn't always the case. For example, new anti-vascular endothelial growth factor drugs, which may increase blood pressure, block the formation of new blood vessels and arteries to solid tumors. Because the drugs are so effective in treating these malignancies, the benefit outweighs the cost, he believes.

But that doesn't mean that patients shouldn't be watched closely for signs of hypertension. "Once a patient has won a longer life with the use of these drugs, you don't want to expose them to problems associated with blood pressure, such as stroke," says Prof. Grossman. There are simple ways to counteract drug-induced hypertension, such as the thoughtful addition of anti-hypertensive medications to a treatment plan, he says.

Excess Fat May Be "Protective" in Seniors Over 85
2/28/2012

Surprising TAU research finds obesity can decrease risk of mortality in people over 85 years of age

Obesity is considered the leading preventable cause of death worldwide — until you reach old age, that is. Though obesity increases the risk of an early death, shaving an average of six to seven years off a person's lifespan, Tel Aviv University researchers have found that this trend may reverse itself after the age of 85. In these people, excess fat seems to have a "protective" effect, decreasing the risk of death when compared to those who are considered at a normal body weight.

When we reach a very old age, some of the factors that affect mortality in younger people may no longer be significant, explain Prof. Jiska Cohen-Mansfield and Rotem Perach of the Herczeg Institute on Aging and the Sackler Faculty of Medicine. Heavier people have lower rates of osteoporosis, which could decrease incidences of falls and subsequent injury. Obesity could also provide excess energy storage in times of trauma or stress, or prolong the period of weight loss caused by a decrease in appetite, a common occurrence as people near death.

This research was recently published in the Journal of Aging Research.

The survival effect

Research has consistently shown that people who are underweight in their old age have a higher mortality risk. But until now, the protective impact of obesity on mortality in this same age group has been unexplored.

The study was based on data collected as part of the Cross Sectional and Longitudinal Aging Study (CALAS), which included 1,349 people between the ages of 75-94. Participants were asked basic questions about their height and weight, age, gender, family, education, socioeconomic status, and smoking history. Two decades after the data was first collected, the researchers completed a mortality analysis on the original sample. During the course of these 20 years, 95 percent of the participants had died, leaving 59 subjects still living.

Obesity continued to be a predictor of death for those aged 75-84, notes Prof. Cohen-Mansfield. But past the age of 85, participants who were in the obese category were not only at lower risk of death than their underweight peers, but also appeared to be less at risk than those who had a normal weight as well.

There is a "selective survival" rate at play, say the researchers. Often, obese people die early in life due to obesity-related illnesses. So those who survive to old age could simply be more resilient. The same principle may be true of other factors, such as smoking.

Life at a cost

Though the findings are surprising, Prof. Cohen-Mansfield points out that obesity only has a protective effect when it comes to mortality. Quality of life, she warns, is another matter. "Though obese people over the age of 85 may be less at risk of death, they may suffer more from obesity-related illnesses," she says. "There are other factors to consider, such as pain, multiple ailments, and mobility."

To read the article, see:
http://www.hindawi.com/journals/jar/2011/765071/


Taking Depression to Heart
2/14/2012

Mental state can play a crucial role in physical health — medical professionals have long known about the connection between anxiety and the immune system, for example. Now researchers at Tel Aviv University have found that mental health can also interfere with the heart.

Heart attack patients who also suffer from depression are more likely to be readmitted for cardiac events and chest pains in the future, and have 14 percent more days of hospitalization than their happier counterparts, says researcher Vicki Myers of TAU's Sackler Faculty of Medicine. Along with Dr. Yariv Gerber and other members of the Israel Study Group of First Acute Myocardial Infarction, Myers examined the association between depressive symptoms in heart attack patients and hospital admissions more than a decade after the initial attack.

These findings have long-term ramifications, says Myers. Spending more time in the hospital, these patients are a massive financial burden on health services, but an investment in extra psychiatric support may have a large positive payoff.

The study was funded by the Israel National Institute for Health Policy and Health Services Research and has been published in the Journal of Psychosomatic Research.

Making better lifestyle choices

Most studies examining the connection between heart attack recovery and mental health have only included short term follow up, says Myers. To study the effect of depression on the long-term health of heart attack patients, the researchers used data collected from 632 heart attack patients under the age of 65 admitted to Israeli hospitals between 1992 and 1993, comparing their recoveries using follow-up data through 2005.

Although a large percentage of people who survive a heart attack will be re-admitted to the hospital at some point, people identified as at least "mildly depressed" during their first hospital stay were far more likely to be re-hospitalized later with further cardiac health problems. Patients with a higher depression score spent 14 percent more time in the hospital than those with a low score. Data were controlled for measures of co-morbidity, including other illnesses and risk factors such as smoking and socioeconomic status.

Making the right choices

Post-heart-attack lifestyle choices played a major role in this relationship, explains Myers. Most heart attack patients are offered rehabilitation services, and are advised to change their lifestyle to include exercise, diet, and smoking cessation programs. Depressed patients are far less likely to avail themselves of rehab services, or elect to make life changes themselves, she says. Overall, depressed patients were 20 percent less likely to be physically active after suffering a heart attack, 26 percent less likely to participate in a cardiac rehabilitation program, and 25 percent less likely to quit smoking.

"The message is that doctors cannot ignore psychological factors in patients who have had a heart attack. Patients who exhibit signs of depression need to be followed more closely, and may need extra help in following lifestyle recommendations. Ignoring this problem weighs heavily on health services," she adds.


