Gulf War Illness Information on Irritable Bowel Syndrome

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There are 6 new developments to report on under Irritable Bowel Syndrome that gulf war veterans should be aware. The 6 studies are listed below and then the articles in full follow. All of this is key research that all gulf war veterans with gulf war illness should be made aware of and I would suggest they keep a file for themselves and then also share the information with their own doctors civilian and/or VA.

Doctors are very busy and have little time to keep up on all the developments in research and this would be nice if veterans provide them a copy. It lets the doctors know you are educated and are good client consumers. It will also help bring the doctors up to speed faster to help us. I would also encourage extra copies to other health care providers.

And of course share this with other gulf war veterans freely!!! We need to help all in the educational process. As always please make your comments known either here in our comments section after the article or send me an email at [email protected]

If you are on facebook place it on your facebook page which helps others to be more informed. Everyone should transmit by all means email, facebook, etc etc!

1. N30 Pharma Announces FDA Approval To Initiate Phase 1 Clinical Trial For First-in-Class Drug

2. UCD Scientists Pinpoint Potential Key Regulator In Battle To Target Inflammatory Bowel Disease (IBD)

3. Scientists Target Possible Cause Of One Form Of Bowel Disease

4. Researchers Discover New Genetic Candidates For Irritable Bowel Syndrome

5. New Tool To Accelerate Discovery Of Autoimmune Disease Mechanisms And Therapies

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6. Study Finds Structural Brain Alterations In Patients With Irritable Bowel Syndrome

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1.
N30 Pharma Announces FDA Approval To Initiate Phase 1 Clinical Trial For First-in-Class Drug

Article Date: 05 Aug 2010 – 4:00 PDT

N30 Pharmaceuticals, LLC announced the approval of its Investigational New Drug Application for N6022 by the U.S. Food and Drug Administration. N6022, a first-in-class inhibitor of s-nitrosoglutathione reductase (GSNOR), has the potential to be an important new treatment for acute exacerbations of asthma, chronic obstructive pulmonary disease (COPD) and inflammatory bowel disease (IBD). N30 Pharma will now begin a first-in-man, Phase 1, dose escalation trial of N6022 in healthy subjects. The trial will assess the safety profile, tolerability and pharmacokinetics of single intravenous doses of N6022.

About N6022

N6022 is a highly potent, selective and reversible inhibitor of GSNOR. It is the lead product in N30 Pharma’s portfolio of drugs which are designed to treat asthma, COPD and IBD. N6022 will initially be tested using intravenous administration. Data from this first-in-man trial will provide important safety, pharmacokinetic, and biomarker information on which to base the design of subsequent trials of N6022 as well as the development of dosage forms suitable for chronic administration.

Targeting GSNOR

GSNOR breaks down s-nitrosoglutathione (GSNO), reducing the body’s pool of GSNO. In the lung, GSNO likely plays an important role in maintaining normal respiratory function through its influence on bronchial tone and anti-inflammatory effects. Similarly in the gut, GSNO supports barrier function and maintains the integrity of the gut surface. In asthmatics, GSNOR upregulation and decreased GSNO levels have been shown to contribute to respiratory disease, and genetic variants of GSNOR have been correlated with disease susceptibility and poor response to therapy. GSNO has also been found to be important in the cardiovascular system as well as the control of breathing.

About inhibitors of GSNOR

N30 Pharma’s portfolio of proprietary compounds provides a platform of potent, selective and reversible inhibitors of GSNOR. They increase levels of GSNO, an s-nitrosothiol that plays a central role in health and disease. N30 Pharma’s research efforts, along with the published literature, strongly support the concept that many aspects of asthma, COPD, IBD and cardiovascular diseases can be attenuated by inhibiting GSNOR. N30 Pharma’s discovery efforts have produced advanced development candidates that show efficacy with remarkable specificity when administered orally, intravenously and by inhalation in pre-clinical models of asthma, COPD, IBD, and cardiovascular disease. N30 Pharma has also developed a humanized monoclonal antibody to GSNOR which may be useful in identifying patient subsets that are more likely to respond to GSNOR inhibition.

Source: N30 Pharma

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2.
UCD Scientists Pinpoint Potential Key Regulator In Battle To Target Inflammatory Bowel Disease (IBD)

Article Date: 05 Aug 2010 – 4:00 PDT

Research into inflammatory bowel disease (IBD) led by UCD Conway Institute scientists with national and international collaborators has identified a key regulator involved in maintaining the functional integrity of the gut lining. The findings, published recently in the scientific journal, Gastroenterology, provide information that may be important in developing a new therapeutic approach to the treatment of the disease.

The underlying genetic or environmental causes of inflammatory bowel disease remain largely unknown. However, the major problem associated with this chronic condition is that the lining of the gut becomes leaky, allowing material from the lumen of the intestine to pass through this barrier and trigger an inflammatory response.

