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Gene expression pattern could lead to improved treatment of pediatric septic shock

A consortium of researchers headed by Cincinnati Children's Hospital Medical Center has discovered a gene expression pattern that could lead to improved diagnosis and treatment of pediatric septic shock -- still a serious public health problem despite today's potent antibiotics and pediatric intensive care units.

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Keywords: gene, expression, pattern, lead, improved, treatment, pediatric, septic, shock

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1. Advance in understanding of blood pressure gene could lead to new treatments
   02-04-2007 · EurekAlert!
   Research by scientists at UCL (University College London) has clearly demonstrated for the first time the structure and function of a gene crucial to the regulation of blood pressure. The discovery could be important in the search for new treatments for illnesses such as heart disease, the UK's biggest killer. In a paper published online today in Nature Medicine, the team, led by Professor Patrick Vallance and Dr James Leiper, UCL Department of Medicine, reveal the role of the human gene dimethylarginine dimethylaminohydrolase (DDAH), showing that loss of DDAH activity disrupts nitric oxide (NO) production. NO is critical in the regulation of blood pressure, nervous system functions and the immune system. The role of DDAH is to break down modified amino acids (Asymmetric dimethylarginine (ADMA) and monomethyl arginine (L-NMMA)) that are produced by the body and have been shown to inhibit NO synthase. These molecules accumulate in various disease states including diabetes, renal failure and pulmonary and systemic hypertension, and their concentration in plasma (the fluid component of blood) is strongly predicative of cardiovascular disease and death. In a healthy human body, the majority of ADMA is eliminated through active metabolism by DDAH. Scientists have hypothesised that if DDAH function is impaired, NO production is reduced, and that this could be an important feature of increased cardiovascular risk. To examine this pathway in more detail, the researchers deleted the DDAH gene in mice. These mice went on to develop hypertension, or high blood pressure. They also designed specific inhibitors (small molecules) which bind to the active site of human DDAH. These small molecule inhibitors also induced hypertension in mice, confirming the importance of DDAH in the regulation of blood pressure. Dr Leiper, UCL Medicine, said: “These genetic and chemical approaches to disrupt DDAH showed remarkably consistent results, and provide compelling evidence that loss of DDAH function increases the concentration of ADMA and thereby disrupts vascular NO signalling. “There has been considerable scientific interest in this pathway and the role of ADMA as a novel risk factor, but so far there's been little evidence to support the idea that it's a cause of disease, rather than just a marker. Genes and their pathways are crucial to our understanding of cardiovascular disease and a better understanding of DDAH-1 could lead to important new treatments. “It could help us to establish if genetic variation predisposes certain people to these diseases, or whether environmental factors exert some of their effects through modulation of DDAH activity. “Our research also shows that this pathway could be harnessed therapeutically to limit production of NO in certain situations where too much nitric oxide is a bad thing; for example, hypotension and septic shock. These are some of the biggest problems in intensive care medicine and there is a huge unmet need for drug treatments.” The study, which was carried out at UCL's Rayne Institute, was funded by grants from the British Heart Foundation, the Wellcome Trust and the Medical Research Council. Professor Jeremy Pearson, Associate Medical Director of the British Heart Foundation, said: "The unexpected finding in the 1980s that a simple gas, nitric oxide (NO), is made by cells in the blood vessel wall and is a powerful control of blood vessel relaxation led to the award of the Nobel Prize in 1998 to its discoverers. "More recently, there has been increasing evidence that impairment of NO production is likely to be an important factor in the development of heart and circulatory disease, but the mechanisms responsible are not fully understood. "This study suggests for the first time that the loss of the activity of the enzyme DDAH-1 leads to reduced NO production and may cause heart and circulatory disease. These findings are likely to be important in the search for new ways to optimise the health of our blood vessels." ### Notes for Editors 1. For more information, please contact Ruth Metcalfe in the UCL Media Relations Office on tel: +44 (0)20 7679 9739, mobile: +44 (0)7990 675 947, out of hours: +44 (0)7917 271 364, e-mail: r.metcalfe@ucl.ac.uk2. 'Disruption of methylarginine metabolism impairs vascular homeostasis' is published in the February issue of the journal Nature Medicine. Advance online publication is embargoed to 18.00 GMT (13.00 US Eastern) Sunday 4 February 2007. Journalists can obtain copies of the paper by contacting the UCL Media Relations Office.3. The study was funded by the British Heart Foundation, the Wellcome Trust and the Medical Research Council. About UCL Founded in 1826, UCL was the first English university established after Oxford and Cambridge, the first to admit students regardless of race, class, religion or gender, and the first to provide systematic teaching of law, architecture and medicine. In the government's most recent Research Assessment Exercise, 59 UCL departments achieved top ratings of 5* and 5, indicating research quality of international excellence. UCL is the fourth-ranked UK university in the 2006 league table of the top 500 world universities produced by the Shanghai Jiao Tong University. UCL alumni include Mahatma Gandhi (Laws 1889, Indian political and spiritual leader); Jonathan Dimbleby (Philosophy 1969, writer and television presenter); Junichiro Koizumi (Economics 1969, Prime Minister of Japan); Lord Woolf (Laws 1954, Lord Chief Justice of England & Wales); Alexander Graham Bell (Phonetics 1860s, inventor of the telephone), and members of the band Coldplay.