Top Off Breakfast with -- Chocolate Cake?
2/7/2012

A full breakfast that includes a sweet dessert contributes to weight loss success, say TAU researchers

When it comes to diets, cookies and cake are off the menu. Now, in a surprising discovery, researchers from Tel Aviv University have found that dessert, as part of a balanced 600-calorie breakfast that also includes proteins and carbohydrates, can help dieters to lose more weight — and keep it off in the long run.

They key is to indulge in the morning, when the body's metabolism is at its most active and we are better able to work off the extra calories throughout the day, say Prof. Daniela Jakubowicz, Dr. Julio Wainstein and Dr. Mona Boaz of Tel Aviv University's Sackler Faculty of Medicine and the Diabetes Unit at Wolfson Medical Center, and Prof. Oren Froy of Hebrew University Jerusalem.

Attempting to avoid sweets entirely can create a psychological addiction to these same foods in the long-term, explains Prof. Jakubowicz. Adding dessert items to breakfast can control cravings throughout the rest of the day. Over the course of a 32 week-long study, detailed in the journal Steroids, participants who added dessert to their breakfast — cookies, cake, or chocolate — lost an average of 40 lbs. more than a group that avoided such foods. What's more, they kept off the pounds longer.

The scale tells the tale

A meal in the morning provides energy for the day's tasks, aids in brain functioning, and kick-starts the body's metabolism, making it crucial for weight loss and maintenance. And breakfast is the meal that most successfully regulates ghrelin, the hormone that increases hunger, explains Prof. Jakubowicz. While the level of ghrelin rises before every meal, it is suppressed most effectively at breakfast time.

Basing their study on this fact, the researchers hoped to determine whether meal time and composition impacted weight loss in the short and long term, says Prof. Jakubowicz, or if it was a simple matter of calorie count.

One hundred and ninety three clinically obese, non-diabetic adults were randomly assigned to one of two diet groups with identical caloric intake — the men consumed 1600 calories per day and the women 1400. However, the first group was given a low carbohydrate diet including a small 300 calorie breakfast, and the second was given a 600 calorie breakfast high in protein and carbohydrates, always including a dessert item (i.e. chocolate).

Halfway through the study, participants in both groups had lost an average of 33 lbs. per person. But in the second half of the study, results differed drastically. The participants in the low-carbohydrate group regained an average of 22 lbs. per person, but participants in the group with a larger breakfast lost another 15 lbs. each. At the end of the 32 weeks, those who had consumed a 600 calorie breakfast had lost an average of 40 lbs. more per person than their peers.

Realistic in the long run

One of the biggest challenges that people face is keeping weight off in the long-term, says Prof. Jakubowicz. Ingesting a higher proportion of our daily calories at breakfast makes sense. It’s not only good for body function, but it also alleviates cravings. Highly restrictive diets that forbid desserts and carbohydrates are initially effective, but often cause dieters to stray from their food plans as a result of withdrawal-like symptoms. They wind up regaining much of the weight they lost during the diet proper.

Though they consumed the same daily amount of calories, "the participants in the low carbohydrate diet group had less satisfaction, and felt that they were not full," she says, noting that their cravings for sugars and carbohydrates were more intense and eventually caused them to cheat on the diet plan. "But the group that consumed a bigger breakfast, including dessert, experienced few if any cravings for these foods later in the day."

Ultimately, this shows that a diet must be realistic to be adopted as part of a new lifestyle. Curbing cravings is better than deprivation for weight loss success, Prof. Jakubowicz concludes.


New Method to Manage Stress Responses for More Successful Tumor Removal
1/30/2012

TAU-developed drug treatment in clinical trials may improve the outcome for cancer surgery patients

The week before and two weeks after surgery are a critical period for the long-term survival rate of cancer patients. Physiological and psychological stresses caused by the surgery itself can inhibit the body's immune responses, heightening vulnerability to tumor progression and spreading.

Now a new clinical trial by Prof. Shamgar Ben-Eliyahu of Tel Aviv University's School of Psychological Sciences and Dr. Oded Zmora will combine two medications originally used to treat excessive stress and inflammatory responses at Israel's Tel Hashomer Sheba Medical Center. The trial is the culmination of 15 years of research on the connection between the body's stress responses, immune functions, and tumor metastasis — the process of cancer cells spreading to new tissue. In pre-clinical studies on animal models, long-term post-operative survival rates increased by up to 300 percent.

"Given our current understanding of how psychological and physiological stress help tumor cells to spread, we can now intervene in a simple and effective manner," says Prof. Ben-Eliyahu, whose research has been published in a number of journals, including the Journal of Immunology, PLoS One, and Annals of Surgery.

The mind-body connection

Though critical for the treatment of cancerous tumors, surgery can cause untold stress on the patient. The psychological stress and anxiety surrounding the surgery itself is obvious, but physiological processes that occur due to the surgical removal of the primary tumor also cause the body to release stress hormones that markedly inhibit the functioning of the immune system.

And just when the body is lowering its defenses, tumor cells are shifting into high gear. Hormones like prostaglandins and catecholamines, which weaken the body's immune defence, also directly strengthen cancer cells, making them more aggressive and efficient in their invasion of new tissues throughout the body, Prof. Ben-Eliyahu explains. "Through selection, similar to evolutionary processes, tumor cells have acquired a mechanism to synchronize the timing of their progression when the body is more vulnerable to metastasis. When the entire body is under stress, they metastasize because they have a greater chance of surviving," he says.

