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Pitt Researchers Find Immune Cells May Play Previously Unrecognized Role in Inflammation in HIV/AIDS
“Such a medication could be a very helpful preventive strategy for soldiers and other people who work in situations where exposure to very loud noise is likely,” Dr. Tzounopoulos said. “It might also be useful for other conditions of phantom perceptions, such as pain in a limb that has been amputated.”
Co-authors of the paper are Shuang Li and Veronica Choi, both of Pitt’s Department of Otolaryngology. The project was funded by U.S. Department of Defense grant PR0934050, National Institutes of Health/National Institute on Deafness and Other Communication Disorders grant DC007905, UPMC and The Eye and Ear Foundation of Pittsburgh.
Jana Al Hashash, MD, a Year III gastroenterology fellow with the Division of Gastroenterology, Hepatology and Nutrition, has been awarded a 2013 American Gastroenterological Association (AGA)-Horizon Pharma Fellow Abstract Prize from the AGA Research Foundation.
Dr. Al Hashash will receive this honor at the 2013 Digestive Disease Week (DDW) international GI research meeting in May 2013. This award will be presented in recognition of her DDW Research Forum oral presentation in the Confocal Endomicroscopy, Enhanced Endoscopy, and Other Emerging Technologies II session, Nuclear Nano-Morphology Markers from Rectal Tissue Predict Colonic Dysplasia/Neoplasia in Ulcerative Colitis Patients. Dr. Al Hashash’s sponsor for this project is Miguel D. Regueiro, MD.
Experts from the Division of Gastroenterology, Hepatology, and Nutrition will have a strong presence at Digestive Disease Week 2013, with UPMC physicians and researchers making 16 oral presentations and 35 poster presentations. Preview of the key findings to be presented at the conference:
Are you attending DDW?
To learn more about our clinical programs, research efforts, and fellowship opportunities, visit us at DDW booth 1533, May 18 to 21.
Pitt Transplant Experts Challenge Assumption, Describe Biological Pathway That Leads To Organ Rejection
Adding Breast Milk Ingredient to Formula Could Prevent Deadly Intestinal Problem in Premature Babies
PITTSBURGH, May 6, 2013 – An ingredient that naturally occurs in breast milk might be used to prevent premature babies from developing a deadly intestinal condition that currently is largely incurable, according to researchers at the University of Pittsburgh School of Medicine and Children’s Hospital of Pittsburgh of UPMC in this week’s online early edition of the Proceedings of the National Academy of Sciences.
The story begins with a baby who is born too early, meaning before 36 weeks gestation, said senior author David Hackam, M.D., Ph.D., Watson Family Professor of Surgery, Pitt School of Medicine, and co-director of the Fetal Diagnosis and Treatment Center at Children’s Hospital. Once stable, typically the baby is fed with formula because often breast milk is not readily available to premature infants.
“Within about 10 days of birth, the baby starts to vomit and a few hours later, the belly becomes distended and discolored,” Dr. Hackam said. “It becomes clear that the child has developed a major problem in his or her tummy, and an X-Ray will usually confirm the diagnosis of necrotizing enterocolitis, or NEC, in which the intestinal tissue is dying. We have no choice but to remove the dead parts of the intestine, but despite surgery, half of these preemie babies still die from the condition.”
Dr. Hackam and his team noted NEC occurs when the intestines start getting colonized with bacteria, a process that occurs normally after birth. They focused on toll-like receptor 4 (TLR4), an immune protein that is involved in recognizing microbes and which they recently discovered plays a role in gut development. In the current work, Hackam and colleagues found that TLR4 is present in higher amounts in the blood vessel lining in preemies than in full-term babies.
The study shows that unlike normal mice, those bred to lack TLR4 in their blood vessels did not develop NEC in a model designed to induce the condition. The findings indicate that bacteria in the blood activate TLR4 leading to a reduction in nitric oxide, which in turn narrows blood vessels and decreases blood flow, Dr. Hackam said.
“This pathway can be dangerous when the preemie’s immature gut becomes inflamed from exposure to the bacteria normally present in the intestine,” he said. “Abundant TLR4 triggers a shutdown of the blood supply to the intestine, leading to tissue death or necrosis.”
Premature babies who are nursed rather than formula-fed are more likely to survive NEC, so co-author and nitric oxide expert Mark Gladwin, M.D., chief, Division of Pulmonary Allergy and Critical Care Medicine, Pitt School of Medicine, and director of Pitt’s Vascular Medicine Institute, and the team took a closer look at the components of breast milk.
They found that breast milk contains high levels of sodium nitrate, which is converted to nitrite by gut bacteria. Nitrite can be directly converted to the vasodilator nitric oxide, which can both protect the intestinal lining and improve blood flow.
“The additional nitrite appears to overcome the effects of TLR4 activation and corrects the blood flow problem,” Dr. Gladwin said. “When we gave formula supplemented with a sodium nitrate and nitrite analog to the premature mice, we saw improved blood flow in the intestine, and NEC did not develop.”
Drs. Hackam and Gladwin are testing the compound, which is FDA approved for other uses, in other models of NEC with the hope that it could be routinely added to formula fed to premature infants to prevent NEC.
“This condition is frightening for parents and frustrating for doctors because currently there is little we can do to treat it,” said Dr. Hackam, a pediatric surgeon. “I look forward to one day putting myself out of business and having a therapy that truly saves these children.”
Co-authors of the paper include researchers from the divisions of Pediatric Surgery, Newborn Medicine, and Pathology at Children’s Hospital; the Division of Gastroenterology and the departments of Pediatrics, Pathology, and Surgery at Pitt School of Medicine.
The project was funded by National Institutes of Health grants GM078238, DK08752, GM053789, HL098032, HL096973 and HL103455; the Hartwell Foundation; the Institute for Transfusion Medicine; and the Hemophilia Center of Western Pennsylvania. Dr. Gladwin holds a patent for the use of nitrite salts in cardiovascular diseases and consults with Aires Pharmaceuticals.
- Erythema nodosum
- Pyoderma gangrenosum
- Aphthous ulcers/aphthous stomatitis
- Dermatitis herpetiformis and celiac disease
- TNFα associated psoriasiform dermatoses
- Nutritional deficiency dermatoses
Dr. Grandinetti joined UPMC in 2009, and has since been receiving referrals from gastroenterologists for patients with IBD who have skin-related problems. Her interest in cutaneous manifestations of GI disease began after medical school, during her residency at the Cleveland Clinic.
“I saw firsthand how patients’ quality of life was significantly affected by their skin condition, often when their GI disease was under control,” noted Grandinetti. “With time, experience and a growing number of patients with cutaneous manifestations of GI diseases, I felt it was a good time to create a specialized clinic that would provide dermatologic and gastroenterologic coordinated care to patients with IBD and other GI issues.”