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With obesity rates rising and no good treatments, scientists have upped the ante in their search for new approaches. Now, an international consortium led by Joel Hirschhorn, MD, PhD, of the Divisions of Genetics and Endocrinology at Children's Hospital Boston, and collaborators in the United States and United Kingdom, has made significant headway. Analyzing data from some 90,000 people, they discovered six new genetic variants linked with body mass index. Most of the variants are active in the brain, suggesting that differences in appetite regulation may play a role in obesity. The consortium is now performing much larger-scale studies to identify additional genetic variants—with the hope that at least one will lead to an effective treatment. (Nature Genetics, December 14, 2008)
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The 1995 discovery of leptin—an appetite-suppressing hormone secreted by fat tissue—generated headlines worldwide and raised hopes for an effective obesity treatment. But researchers later found that the brains of obese people become leptin-resistant. Now, Umut Ozcan, MD, and colleagues in Children's Division of Endocrinology, report that two existing drugs, already FDA-approved and known to be safe, can restore the brain's sensitivity to leptin in mice. Funding is now being sought for clinical trials in humans. (Cell Metabolism, January 7, 2009)
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Children whose mothers took acid-suppressing drugs for heartburn during pregnancy may have up to a 1.5 times higher risk of asthma, finds a population-based study by Elizabeth Hait, MD, MPH, Edda Fiebiger, PhD, and Eleonora Dehlink, MD PhD, of Children's Division of Gastroenterology/Nutrition. The researchers analyzed national birth, hospital discharge and drug prescription registers in Sweden, linking children with their mothers. Fiebiger, who researches the immune mechanisms of food allergy, speculates that if proteins aren't broken down completely by stomach acid, the immune system may recognize them as allergens. (Journal of Clinical and Experimental Allergy, February 2009)
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Seizures in babies with fever are frightening for parents, who often rush them to the emergency room. Frequently, the physician will do a spinal tap to rule out bacterial meningitis. Now, in the largest study to date, Amir Kimia, MD, and colleagues in Children's Emergency Department (ED) report that this uncomfortable procedure probably isn't necessary in well-appearing children with a first "simple" febrile seizure (generalized, lasting no more than 15 minutes and not recurring within 24 hours). Reviewing medical charts of 704 babies seen in Children's ED between 1995 and 2006, they found no cases of bacterial meningitis. Kimia hopes these findings will reassure parents. (Pediatrics, January 2009)
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People with sickle-cell disease and thalassemia cannot produce normal hemoglobin, the molecule in red blood cells that takes oxygen around the body. Most are left with life-threatening anemia, but some people are able to produce a fetal form of hemoglobin (HbF) that binds to oxygen more strongly, keeping their symptoms relatively mild. Now, Stuart Orkin, MD and Vijay Sankaran, in Children's Division of Hematology/Oncology, have identified a way to get red blood cells to keep making HbF after infancy—by blocking a gene that suppresses HbF production. The gene, BCL11A, is part of five genetic variants found last July that influence HbF levels. Targeting it could potentially transform the diseases into benign or nearly benign conditions. (Science Express, December 4, 2008)
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While cure rates for most childhood leukemias are about 80 percent, they are much lower for a subtype of acute lymphoblastic leukemia (ALL) in which a gene called MLL is mutated. Recently, a study led by Scott Armstrong, MD, PhD, Andrei Krivtsov, PhD, and Zhaohui Feng, of Children's Division of Hematology/Oncology, discovered a small but potent epigenetic change—a change in gene activation—that launches the cancer. As a result of the mutation, an enzyme called DOT1L modifies one of the "scaffolding" proteins (histones) that give chromosomes their shape—changing chromosome structure and activating genes that are normally silenced. The good news: Enzymes are relatively easy to target, and the search for an inhibitory drug is underway. (Cancer Cell, November 4, 2008)
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Prostate cancer affects about one in six men in the United States, and while cure rates are high, the treatments often reduce quality of life. Now, Keith Solomon, PhD, and Michael Freeman, PhD, of the Departments of Orthopedic Surgery and Urology at Children's, show that lowering blood cholesterol levels delays progression of prostate cancer in a mouse model. When mice with human prostate tumors were fed a no-cholesterol diet plus ezetimibe, a cholesterol-lowering drug, tumor growth was slowed. Mice with the lowest cholesterol levels also showed dramatically reduced tumor blood-vessel growth, suggesting that ezetimibe acts at least in part by inhibiting angiogenesis. (American Journal of Pathology, March 2009)
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The ability to predict people's lifelong risk of stroke would allow clinicians to advise individuals at high risk. Marco Ramoni, PhD, and colleagues in the Children's Hospital Informatics Program recently developed a statistical model that draws on 1,313 known genetic predictors. Upon receiving genetic information from 569 random subjects, the model, known as a Bayesian network, was able to identify and calculate the strength of interactions between genetic risk factors and predict the overall risk of stroke with 86 percent accuracy. Ramoni is now refining this model and believes this technology could be used to predict inherited risk of many conditions. (Stroke, March 2009)
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