Prof. Ben-Eliyahu's clinical approach addresses this problem, hindering tumor metastasis by addressing the patient's anxiety and physiological stress responses to surgery. The two-drug cocktail, which includes a generic version of a beta-adrenergic antagonist and a COX2 inhibitor — used to treat hypertension and anxiety, and to inhibit inflammation and pain — will be administered to patients over a twenty day period before, during and after surgery.

Saving on healthcare costs

For the first phase of the trial, Prof. Ben-Eliyahu and his team have already begun to recruit the 400 patients they want to include. The researchers are seeking grants and outside funding for a trial that is a crucial step in testing this treatment and hopefully making it widely available.

Typically, he says, pharmaceutical companies have strong financial incentives to support clinical trials, knowing that they could benefit from a new drug. In this case, however, the trial is based on medications that have been previously approved, are safe, inexpensive, and already widely used. Prof. Ben-Eliyahu is currently aiming to recruit the necessary funds to conduct this clinical trial without the help of commercial resources.

"In the broader scheme of health and healthcare systems, we can help save lives and a lot of money," he notes, pointing out that with this drug treatment, governments and individuals will spend less on the long-term care of cancer patients, with fewer numbers experiencing tumor recurrence.


Muscling In on MS
1/26/2012

Multiple sclerosis (MS), a neurodegenerative disease, causes periodic attacks of neurologic symptoms such as limb weakness and mobility defects. And while MS patients' walking abilities and muscle strength are examined on a regular basis, doctors have yet to determine when the lower limb muscles begin to deteriorate. That's important because with earlier identification of mobility problems, doctors would be able to implement early intervention programs that could make all the difference for those with MS.

Now, Dr. Alon Kalron and his fellow researchers from Tel Aviv University's Sackler Faculty of Medicine and the Multiple Sclerosis Centre in Sheba Medical Center, Tel-Hashomer, have discovered that specific laboratory tests for leg muscle endurance and gait — the pattern of movement while walking or running — are highly effective in identifying mobility deficits at the initial stage of MS. These deficits are difficult to discover during standard neurological testing.

According to Dr. Kalron, who was supervised by Profs. Anat Achiron and Zeevi Dvir, patients in the early stages of MS had 40 percent less muscle endurance compared to their healthy counterparts. Additionally, distinct abnormalities were observed in their walking patterns. The study, which was published in the Journal of Neurologic Physiotherapy, could help researchers understand the mechanisms underlying the evolution of MS, and improve the management of patients afflicted with the disease.

One step at a time

Reduced muscle endurance may be one of the earliest signs of MS and is a common complaint among patients, but it is hard to detect, says Dr. Kalron. In order to quantify muscle fatigue, the researchers conducted a study that included 52 patients in the early stage of MS, and a control group of 28 healthy subjects.

Participants were examined using an isokinetic dynamometer, a special instrument for measuring lower limb muscle strength and endurance. They were asked to attempt to bend or straighten a knee exerting maximum effort, and maintain this position for 30 seconds. Muscle fatigue was calculated by measuring the decline in muscle strength during that period. On average, those in the early stages of MS were not able to maintain their strength — they demonstrated 40 percent less endurance compared to the healthy control group.

In addition, patients' gait was observed for factors such as how far a patient spreads his legs while walking, the length of their steps, and symmetry of movement. By examining walking patterns, the researchers discovered specific abnormalities in the MS group. Patients in the early stages of MS "tend to walk with a wider base, because walking with your legs further apart helps to improve stability. It's probably a compensation strategy due to the lower muscle endurance," explains Dr. Kalron. The participants in the MS group also walked more slowly, in an asymmetrical pattern with shorter steps.

Giving physical therapy a head start

Clinicians should be more aware of possible gait and lower limb muscle deficits very early in the disease process, especially because minor impairments are difficult to detect with regular neurological examinations. "The downside of detecting such deficits using advanced instruments is offset by the positive potential of early intervention programs," suggests Dr. Kalron. "If we find the abnormalities earlier, then we can start intervention programs when they have a chance to benefit the most." Programs based around physical therapy and fitness can help MS patients maintain higher levels of muscle endurance and improve balance, holding off the fatigue that typically accompanies the disease.


Patterns of Chromosome Abnormality: The Key to Cancer?
1/23/2012

Chromosome aberrations happen in pairs when it comes to cancer, TAU research finds

A healthy genome is characterized by 23 pairs of chromosomes, and even a small change in this structure — such as an extra copy of a single chromosome — can lead to severe physical impairment. So it's no surprise that when it comes to cancer, chromosomal structure is frequently a contributing factor, says Prof. Ron Shamir of the Blavatnik School of Computer Science at Tel Aviv University.

Now Prof. Shamir and his former doctoral students Michal Ozery-Flato and Chaim Linhart, along with fellow researchers Prof. Shai Izraeli and Dr. Luba Trakhtenbrot from the Sheba Medical Center, have combined techniques from computer science and statistics to discover that many chromosomal pairs are lost or gained together across various cancer types. Moreover, the researchers discovered a new commonality of chromosomal aberrations among embryonic cancer types, such as kidney, skeleton, and liver cancers.

These findings, recently published in Genome Biology, could reveal more about the nature of cancer. As cancer develops, the genome becomes increasingly mutated — and identifying the pattern of mutation can help us to understand the nature and the progression of many different kinds of cancer, says Prof. Shamir.

Looking at the big picture

As cancer progresses, the structure of chromosomes is rearranged, individual chromosomes are duplicated or lost, and the genome becomes abnormal. Some forms of cancer can even be diagnosed by identifying individual chromosomal aberrations, notes Prof. Shamir, pointing to the example of a specific type of leukemia that is caused by small piece of chromosome 9 being moved to chromosome 22.