The intestinal barrier works by maintaining a delicate balance between the proliferation and death of epithelial cells at the surface of the barrier. If the balances tips so that more cells die than grow, as is the case in IBD, the barrier is no longer intact and cannot function properly.

This latest research led by Conway Fellow, Professor Cormac Taylor has shown that in the absence of an oxygen-sensing enzyme, prolyl hydroxylase 1 (PHD1), epithelial cell death is reduced and the intestinal barrier function is enhanced. Therefore, PHD1 may be a useful target for pharmacologic inhibition in IBD.

The team, which includes scientists from the University of Leuven, Belgium; University of Heidleberg, Germany; University College London and the Institute of Molecular Medicine, Trinity College Dublin, propose that by delaying or suppressing epithelial cell death, the gut lining would be given time to heal and the integrity of the intestinal barrier could be restored.

Commenting on the research, Professor Taylor said “Inflammatory bowel disease is a condition in need of new and improved therapeutic options. Our current results indicate that targeting the PHD1 enzyme may represent one such approach.”

In separate but related research, the Taylor group collaborate with the Irish biopharmaceutical development company, Sigmoid Pharma to facilitate targeted drug delivery to specific areas of the gut as part of a new therapeutic approach to the treatment of IBD.

Science Foundation Ireland and the German Research Foundation funded the research by this group.

Source: UCD Conway Institute of Biomolecular & Biomedical Research

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3.
Scientists Target Possible Cause Of One Form Of Bowel Disease

Article Date: 04 Aug 2010 – 3:00 PDT

A possible cause of irritable bowel syndrome has been traced to a small piece of RNA that blocks a substance protecting the colon membrane, leading to hostile conditions that can produce diarrhea, bloating and chronic abdominal pain.

New research shows that this RNA segment sends signals that stop the activity of the gene that produces glutamine, an amino acid. Previous research has linked a shortage of glutamine in the gut with the seepage of toxins and bacteria through the intestinal wall, irritating nerves and creating disease symptoms.

Scientists say that trying to generate glutamine in the disordered bowel by silencing this RNA segment could open up a whole new way of thinking about treating the diarrhea-predominant type of irritable bowel syndrome (IBS). In the meantime, they are making plans to conduct a clinical trial to see if glutamine supplements could also reduce common IBS symptoms.

This form of the disorder is characterized by diarrhea and bloating as well as chronic abdominal pain that is difficult to treat. About a third of IBS patients have the diarrhea-predominant type, another third experience consistent constipation, and the rest experience alternating bouts of diarrhea and constipation.

In the Ohio State University study, researchers observed that in human tissue samples, the presence of this small piece of RNA was associated with reduced activity by the gene that produces glutamine. Lower levels of glutamine were seen only in tissue samples from patients with the diarrhea-predominant type of IBS.

A group of these patients also had a condition called increased intestinal permeability, which allows toxins and bacteria into the colon that typically can’t get in. The resulting irritation to nerves in the colon is believed to contribute to diarrhea and abdominal pain. The finding suggests that the glutamine deficiency is connected to the increased intestinal permeability, which dramatically increases the likelihood that diarrhea-predominant IBS symptoms will follow The researchers say that manipulating that tiny piece of RNA, known as microRNA-29a, has potential as a novel treatment for IBS. “We’ve known about characteristics of this disease, but we didn’t know the reasons behind them. This study helps us connect everything together. Maybe if we can modulate the microRNA, we can heal the disease. That is our whole hypothesis,” said QiQi Zhou, assistant professor of internal medicine at Ohio State and lead author of the study.

The research is published in a recent issue of the journal Gut.

While testing the effectiveness of glutamine supplementation in IBS patients could lead to a viable treatment for symptoms, the researchers say it is important to continue to pursue the underlying cause of IBS.

“We treat the disorder, but we still don’t understand it completely,” said study senior co-author G. Nicholas Verne, professor of internal medicine and director of the Division of Gastroenterology, Hepatology and Nutrition at Ohio State. “We often have to use multiple therapies to attack the symptoms, but the pain is by far the most difficult to treat. For some patients, the pain responds only to escalating doses of narcotics or tricyclic antidepressants.

“That’s why if we had a specific target for an underlying structural defect, we could try to resolve that defect as a much more effective way to reduce the symptoms.”

Zhou, Verne and colleagues are the first group of scientists to report on a link between microRNAs, glutamine deficiency and IBS. Most studies of microRNAs have identified their role in the development of cancer.

RNA in cells is responsible for using instructions carried in the DNA to make proteins, but microRNAs are small segments of RNA that, when they become overactive themselves, can block the protein-building process. Each microRNA can target numerous genes, but Zhou concentrated on microRNA-29a and its connection to the production of glutamine in this study because of glutamine’s established connection to intestinal permeability.

