Tag: Medicine

Researchers from Tel Aviv University compared treatment with a dedicated protocol of hyperbaric oxygen therapy (HBOT) to the pharmacology (drugs) treatment available today for patients suffering from fibromyalgia, a chronic pain syndrome, caused by traumatic brain injury (TBI). Their findings showed that dedicated hyperbaric oxygen therapy is much more effective in reducing pain than the drug treatment and ended up healing two out of five of the participants in the study.

Chronic Pain Syndrome

The study was conducted by researchers from Tel Aviv University’s Sackler Faculty of Medicine, led by Prof. Shai Efrati, MD, from the Sagol Center for Hyperbaric Medicine and Research at the Shamir Medical Center, and Prof. Jacob Ablin, MD, from the Tel Aviv Sourasky Medical Center. The results of the study were published in the journal PLOS One.  

“At the end of the treatment, two out of five patients in the hyperbaric treatment group showed such a significant improvement that they no longer met the criteria for fibromyalgia. In the drug treatment group, this did not happen to any patient.” Prof. Shai Efrati

“Fibromyalgia is a chronic pain syndrome, from which between 2% – 8% of the population suffers,” explains Prof. Shai Efrati. “Until 15-20 years ago, there were doctors who believed that it was a psychosomatic illness and recommended that patients with chronic pain seek mental health care. Today we know that it is a biological illness, which damages the brain’s processing of the signals received from the body. When this processing is malfunctioning, you feel pain without any real damage in related locations.”

“Fibromyalgia can be induced by variable triggers – from certain infections, as we have recently seen in post-COVID patients, through post-traumatic stress syndrome to head injuries. We wanted to test whether the new protocols of hyperbaric medicine can provide better results than pharmacological medicine, for patients in whom the fibromyalgia was induced by traumatic brain injury.”

Prof. Shai Efrati

Dramatic Results

Hyperbaric medicine is a form of treatment in which the patients stay in special chambers where the pressure is higher than the atmospheric pressure at sea level, and where the patients breathe 100% oxygen. Hyperbaric medicine is considered safe, used in many places including Israel, and is already used to treat a long list of medical conditions.

In recent years, scientific evidence has been accumulating that certain, newly developed, dedicated hyperbaric treatment protocols can lead to the growth of new blood vessels and neurons in the brain.

“Overall, existing treatments are not good enough. [Fibromyalgia] is a chronic disease that significantly affects the quality of life, including young people, and hyperbaric medicine meets an acute need of these patients.” Prof. Jacob Ablin

In their current study, the researchers from Tel Aviv University recruited 64 Israelis aged 18 and older who suffered from fibromyalgia as a result of a head injury, and randomly divided them into two groups: one group was exposed to 100% pure oxygen at a pressure of two atmospheres for 90 minutes (with fluctuations in oxygen during the treatment every 20 minutes), five days a week, for three months. The second group received the conventional pharmacological treatment (i.e., the drugs pregabalin, which is known under the trade name “Lyrica”, and duloxetine, which is better known as “Cymbalta”).

“The results were dramatic,” says Prof. Efrati. “At the end of the treatment, two out of five patients in the hyperbaric treatment group showed such a significant improvement that they no longer met the criteria for fibromyalgia. In the drug treatment group, this did not happen to any patient. Furthermore, the average improvement in the pain threshold tests was 12 times better in the hyperbaric group compared to the medication group. And in terms of quality-of-life indicators, as reported by the patients, we saw significant improvements in all the indicators among the patients who received hyperbaric treatment.”

Meets Acute Need

“Today’s accepted treatment for fibromyalgia includes pharmacologic and non-pharmacologic components,” says Prof. Ablin. “with respect to the pharmacologic approach, these drugs are not very effective and therefore the emphasis is on the non-pharmacological side, that is, on external correction of pain processing within the nervous system. Currently used recommendations includes aerobic activity, hydrotherapy, cognitive-behavioral therapy and movement-based therapies such as Tai Chi. In addition, quite a few patients request treatment with medical cannabis, and for some it helps.”

“In the group that received hyperbaric treatment, you could see the repair of the brain tissue, while in the control group there was only an attempt to relieve the pain – without treating the damaged tissue – and of course the medication group experienced the side effects associated with drug treatment.” Prof. Shai Efrati

“Overall, existing treatments are not good enough. [Fibromyalgia] is a chronic disease that significantly affects the quality of life, including young people, and hyperbaric medicine meets an acute need of these patients. Of course, these are preliminary studies, and we must follow and see what effect the medical protocol has on the patients after one, two and three years – and if it is necessary to maintain the positive results with further exposure to hyperbaric sessions.”