When analyzing many different kinds of cancer, however, the researchers discovered that chromosomal aberrations among different cancers happen together in a noticeable and significant way. The researchers studied a collection of more than fifty thousand cancer karyotypes — representations of chromosomal layouts in a single cell — and charted them according to commonalities. The researchers were not only able to confirm different chromosomal aberrations that appeared in specific cancer types, but also for the first time identified a broader effect of pairs of chromosomes being lost or gained together across different cancer types.

It was also the first time that researchers saw a connection among solid kidney, skeleton, and liver cancers. While it was known that these cancers all develop in the embryo, they were previously analyzed independently. The TAU researchers have now confirmed that they share chromosomal characteristics and aberrations, much like various forms of leukemia or lymphomas.

Aberrations a driving force for cancer

Under normal circumstances, even a small change to a person's chromosomal structure can be devastating. For example, Down's syndrome is caused by a single extra copy of Chromosome 21. "But in cancer, there are many cases of extra or missing chromosomes. Yet cancer cells thrive more effectively than other cells," Prof. Shamir says.

Prof. Shamir hopes that future investigation into these chromosomal aberrations will give researchers more clues into why something that is so detrimental to our healthy development is so beneficial to this disease. Cancer is the result of sequences of events, he says, each causing the genome to become more mutated, mixed, and duplicated. Tracking these changes could aid our understanding of the driving forces of cancer's progress.

Prof. Shamir heads the Edmond J. Safra Program for Bioinformatics and holds the Raymond and Beverly Sackler Chair in Bioinformatics.


East Meets West to Boost Fertility
1/9/2012

Traditional Chinese medicine makes fertility treatments far more effective, TAU researchers discover

Traditional Chinese medicine has long been used to ease pain, treat disease, boost fertility, and prevent miscarriage. Known in the Western medical community by its acronym TCM, these traditional remedies include herbal preparations and acupuncture. Now Tel Aviv University researchers have discovered that a combination of TCM therapy and intrauterine insemination (IUI) is a winning solution for hopeful mommies who are having trouble conceiving.

In the first study that measures the effectiveness of both herbs and acupuncture in combination with IUI infertility treatment, Dr. Shahar Lev-Ari and Keren Sela of TAU's Sackler Faculty of Medicine and the Tel Aviv Medical Center say that the results, which have been published in the Journal of Integrative Medicine, show a significant increase in fertility when the therapies are administered side-by-side.

When combining IUI with TCM treatments, 65.5 percent of the test group were able to conceive, compared with 39.4 percent of the control group, who received no herbal or acupuncture therapy. The method is as "close to nature" as possible and can be used by women employing sperm donors, or after a partner's sperm is centrifuged to enhance its motility in the uterus.

Age-old therapies, contemporary medicine

Dr. Lev-Ari, a cellular biologist and head of the integrative medicine unit, works with both medical doctors and TCM practitioners at Tel Aviv Medical Center's Fertility Research Institute. He and Sela, a TCM practitioner specializing in women's health, have long been interested in how Chinese herbal and acupuncture therapies could work to boost Western-style fertility treatments, contributing to an increase in conception and take-home baby rates.

In a retrospective study, Dr. Lev-Ari and Sela followed the progress of 29 women between the ages of 30 and 45 who were receiving IUI treatment combined with TCM therapy, and compared their results to a control group of 94 women between the ages of 28 and 46 who were undergoing IUI treatment alone. In addition to their IUI treatments, the 29 women in the first group received weekly sessions of acupuncture and a regime of Chinese medicinals, which consisted of powdered or raw Chinese herbs such as PeoniaAlbae and Chuanxiong, designed to meet each woman's specific needs. All herbal preparations were approved by the Israeli Health Ministry.

In terms of both conception and take-home baby rates, the test group fared far better than the control group. Out of the 29 women in the test group, 65.5 percent conceived, and 41.4 percent delivered healthy babies. In the control group, only 39.4 percent conceived and 26.9 percent delivered. The vast difference in success rates is even more surprising when the age of the average participant was taken into account, Dr. Lev-Ari and Sela note. "The average age of the women in the study group was 39.4, while that of the control group was 37.1. Normally, the older the mother, the lower the pregnancy and delivery rates," they explain.

Promoting balance and harmony in the womb

According to the researchers, TCM is aimed at correcting imbalances in the body's natural energy flow, promoting an overall sense of well-being. There are several theories as to why Chinese medicine can be beneficial to fertility rates, including the possibility that herbal remedies and acupuncture can affect the ovulation and menstrual cycle, enhance blood flow to the uterus, and enhance endorphin production and secretion to inhibit the central nervous system and induce calm — all of which can contribute to successful conception.

Now that the researchers have established that TCM can have a major impact on the success of fertility treatments, they plan to design randomized clinical trials, including placebos, to further validate their initial findings.


Diabetic Mice Provide a Surprising Breakthrough for Multiple Sclerosis Research
1/5/2012

New laboratory approach could aid brain recovery, TAU research finds

In humans, active periods of the debilitating disease Multiple Sclerosis (MS) can last for mere minutes or extend to weeks at a time. They're caused by lesions in the brain that develop, partly heal, and then recur. Research into a cure has been difficult, because to date scientists have not been able to replicate these brain recurring symptoms in laboratory mice. That's frustrating because these lab animals, known as animal "models," are the primary tool for research into the mechanisms and potential treatments for MS.