The researchers collected intestinal tissue and blood samples from three groups: IBS patients with increased intestinal permeability, IBS patients with normal intestinal permeability and control participants with no bowel disease.

The samples showed that microRNA-29a levels were four times higher in the tissues of IBS patients with increased intestinal permeability than were levels seen in IBS patients with normal intestinal permeability conditions and in participants with no bowel disease.

The scientists further tested this relationship by manipulating the microRNA-29a in experiments. When the microRNA-29a levels were driven up, the function of the gene that produces glutamine was prevented and intestinal membrane permeability increased, as well. When the microRNA-29a was artificially silenced, gene function was active, glutamine was produced and the intestinal membrane permeability was closer to normal.

“We’ve only tested the one target gene, and we’ve shown that when the gene activity is low, or the gene is not expressed, that’s when disease characteristics come into play,” Zhou said. “But there still may be other target genes related to this process.”

The study also sought to determine how much related genetic information was contained in blood microvesicles, which are tiny blood vessel membrane fragments. Because the heightened expression of microRNA-29a was also detected in microvesicles from IBS patients with increased permeability in this study, the scientists believe a specially handled blood sample could provide as much disease information as a tissue sample for diagnostic purposes.

This work was supported by the National Institutes of Health and the Medical Research Service of the Department of Veterans Affairs.

Co-authors, both from Ohio State, include Wiley Souba, dean of the College of Medicine; and Carlo Croce, professor and chair of the Department of Molecular Virology, Immunology and Medical Genetics. Verne and Zhou also are affiliated with the Cincinnati VA Medical Center Research Service.

Source: Ohio State University
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4.

Researchers Discover New Genetic Candidates For Irritable Bowel Syndrome

Article Date: 05 May 2010 – 2:00 PDT

Most people associate serotonin with brain neurology, but over 95 percent of the body’s serotonin occurs in the gastrointestinal tract, which has a complex neuronal circuit that has been called “the second brain” of the body. Now a Mayo Clinic research team has identified a number of genetic variants in serotonin genes that impact irritable bowel syndrome or IBS. The findings are being presented today at Digestive Disease Week 2010 in New Orleans.

IBS is one of the most common chronic disorders of the digestive tract. It can cause years of discomfort or pain and altered bowel habits, limit a person’s personal and professional life, and cost millions nationally in medical costs and loss of time from work or school.

“It’s been known that some drugs that alter serotonin levels in the body also have an effect on motility, thus prompting IBS-like symptoms, but the genetic and molecular mechanism for IBS was unclear,” says Yuri Saito, M.D., Mayo Clinic gastroenterologist and presenter of the study. “A number of studies had looked at a few polymorphisms and a handful of genes.”

The Mayo team used high throughput technology to study nearly 400 tagged single-nucleotide polymorphisms (SNPs) in over 20 serotonin-related genes.

Using a familiar analogy, Dr. Saito says, “Rather than sending out a few patrol cars to look for culprits by rounding up ‘the usual suspects,’ we launched a genetic dragnet that took an objective, unbiased look at a broader range of possibilities.” They found a number of previously unknown IBS associations. The conclusion: Many more serotonin-related SNPs were implicated in IBS than first thought. The implicated genes relate to serotonin synthesis, metabolism and receptors. The researchers also found IBS may be caused by multiple genes — not just one or a few — and there may be distinct as well as overlapping molecular mechanisms that cause diarrhea and constipation, two major symptoms of IBS.

The findings offer future researchers specific targets for drug development or other therapies to combat IBS.

Other involved in the study were Joseph Larson; Elizabeth Atkinson; Euijung Ryu, Ph.D.; Ann Almazar-Elder; Nicholas Talley, M.D., Ph.D.; Michael Camilleri, M.D.; and Gloria Petersen, Ph.D., all of Mayo Clinic. The study was supported by the National Institutes of Health.

Source
Mayo Clinic

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5.

New Tool To Accelerate Discovery Of Autoimmune Disease Mechanisms And Therapies
Main Category: Arthritis / Rheumatology

Article Date: 31 Oct 2009 – 0:00 PDT

Currently, 5 – 8% of the U.S. population is afflicted with an autoimmune disease. Many of these are chronic and require life-long care. Moreover, different autoimmune diseases aggregate within a single family, suggesting they are caused by disruptions in common biological pathways.

To help researchers investigate these common pathways, The Jackson Laboratory has published Pathways to Discovery: Autoimmune Diseases (http://www.jax.org/jaxmice/pathways/autoimmune), a unique, interactive, and publicly accessible online resource that illustrates the genetic networks involved in five common autoimmune diseases: inflammatory bowel disease, rheumatoid arthritis, asthma, multiple sclerosis, and psoriasis.