Looking to Cure

According to Prof. Efrati, the importance of the research is in healing the damaged brain tissue – and not in treating its superficial symptoms: “In the group that received hyperbaric treatment, you could see the repair of the brain tissue, while in the control group there was only an attempt to relieve the pain – without treating the damaged tissue – and of course the medication group experienced the side effects associated with drug treatment. This is a difference in approach: to cure instead of just treating the symptoms.”

“We assessed the improvement of the participants in the hyperbaric group more than a week after the last hyperbaric session. More follow-up studies are needed to see the duration of the beneficial effect of the treatment and if and for whom additional treatment will be needed. Our goal as doctors is not only to treat the symptoms but, to the extent possible, also to treat the source of the problem, thus improving the quality of life of fibromyalgia patients.”

“It is important to emphasize that the dedicated hyperbaric oxygen treatment protocol found to be effective is only available in medical centers that have licensed hyperbaric chambers. Be careful of so-called ‘private chambers’, since these cannot provide the therapeutic protocol found to be effective, and they are not regulated or approved for medical use,” cautions Prof. Efrati.

Brain metastases are one of the deadliest forms of cancer metastasis, with grave survival rates of less than one year in many cases. The incidence of brain metastases has been increasing in recent years and developing better therapeutic strategies for brain metastasis is an urgent need. In a new study from Tel Aviv University, researchers identified and characterized a new mechanism that facilitates the formation of brain metastases and found that impairing this mechanism significantly reduced the development of brain metastases in lab models.

“The findings establish LCN2 as a new prognostic marker and a potential therapeutic target.” Prof. Neta Erez

On the Radar: LCN2

The research was led by Prof. Neta Erez, head of the laboratory for the biology of tumors from the Department of Pathology at the Sackler Faculty of Medicine, and members of her team: Omer Adler, Yael Zeit, and Noam Cohen, in collaboration with Prof. Shlomit Yust Katz from Rabin Medical Center (Beilinson Hospital) and Prof. Tobias Pukrop from Regensburg Hospital, Germany. The study was supported by the Melanoma Research Alliance (MRA), the Cancer Biology Research Center at Tel Aviv University, the Personalized Medicine Program of the Israel Science Foundation (ISF IPMP) and the German Cancer Research Foundation (DFG), and was published in the journal Nature Cancer.

In this new study, the researchers show that Lipocalin-2 (LCN2) [a protein which in humans is encoded by the LCN2 gene] is a key factor in inducing neuroinflammation in the brain. Moreover, the researchers found that high LCN2 levels in patients’ blood and brain metastases from several types of cancer are associated with disease progression and reduced survival.

LCN2 is a secreted protein that functions in the innate immune system and was originally discovered due to its ability to bind iron molecules and as part of the inflammatory process in fighting bacterial infection. LCN2 is produced by a large variety of cells and was shown to be involved in multiple cancer-related processes.

“Our findings reveal a previously unknown mechanism, mediated by LCN2, which reveals a central role for the mutual interactions between immune cells recruited to the brain (granulocytes) and brain glial cells (astrocytes) in promoting inflammation and in the formation of brain metastases. The findings establish LCN2 as a new prognostic marker and a potential therapeutic target,” says Prof. Neta Erez.

“In blood and tissue samples from patients with brain metastases from three types of cancer, blood LCN2 levels were correlated with disease progression and with shorter survival, which positions LCN2 as a potential prognostic marker for brain metastases.” Prof. Neta Erez

LCN2 as a Predictive Marker for Brain Metastases

The researchers used models of melanoma and breast cancer brain metastases to reveal the mechanism by which neuroinflammation is activated in the metastatic niche in the brain.

“We show that signals secreted into the blood from the primary tumor stimulate pro-inflammatory activation of astrocytes in the brain. The astrocytes promote the recruitment of inflammatory cells from the bone marrow (granulocytes) into the brain, and they in turn become a main source of signaling by LCN2,” explains Prof. Erez.

“We demonstrated the importance of LCN2 for the development of metastases by genetically inhibiting its expression in mice, which resulted in a significant decrease in neuroinflammation and reduced brain metastases. Moreover, in blood and tissue samples from patients with brain metastases from three types of cancer, blood LCN2 levels were correlated with disease progression and with shorter survival, which positions LCN2 as a potential prognostic marker for brain metastases.”

Prof. Erez adds: “We analyzed the LCN2 protein levels in the blood and cerebrospinal fluid (CSF) of mice with brain metastases and found that LCN2 levels increased greatly in mice with melanoma and breast cancer metastases compared to healthy mice. Importantly – an increase in blood LCN2 preceded the detection of brain metastases by MRI. Furthermore, the mice in which LCN2 levels were very high developed brain metastases later, further establishing LCN2 as a predictive marker for brain metastases.”