But now, by using a mouse model for diabetes instead, Dr. Dan Frenkel of Tel Aviv University's Department of Neurobiology, working alongside Prof. Yaniv Assaf and Ph.D. student Hilit Levy, may provide a surprising breakthrough for research into a cure for MS. The team has discovered that when mice with Type 1 Diabetes are injected with myelin protein — the insulating material that coats neurons — they experience the periods of relapsing and remitting disability associated with brain lesions in humans. And for the first time, they've been able to monitor this brain lesion process using magnetic resonance imaging.

Dr. Frenkel believes his finding will lead to the development of more effective treatments for MS. This research has been published in Experimental Neurology.

Tracking lesions in the brain

MS, an autoimmune disease in which the immune system attacks in the brain and inhibits the transfer of signals between neurons, often leads to devastating disabilities such as blindness and paralysis. From its onset, the disease attacks in peaks which become increasingly more severe until patients are permanently disabled.

Traditionally, mouse model populations for MS research have been created by injecting mice with myelin protein emulsified in bacteria. With the addition of bacteria, the immune system mobilizes against the myelin, creating an MS-like autoimmune response. However, the disease does not present in this model as it does in human sufferers — most mouse models experience a single inflammatory peak which leaves them with permanent symptoms such paralysis of the legs. The damage can be detected in the spinal cord, but not in the brain.

"We discovered that when we gave them the same myelin protein injection, a mouse model that develops Type 1 Diabetes will instead exhibit peaks of inflammatory responses similar to those of chronic progressive MS, which relapses and remits," Dr. Frenkel says. The mice also suffer from brain lesions in addition to spinal cord damage, making them a more viable model for studying and developing treatment for MS in humans.

Using a special MRI machine for imaging small animals, the researchers followed each mouse model over the course of several months, noting the activity of the brain and the development of lesions corresponding to peaks of inflammation. The lesions and the inflammation in the brain can be followed in the same way within these animals as in a human with MS, says Dr. Frenkel. "Now, we can follow the different stages that occur after the autoimmune response is already triggered, and look for different targets that will not only help to enhance recovery, but prevent further damage as well."

Turning temporary recovery into permanent repair

Currently, all FDA approved drugs on the market to treat MS were developed using traditional mouse models. Their focus is to delay the clinical signs of the disease caused by autoimmunity, lengthening the time between attacks. So far, this method has led to a temporary fix, but not a cure. With his alternative mouse model, Dr. Frenkel says, researchers can gather more information on how the brain heals after an attack, and start to develop treatment options that mimic this natural recovery process — turning temporary recovery into permanent repair.

"With the use of magnetic resonance imaging, we can follow the brain lesions within the mouse model, and characterize the process of relapsing," Dr. Frenkel says. They have already begun to develop treatments with initial success. “We are looking at ways to encourage the glia cells — cells in the brain that support the neurons — to promote brain repair," he says.


Turn Down the iPod to Save Your Hearing
12/28/2011

Using MP3 players at high volume puts teens at risk for early hearing loss, say TAU researchers

Today's ubiquitous MP3 players permit users to listen to crystal-clear tunes at high volume for hours on end — a marked improvement on the days of the Walkman. But according to Tel Aviv University research, these advances have also turned personal listening devices into a serious health hazard, with teenagers as the most at-risk group.

One in four teens is in danger of early hearing loss as a direct result of these listening habits, says Prof. Chava Muchnik of TAU's Department of Communication Disorders in the Stanley Steyer School of Health Professions at the Sackler Faculty of Medicine and the Sheba Medical Center. With her colleagues Dr. Ricky Kaplan-Neeman, Dr. Noam Amir, and Ester Shabtai, Prof. Muchnik studied teens' music listening habits and took acoustic measurements of preferred listening levels.

The results, published in the International Journal of Audiology, demonstrate clearly that teens have harmful music-listening habits when it comes to iPods and other MP3 devices. "In 10 or 20 years it will be too late to realize that an entire generation of young people is suffering from hearing problems much earlier than expected from natural aging," says Prof. Muchnik.

Hearing loss before middle age

Hearing loss caused by continuous exposure to loud noise is a slow and progressive process. People may not notice the harm they are causing until years of accumulated damage begin to take hold, warns Prof. Muchnik. Those who are misusing MP3 players today might find that their hearing begins to deteriorate as early as their 30's and 40's — much earlier than past generations.

The first stage of the study included 289 participants aged 13 to 17. They were asked to answer questions about their habits on personal listening devices (PLDs) — specifically, their preferred listening levels and the duration of their listening. In the second stage, measurements of these listening levels were performed on 74 teens in both quiet and noisy environments. The measured volume levels were used to calculate the potential risk to hearing according to damage risk criteria laid out by industrial health and safety regulations.

The study's findings are worrisome, says Prof. Muchnik. Eighty percent of teens use their PLDs regularly, with 21 percent listening from one to four hours daily, and eight percent listening more than four hours consecutively. Taken together with the acoustic measurement results, the data indicate that a quarter of the participants are at severe risk for hearing loss.

Dangerous decibels

Currently, industry-related health and safety regulations are the only benchmark for measuring the harm caused by continuous exposure to high volume noise. But there is a real need for additional music risk criteria in order to prevent music-induced hearing loss, Prof. Muchnik says. In the meantime, she recommends that manufacturers adopt the European standards that limit the output of PLDs to 100 decibels. Currently, maximum decibel levels can differ from model to model, but some can go up to 129 decibels.