The backbone of the new tool is five “spider-web” diagrams that depict the gene/proteins involved in two or more of the five diseases. The symbols in the diagrams represent cytokines, transmembrane receptors, enzymes, nuclear receptors, and transcriptional regulators. The resource also provides gene- and disease-specific references, links to JAX® Mice strains (including inducible mouse models) that can be used to research the five diseases, and descriptions of JAX® In Vivo Services for compound efficacy testing.

Pathways to Discovery: Autoimmune Diseasespromises to accelerate the discovery of autoimmune disease mechanisms and therapeutic interventions for both new and existing targets.

Source: Joyce Peterson
Jackson Laboratory
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6.
Study Finds Structural Brain Alterations In Patients With Irritable Bowel Syndrome

Article Date: 23 Jul 2010 – 2:00 PDT

A large academic study has demonstrated structural changes in specific brain regions in female patients with irritable bowel syndrome (IBS), a condition that causes pain and discomfort in the abdomen, along with diarrhea, constipation or both.

A collaborative effort between UCLA and Canada’s McGill University, the study appears in the July issue of the journal Gastroenterology.

The findings show that IBS is associated with both decreases and increases in grey matter density in key areas of the brain involved in attention, emotion regulation, pain inhibition and the processing of visceral information.

IBS affects approximately 15 percent of the U.S. population, primarily women. Currently, the condition is considered by the medical field to be a “functional” syndrome of the digestive tract not working properly rather than an “organic” disorder with structural organ changes. Efforts to identify structural or biochemical alterations in the gut have largely been unsuccessful. Even though the pathophysiology is not completely understood, it is generally agreed that IBS represents an alteration in brain-gut interactions.

These study findings, however, show actual structural changes to the brain, which places IBS in the category of other pain disorders, such as lower back pain, temporomandibular joint disorder, migraines and hip pain conditions in which some of the same anatomical brain changes have been observed, as well as other changes. A recent, smaller study suggested structural brain changes in IBS, but a larger definitive study hadn’t been completed until now.

“Discovering structural changes in the brain, whether they are primary or secondary to the gastrointestinal symptoms, demonstrates an ‘organic’ component to IBS and supports the concept of a brain-gut disorder,” said study author Dr. Emeran Mayer, professor of medicine, physiology and psychiatry at the David Geffen School of Medicine at UCLA. “Also, the finding removes the idea once and for all that IBS symptoms are not real and are ‘only psychological.’ The findings will give us more insight into better understanding IBS.”

Researchers employed imaging techniques to examine and analyze brain anatomical differences between 55 female IBS patients and 48 female control subjects. Patients had moderate IBS severity, with disease duration from one to 34 years (average 11 years). The average age of the participants was 31.

Investigators found both increases and decreases of brain grey matter in specific cortical brain regions.

Even after accounting for additional factors such as anxiety and depression, researchers still discovered differences between IBS patients and control subjects in areas of the brain involved in cognitive and evaluative functions, including the prefrontal and posterior parietal cortices, and in the posterior insula, which represents the primary viscerosensory cortex receiving sensory information from the gastrointestinal tract.

“The grey-matter changes in the posterior insula are particularly interesting since they may play a role in central pain amplification for IBS patients,” said study author David A. Seminowicz, Ph.D., of the Alan Edwards Centre for Research on Pain at McGill University. “This particular finding may point to a specific brain difference or abnormality that plays a role in heightening pain signals that reach the brain from the gut.”

Decreases in grey matter in IBS patients occurred in several regions involved in attentional brain processes, which decide what the body should pay attention to. The thalamus and midbrain also showed reductions, including a region the periaqueductal grey that plays a major role in suppressing pain.

“Reductions of grey matter in these key areas may demonstrate an inability of the brain to effectively inhibit pain responses,” Seminowicz said.

The observed decreases in brain grey matter were consistent across IBS patient sub-groups, such as those experiencing more diarrhea-like symptoms than constipation.

“We noticed that the structural brain changes varied between patients who characterized their symptoms primarily as pain, rather than non-painful discomfort,” said Mayer, director of the UCLA Center for Neurobiology of Stress. “In contrast, the length of time a patient has had IBS was not related to these structural brain changes.”

Mayer added that the next steps in the research will include exploring whether genes can be identified that are related to these structural brain changes. In addition, there is a need to increase the study sample size to address male-female differences and to determine if these brain changes are a cause or consequence of having IBS.

The study was funded by the National Institutes of Health.

Additional authors include M. Catherine Bushnell, Ph.D., of McGill University, and Jennifer B. Labus, Joshua A. Bueller, Kirsten Tillisch and Bruce D. Naliboff, Ph.D., all of UCLA.

Source: University of California, Los Angeles (UCLA)

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