The researchers also examined whether LCN2 is elevated in the blood of melanoma patients at the time of initial diagnosis, and whether it can be a prognostic factor. The findings indicated that patients with melanoma had significantly higher levels of LCN2 in their blood compared to samples from healthy individuals. Strikingly, patients who developed brain metastases displayed significantly higher levels of LCN2 even before the diagnosis of the metastases, and high levels of LCN2 in the blood correlated with worse survival.

“We have identified a new mechanism in which LCN2 mediates the communication between immune cells from the bone marrow and supporting cells in the brain, activates inflammatory mechanisms and thus helps the progression of metastatic disease in the brain, and demonstrated its importance. The functional and prognostic aspects of LCN2 that we have identified in brain metastases in mouse models as well as in cancer patients suggest that targeting LCN2 may be an effective therapeutic strategy to delay or prevent the recurrence of brain metastases,” summarizes Prof. Erez.

Researchers at Tel Aviv University identified a new genetic risk factor for the complex eye disease AMD (Age-related Macular Degeneration), a leading cause for loss of eyesight at an advanced age. For the first time, the researchers identified proteins that play a key role in the development and functioning of the tissue affected by the disease, found their exact sites in the genome, and discovered the connection between variations in these genomic regions and the risk for AMD. The researchers: “The new discovery enhances our understanding of the previously unknown function of genomic regions outside the genes. The method we applied may enable the deciphering of additional genetic mechanisms involved in various complex genetic diseases.”

“Comparative studies have identified whole genomic regions that are probably related to the disease but were unable to pinpoint any specific feature in these regions and define it as a risk factor. Our study addressed this problem.” Prof. Ran Elkon

Decoding Mechanisms of a Complex Disease

The study was led by Prof. Ruth Ashery-Padan and Prof. Ran Elkon and their research teams, Mazal Cohen Gulkar, Naama Mesika, Ahuvit David, and May Eshel, from the Department of Human Molecular Genetics and Biochemistry at the Sackler Faculty of Medicine and the Sagol School of Neuroscience at Tel Aviv University. The paper was published in PLOS Biology.

Prof. Ashery-Padan explains that “one of the greater challenges in genetic research today is decoding the genetic mechanisms of complex diseases caused by a combination of several different genetic and environmental factors (rather than an identifiable defect in a single gene). Diabetes, bowel diseases, and various mental illnesses are just a few examples. In our study we chose to focus on AMD, which causes degeneration of the central retina – a major cause of loss of vision at an advanced age in developed countries.”

Prof. Elkon adds: “AMD has a significant genetic component. Studies comparing the genomes of people with and without AMD (as well as a range of other complex genetic diseases) have found differences in several genomic regions, probably associated with risk factors for the disease. However, these differences were not detected in any specific gene, but rather in the extensive regions that stretch between the genes, whose functions and modes of operation are still largely unknown. In fact, comparative studies have identified whole genomic regions that are probably related to the disease but were unable to pinpoint any specific feature in these regions and define it as a risk factor. Our study addressed this problem.”

The study focused on the cells of a layer of tissue called retinal pigmented epithelium (RPE), which supports photoreceptors in the retina, and is essential for their initial development as well as their survival throughout an individual’s lifetime. According to the researchers, this tissue is affected right from the earliest stages of AMD.

Prof. Ruth Ashery-Padan

“Our findings provide new insight into a previously unsolved issue: the functions and mode of operation of genomic sequences located outside the genes, and how they are involved in complex genetic diseases.” Prof. Ruth Ashery-Padan

Novel Research Methodology

“First, we wanted to understand the genetic mechanism that activates and regulates the specific activity of pigmented epithelium cells,” says Prof. Ashery-Padan. “Through a series of experiments, knocking down different proteins in both a mouse model and human cells, we identified two key proteins, LHX2 and OTX2, which together dictate the expression of many genes unique to this tissue. The proteins act as transcriptional activators – binding to specific regulatory sites in the genome to determine which genes will be expressed in a particular cell.”

The next challenge was mapping the precise locations of the two proteins in the genome. The researchers used the innovative technology ChIP-seq – a DNA sequencing method that identifies binding sites where proteins bind to the DNA.

“We found that the binding sites of the two proteins were quite close to each other,” explains Prof. Elkon. “Moreover, these same sites had previously been identified as related to risk factors for AMD (namely, sequences that showed differences between people with and without AMD). We assume that due to changes in DNA sequences in these genomic regions, transcriptional proteins cannot easily find and bind with their binding sites. This reduces the expression of the nearby gene regulated by the transcriptional proteins, which encodes an ion channel known as important to eye function. The decrease in the gene’s activity affects the entire tissue, increasing the risk for development of AMD.”