Steps can also be taken by schools and parents, she says. Some school boards are developing programs to increase awareness of hearing health, such as the "Dangerous Decibels" program in Oregon schools, which provides early education on the subject. Teens could also choose over-the-ear headphones instead of the ear buds that commonly come with an iPod.

In the near future, the researchers will focus on the music listening habits of younger children, including pre-teens, and the development of advanced technological solutions to enable the safe use of PLDs.


A "Fantastic Voyage" Through the Body -- with Precision Control
12/15/2011

TAU researcher develops capsule endoscope controlled by MRI to investigate digestive system

Endoscopes — small cameras or optic fibres that are usually attached to flexible tubing designed to investigate the interior of the body — can be dangerously invasive. Procedures often require sedative medications and some recovery time. Now a researcher at Tel Aviv University is developing a "capsule endoscope" that can move through the digestive tract to detect problems independent of any attachments.

According to Dr. Gabor Kosa of TAU's School of Mechanical Engineering, the project is inspired by an endoscopic capsule designed for use in the small intestine. But unlike the existing capsule, which travels at random and snaps pictures every half second to give doctors an overall view of the intestines, the new "wireless" capsules will use the magnetic field of a magnetic resonance imaging (MRI) machine and electronic signals manipulated by those operating the capsule to forge a more precise and deliberate path.

It's a less invasive and more accurate way for doctors to get an important look at the digestive tract, where difficult-to-diagnose tumors or wounds may be hidden, or allow for treatments such as biopsies or local drug delivery. The technology, which was recently reported in Biomedical Microdevices, was developed in collaboration with Peter Jakab, an engineer from the Surgical Planning Laboratory at Brigham and Women's Hospital in Boston, affiliated with Harvard Medical School.

Swimming with the current

What sets this endoscope apart is its ability to actively explore the digestive tract under the direction of a doctor. To do this, the device relies on the magnetic field of the MRI machine as a "driving force," says Dr. Kosa. "An MRI has a very large constant magnetic field," he explains. "The capsule needs to navigate according to this field, like a sailboat sailing with the wind."

In order to help the capsules "swim" with the magnetic current, the researchers have given them "tails," a combination of copper coils and flexible polymer. The magnetic field creates a vibration in the tail which allows for movement, and electronics and microsensors embedded in the capsule allow the capsule's operator to manipulate the magnetic field that guides the movement of the device. The use of copper, a non-ferro magnetic material, circumvents other diagnostic challenges posed by MRI, Dr. Kosa adds. While most magnets interfere with MRI by obscuring the picture, copper appears as only a minor blot on otherwise clear film.

The ability to drive the capsule, Dr. Kosa says, will not only lead to better diagnosis capabilities, but patients will experience a less invasive procedure in a fraction of the time.

Microrobotics of the future

In the lab at the Brigham and Women's Hospital, Dr. Kosa and his fellow researchers have tested the driving mechanism of the capsule in an aquarium inside the MRI. The results have shown that the capsule can successfully be manipulated using a magnetic field. Moving forward, the researchers are hoping to further develop the capsule's endoscopic and signalling functions.

According to Dr. Kosa, a new faculty recruit to TAU, this project is part of a bright future for the field of microrobotics. At the university, his new research lab, called RBM2S, focuses on microsystems and robotics for biomedical applications, and an educational robotics lab, ERL, will teach future robotics experts studying at TAU's School of Mechanical Engineering.  


Beating Superbugs with a High-Tech Cleanser
12/8/2011

TAU engineers an easy-to-use solution to make hospitals safer

According to the World Health Organization, antibiotic-resistant bacteria are one of the top three threats to human health. Patients in hospitals are especially at risk, with almost 100,000 deaths due to infection every year in the U.S. alone.

Now Dr. Udi Qimron of the Department of Clinical Microbiology and Immunology at Tel Aviv University's Sackler Faculty of Medicine has developed an efficient and cost-effective liquid solution that can help fight antibiotic-resistant bacteria and keep more patients safe from life-threatening infections. The solution is based on specially designed bacteriophages — viruses that infect bacteria — that can alter the genetic make-up of antibiotic-resistant bacteria. "We have genetically engineered the bacteriophages so that once they infect the bacteria, they transfer a dominant gene that confers renewed sensitivity to certain antibiotics," explains Dr. Qimron.

The solution, recently detailed in the journal Applied and Environmental Microbiology, could be added to common antibacterial cleansers used on hospital surfaces, turning resistant bacteria into sensitive bacteria. It's easy to prepare, easy to apply, and non-toxic, Dr. Qimron notes. He estimates that one liter of the growth medium — the liquid in which the bacteriophages are grown — will cost just a few dollars.

The research was done in collaboration with Ph.D. student Nir Friedman, lab technician Shahar Mor, and Dr. Rotem Edgar of the Ichilov Medical Center.

Changing bacteria's genetics

Certain antibiotics are designed to target and bind to a part of the bacteria cell called a ribosome — the protein factory of the cell. But after continual and frequent exposure to antibiotics, the bacteria "learn" to change components in the ribosome itself so that the antibiotics are unable to bind.

Dr. Qimron and his colleagues set out to determine whether they could make resistant bacteria sensitive to antibiotics again by re-introducing a component of the ribosome, a gene called rpsL, which restores bacteria's sensitivity to antibiotics. "Our novel approach relies on an effective delivery process and selection procedure, put on the same platform for the first time," says Dr. Qimron. With this system, the sensitive bacteria takes over the ecological niche once occupied by the resistant bacteria. And if a patient does happen to become infected by lingering bacteria anyway, traditional antibiotics can again be used as an effective treatment.