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2. Clues to gene expression in cystic fibrosis will guide research
   03-28-2007 · EurekAlert!
   Genetics tests could help provide cystic fibrosis (CF) patients with targeted treatment in future, pilot study authors suggest. Results from a French clinical trial published today in BMC Medicine show how a small percentage of CF sufferers with a rare genetic stop mutation responded positively to gentamicin treatment.
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3. Annals of Internal Medicine tip sheet for Feb. 5, 2008, issue
   02-04-2008 · EurekAlert!
   In the Feb. 5, 2008 issue of the Annals of Internal Medicine are "No Clear Winner in Comparative Review of Effectiveness and Harms of Treatments for Localized Prostate Cancer"; "Gene Expression Tests for Breast Cancer Are Promising But Limited"; "New Study Refines Thinking on Best Time to Begin HIV Treatment"; and "Expert Group: Do Not Screen Pregnant Women for Bacterial Vaginosis."
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4. All roads lead to GUN1
   03-29-2007 · EurekAlert!
   Scientists have identified three different signals that indicate damage to chloroplasts -- the photosynthetic factories of plant cells that give plants their green color -- but little is known about how the signal gets passed on to the nucleus. Scientists at the Salk Institute for Biological Studies made a big step towards explaining how chloroplasts let a cell's nucleus know when things start to go wrong at the periphery so nuclear gene expression can be adjusted accordingly.
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5. Imaging neural progenitor cells in the living human brain
   11-08-2007 · EurekAlert!
   For the first time, investigators have identified a way to detect neural progenitor cells, which can develop into neurons and other nervous system cells, in the living human brain using a type of imaging called magnetic resonance spectroscopy. The finding, supported by the National Institutes of Health, may lead to improved diagnosis and treatment for depression, Parkinson's disease, brain tumors, and a host of other disorders.
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6. Study shows isolation of stem cells may lead to a treatment for hearing loss
   04-05-2007 · EurekAlert!
   Members of the National Center for Regenerative Medicine research team, Dr. Robert Miller and Dr. Kumar Alagramam, both of Case Western Reserve University School of Medicine, published research findings in Developmental Neuroscience which suggest new ways of treating hearing loss. These researchers have isolated "cochlear stem cells" located in the inner ear and already primed for development into ear-related tissue due to their proximity to the ear and expression of certain genes necessary for the development of hearing.
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7. Unique pattern of gene expression can indicate acetaminophen overdose
   10-31-2007 · EurekAlert!
   In a new study, researchers found they could detect toxic levels of acetaminophen in laboratory animals by analyzing gene expression in the blood. This study by the National Institute of Environmental Health Sciences, part of the National Institutes of Health, could be a first step in developing accurate new tools to detect acetaminophen overdose in humans.
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8. Jefferson scientists find aging gene also protects against prostate cancer development
   11-27-2006 · EurekAlert!
   Cancer researchers have found that a gene that is involved in regulating aging also blocks prostate cancer cell growth. They have shown that the enzyme SIRT1 can block the growth of treatment-resistant prostate cancer cells that overexpress a mutation for the androgen receptor. The scientists hope the newly found connection will aid in better understanding the development of prostate cancer and lead to new drugs against the disease.
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9. Identifying the mechanism behind a genetic susceptibility to type 2 diabetes
   08-01-2007 · EurekAlert!
   Type 2 diabetes is reaching epidemic proportions in the developed world. Determining if and how certain genes predispose individuals to type 2 diabetes is likely to lead to the development of new treatment strategies for individuals with the disease. A new study now shows that certain variants of the gene TCF7L2 make individuals more susceptible to type 2 diabetes and provides a mechanism by which these genetic variants might cause susceptibility to the disease.
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10. Extracellular protein sensitizes ovarian cancer cells to chemotherapy
    12-10-2007 · EurekAlert!
    Scientists have uncovered critical new details about the mechanisms that modulate the response of ovarian cancer cells to chemotherapy. The research, published by Cell Press in the December issue of Cancer Cell, helps to explain why many patients develop resistance to the taxane class of drugs and may lead to improved treatment of ovarian cancer.
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