Prof. Ashery-Padan sums up the study: “In our study we identified two proteins related to risk factors for the complex genetic eye disease AMD. In addition, for the first time, we were able to map the exact genomic sites of these proteins and found that they operate in a region previously identified as related to risk factors for AMD. Our findings provide new insight into a previously unsolved issue: the functions and mode of operation of genomic sequences located outside the genes, and how they are involved in complex genetic diseases. We believe that our novel research methodology will enable the identification and mapping of many other genetic mechanisms related to AMD and other complex genetic diseases.”

A new study examined the pain perception among people with autism and found that they experience pain at a higher intensity than the general population and are less adaptable to the sensation. This finding is contrary to the prevalent belief that people with autism are supposedly ‘indifferent to pain’. The researchers expressed the hope that the findings of their study will lead to more appropriate treatment on the part of medical staff, caregivers, and parents toward people with autism, who do not always express the experience of pain in the usual way.

The study was funded by the Israel Science Foundation and was led by four researchers: Dr. Tami Bar-Shalita of the Sackler Faculty of Medicine at Tel Aviv University who initiated the study, Dr. Yelena Granovsky of the Technion and Rambam Medical Center, and Prof. Irit Weissman-Fogel and Prof. Eynat Gal of the University of Haifa. This study constitutes a framework for the theses of PhD students Tzeela Hofmann and Mary Klingel-Levy, and three articles based on it have already been published or approved for publishing. The present study has been published in the prestigious PAIN journal.

“We know that self-harm could stem from attempts to suppress pain, and it could be that [people with autism] hurt themselves to activate, unconsciously, a physical mechanism of ‘pain inhibits pain’.” Dr. Tami Bar-Shalita

Self-harm Not Proof of Indifference to Pain

“Approximately 10% of the general population suffer from sensory modulation dysfunction, which means sensory hypersensitivity at a level that compromises normal daily functioning and quality of life. These people have difficulty, for example, ignoring or adapting to buzzing or flickering of fluorescent lights, humming of air conditioners or fans, or the crunching of popcorn by someone sitting next to them in the cinema,” explains Dr. Bar-Shalita.

“In previous studies in the lab we found that these people suffer from pain more than those without sensory modulation dysfunction. Since it is known that sensory modulation dysfunction occurs in   people with autism at a rate of 70-90%, it constitutes a criterion for diagnosing autism, and is associated with its severity. We were interested in exploring pain perception in autism, so we asked: do people with autism hurt more than the general population? This question was hardly studied in the lab before we got started.”

According to the researchers, for many years the prevalent opinion was that ‘people with autism hurt less’ or that they were ‘indifferent to pain’. Actually, ‘indifference to pain’ is one of the characteristics presented in the current diagnostic criteria of autism.

The proof of this was, supposedly, their tendency to inflict pain on themselves by self-harm. 

Dr. Bar-Shalita: “this assumption is not necessarily true. We know that self-harm could stem from attempts to suppress pain, and it could be that they hurt themselves to activate, unconsciously, a physical mechanism of ‘pain inhibits pain’.”

“The results of our study indicate that in most cases, the sensitivity to pain of people with autism is higher than that of most of the population, while at the same time they are unsuccessful at effectively suppressing painful stimuli.” Dr. Tami Bar-Shalita

Dr. Tami Bar-Shalita

Contributing to Advancement of Personalized Treatment

This study is a laboratory pain study approved by the ethics committee of the academic institutions and Rambam Medical Center. The study included 52 adults with high-functioning autism (HFA) and normal intelligence – hitherto the largest reported sample in the world in studies on pain among people with autism. The study made use of psychophysical tests to evaluate pain, commonly used in the area of pain study. These methods examine the link between stimulus and response, while the researcher, using a computer, controls the duration and intensity of stimulus and the examinee is asked to rank the intensity of the pain felt by him on a scale of 0 to 100.

The findings have proven beyond doubt that people with autism hurt more. Furthermore, their pain suppression mechanism is less effective.

The researchers conducted a variety of measurements, aimed among other things at examining whether the hypersensitivity to pain derives from a sensitized nervous system or from suppression of mechanisms that are supposed to enable adjustment and, over time, reduce the response to the stimulus. They found that in the case of people with autism, it is a combination of the two: an increase of the pain signal along with a less effective pain inhibition mechanism.

Dr. Bar-Shalita concludes: “our study constituted a comprehensive, in-depth study of the intensity of pain experienced by people with autism. The prevalent belief was that they are supposedly ‘indifferent to pain’, and there are reports that medical and other professional staff treated them accordingly. The results of our study indicate that in most cases, the sensitivity to pain of people with autism is higher than that of most of the population, while at the same time they are unsuccessful at effectively suppressing painful stimuli. We hope that our findings will benefit the professionals and practitioners handling this population and contribute to the advancement of personalized treatment.”

In additional articles soon to be published, the researchers have examined the brain activity of people with autism during pain stimuli, and sub-groups within this population concerning their perception of pain.