Two steps to disarming bacteria

Added to cleansers, Tellurite represents the second step in a two-part process. A Tellurite compound, which is toxic to bacteria, would also be spread on all surfaces to wipe out the bacteria that had not been rendered sensitive, and thus the entire population of the surface bacteria would be sensitized. The combination is designed to first disarm, and then kill dangerous bacteria.

Next, the solution will be tested in pre-clinical animal trials to ensure its safety before being made available for wider use at hospitals. Once its safety is guaranteed, the solution will come in a bottle, says Dr. Qimron, and easily added to a bucket or spray.


Blasting Cancer from the Inside Out
12/6/2011

TAU develops tumor destruction method that also creates immunity

Even when surgical tumor removal is combined with a heavy dose of chemotherapy or radiation, there's no guarantee that the cancer will not return. Now researchers at Tel Aviv University are strengthening the odds in favor of permanent tumor destruction — and an immunity to the cancer's return — with a new method of tumor removal.

Based on "tumor ablation," a process through which the tumor is destroyed inside the body, Prof. Yona Keisari of TAU's Sackler Faculty of Medicine and Prof. Itzhak Kelson of TAU's Department of Physics and Astronomy have developed a radioactive wire, less than an inch long and about the width of a pin. When inserted into a solid tumor, the wire releases lethal radioactive atoms that irradiate the tumor from the inside out.

As it breaks down, the tumor releases antigens which trigger an immune response against the cancerous cells, Prof. Keisari explains. Not only are cancerous cells more reliably destroyed, but in the majority of cases the body develops immunity against the return of the tumor, a rare happening when the tumor is removed surgically.

The research has been published in a number of academic journals, most recently Translational Research.

A cancer-fighting cluster bomb

Currently, cancer patients receive gamma radiation when they undergo radiation therapy. Although alpha particles are much more effective, their range is so short that they're unable to penetrate the skin, and therefore ineffective in traditional radiation treatments. As developed in Prof. Kelson's lab, the radioactive wire circumvents the drawbacks of alpha radiation by implanting radioactive ions directly into the tumor.

"The wire is coated in atoms that emit not just alpha particles, but also daughter atoms which are themselves alpha emitters. These particles diffuse inside the tumor, spreading further and further before disintegrating," Prof. Kelson explains. "It's like a cluster bomb — instead of detonating at one point, the atoms continuously disperse and emit alpha particles at increasing distances." The process takes approximately ten days, leaving only non-radioactive and non-toxic amounts of lead. The wire itself, which is initially inserted into the tumor by hypodermic needle, decays harmlessly in the body.

In pre-clinical trials on mouse models, this method has shown a distinct advantage over surgical tumor removal. One group of the mice was treated with surgical tumor removal, while another group underwent ablation treatment using the radioactive wire. When cells from the tumor were re-injected into the subject, 100 percent of those treated surgically redeveloped their tumor, compared to only 50 percent of those treated with the radioactive wire. The researchers have had excellent results with many types of cancer models, including lung, pancreatic, colon, breast, and brain tumors.

Ultimately, this shows that tumor removal by ablation increases immunity against the return of the cancerous tumor cells. "Surgery can eliminate 80 to 90 percent of a tumor, chemotherapy another 5-15 percent," says Prof. Keisari. "There are often a small number of metastatic cells left in the body, and they kill about 85% of the patients." Ablation methods, through the stimulation of specific anti-tumor immunity, have a better record for killing off the cancer cells that escape other types of treatment. It's also less invasive, more efficient, and more cost-effective.

Technology heads to trial

The treatment, called DαRTTM (Diffusing Alpha-emitters Radiation Therapy), has now been commercialized by Althera Medical Ltd., co-located in Tel Aviv and New York City, and will soon undergo clinical trials at Beilinson Hospital in Israel.

According to Prof. Keisari, this is just the beginning of an emerging field of cancer treatment. He hopes to see researchers from all over the world come together to create a comprehensive view of the advances in tumor ablation and the stimulation of anti-tumor immunity.

In collaboration with Prof. Rafi Korenstein, also of the Sackler Facutly of Medicine, Prof. Keisari has developed a second ablation technique, called pulsed electric current ablation, in which electrodes are inserted into tumors and emit electrical currents to create a chemical reaction that destroys the tumor.


"Just Chill?" Relaxing Can Make You Fatter
12/1/2011

Conventional wisdom says that exercise is a key to weight loss — a no-brainer. But now, Tel Aviv University researchers are revealing that life as a couch potato, stretched out in front of the TV, can actually be "active inactivity" — and cause you to pack on the pounds.

Such inactivity actually encourages the body to create new fat in fat cells, says Prof. Amit Gefen of TAU's Department of Biomedical Engineering. Along with his Ph.D. student Naama Shoham, Prof. Gefen has shown that preadipocyte cells — the precursors to fat cells — turn into fat cells faster and produce even more fat when subject to prolonged periods of "mechanical stretching loads" — the kind of weight we put on our body tissues when we sit or lie down.

The research, which has been published in the American Journal of Physiology — Cell Physiology, demonstrates another damaging effect of a modern, sedentary lifestyle, Prof. Gefen notes. "Obesity is more than just an imbalance of calories. Cells themselves are also responsive to their mechanical environment. Fat cells produce more triglycerides, and at a faster rate, when exposed to static stretching."

Stretching the fat

Prof. Gefen, who investigates chronic wounds that plague bed-ridden or wheelchair-bound patients, notes that muscle atrophy is a common side effect of prolonged inactivity. Studying MRI images of the muscle tissue of patients paralyzed by spinal cord injuries, he noticed that, over time, lines of fat cells were invading major muscles in the body. This spurred an investigation into how mechanical load — the amount of force placed on a particular area occupied by cells — could be encouraging fat tissue to expand.

In the lab, Prof. Gefen and his fellow researchers stimulated preadipocytes with glucose or insulin to differentiate them into fat cells. Then they placed individual cells in a cell-stretching device, attaching them to a flexible, elastic substrate. The test group of cells were stretched consistently for long periods of time, representing extended periods of sitting or lying down, while a control group of cells was not.

Tracking the cultures over time, the researchers noted the development of lipid droplets in both the test and control groups of cells. However, after just two weeks of consistent stretching, the test group developed significantly more — and larger — lipid droplets. By the time the cells reached maturity, the cultures that received mechanical stretching had developed fifty percent more fat than the control culture.

They were, in effect, half-again fatter.

According to Prof. Gefen, this is the first study that looks at fat cells as they develop, taking into account the impact of sustained mechanical loading on cell differentiation. "There are various ways that cells can sense mechanical loading," he explains, which helps them to measure their environment and triggers various chemical processes. "It appears that long periods of static mechanical loading and stretching, due to the weight of the body when sitting or lying, has an impact on increasing lipid production."

Counting more than calories

These findings indicate that we need to take our cells' mechanical environment into account as well as pay attention to calories consumed and burned, believes Prof. Gefen. Although there are extreme cases, such as people confined to wheelchairs or beds due to medical conditions, many of us live a too sedentary lifestyle, spending most of the day behind a desk. Even somebody with healthy diet and exercise habits will be negatively impacted by long periods of inactivity.

Next, Prof. Gefen and his fellow researchers will be investigating how long a period of time a person can sit or lie down without the mechanical load becoming a factor in fat production. But in the meantime, it certainly can't hurt to get up and take an occasional stroll, he suggests.

This research was done in collaboration with TAU's Ruth Gottlieb, Dr. Uri Zaretsky, and Dr. Orna Shaharabani-Yosef from the Department of Biomedical Engineering and Prof. Dafna Benayahu of the Department of Cell and Developmental Biology.


Bats, Dolphins, and Mole Rats Inspire Advances in Ultrasound Technology
11/14/2011

TAU researchers look to animal "return signals" to shape medical and military advances

Sonar and ultrasound, which use sound as a navigational device and to paint accurate pictures of an environment, are the basis of countless technologies, including medical ultrasound machines and submarine navigation systems. But when it comes to more accurate sonar and ultrasound, animals' "biosonar" capabilities still have the human race beat.

But not for long. In a new project that studies bats, dolphins, and mole rats, Prof. Nathan Intrator of Tel Aviv University's Blavatnik School of Computer Science, in collaboration with Brown University's Prof. Jim Simmons, is working to identify what gives biosonar the edge over human-made technologies. Using a unique method for measuring how the animals interpret the returning signals, Prof. Intrator has determined that the key to these animals' success is superior, real-time data processing. "Animal 'echolocations' are done in fractions of milliseconds, at a resolution so high that a dolphin can see a tennis ball from approximately 260 feet away," he says, noting that the animals are able to process several pieces of information simultaneously.

Their research, which has been reported in the Journal of the Acoustical Society of America and presented at the 2010 and 2011 MLSP conferences, could lead to cutting-edge navigation systems and more accurate medical imaging.

Detecting "shape" from sound

Biosonar animals send ultrasonic sounds called "pings" into the environment. The shape of the returning signals, or echoes, determines how these animals "see" their surroundings, helping them to navigate or hunt for prey. In a matter of tens of milliseconds, the neurons in the animal's brain are capable of a full-scale analysis of their surroundings represented in three dimensions, with little energy consumption. Even with the aid of a supercomputer, which consumes thousands of times more energy, humans cannot produce such an accurate picture, Prof. Intrator says. With echolocation, a bat can tell the difference between a fly in motion or at rest, or determine which of two fruits is heavier by observing their movements in the wind.

Intrigued by the quality of the natural world's biosonar over its man-made equivalents, Profs. Intrator and Simmons set out to study how biosonar animals perform echo location so quickly and accurately. Using an electronic system, they altered the frequency and noise levels of the echo returned to the animal.

By manipulating the echo, the researchers could determine what factors of the returning signal reduced an animal's ability to correctly analyze the returns. This in turn led to a better understanding of how the returning echoes are represented and analyzed in the animal's brain.

A more accurate view of the human body

Prof. Intrator and his fellow researchers have created mathematical models, involving machine learning and signal processing, that improve man's ability to interpret the echoes.This will lead to more accurate echo localization and better resilience to background noise.

Once researchers gather more information about animal interpretation of biosonar, they will be able to mimic this technology for better ultrasound and sonar systems, says Prof. Intrator. "Animals explore pings with multiple filters or receptive fields, and we have demonstrated that exploring each ping in multiple ways can lead to higher accuracy," he explains. "By understanding sonar animals, we can create a new family of ultrasound systems that will be able to explore our bodies with more accurate medical imaging."

This could provide a variety of benefits to the medical field, such as earlier detection of defects in embryos or non-invasive detection of cancer tumors. Unlike an MRI or CT machine, which are large, expensive to operate, and often use dangerous radiation, the new generation of ultrasound machines could be used in a doctor's office at a fraction of the cost. The research could also benefit military reconnaissance efforts both underwater and underground.


Polio Still a Threat to Public Health