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February 7, 2008


Maternal-fetal medicine studies presented

Hyagriv Simhan, assistant professor of obstetrics, gynecology and reproductive sciences at the School of Medicine, presented research from Pitt studies that links genetic mutations to increased risks of preterm birth or injury to the placenta at the annual meeting of the Society for Maternal-Fetal Medicine last week.

Researchers in Pitt’s Department of Obstetrics, Gynecology and Reproductive Sciences have found that mutations in the enzyme methylenetetrahydrofoloate reductase (MTHFR) and coagulation protein Factor V appear to have significant association with blood clots and tissue injury to the placenta and developing fetus.

“This indicates a possible genetic predisposition to a condition of real clinical consequence in terms of intrauterine growth restriction, preeclampsia and spontaneous preterm birth,” said, Simhan. “These are conditions that can have lifelong consequences for those affected.”

MTHFR is an enzyme related to amino acid metabolism. Intrauterine growth restriction results in malnutrition of the developing fetus and babies of low birth weight and can be related to a host of factors usually reflective of the mother’s health, including infection, high blood pressure, use of tobacco, alcohol or illicit drugs.

Women and babies with MTHFR mutation were 4.2 times more likely to exhibit blood clots and injury to placental tissue than those without the mutation, Simhan noted. For those with Factor V mutation, the association was less pronounced, but still elevated.

“These are different mutations than those that have been previously described in MTHFR and Factor V,” Simhan said.

In addition, researchers from Pitt and Magee-Womens Hospital who evaluated blood samples from 111 women and cord blood samples from their babies have found mutations in the toll-like receptor 4 (TLR4) gene show significant association with risk of inflammatory injury to the placenta. TLR4 enables the body to recognize pathogens and activate the immune system. Inflammatory placental lesions are more common in babies who are born preterm, prior to 37 weeks gestation.

“This indicates a possible genetic predisposition to a kind of misfire in immune system response that could contribute to placental inflammation and spontaneous preterm birth,” said Simhan. “These injuries are important because they are more common in preterm babies and associated with major health consequences like cerebral palsy.”

Women with TLR4 mutation were 5.2 times more likely to exhibit inflammatory injury to placental tissue than those without the mutation, Simhan noted. Babies with TLR4 mutation were nearly five times more likely to exhibit inflammatory placental injury than those without the mutation.

“Being aware of these genetic mutations may lead to better screening efforts,” Simhan said.


Avian flu vaccine tested

A vaccine against the most common and deadliest strain of avian flu, H5N1, has been engineered and tested by researchers at Pitt’s Center for Vaccine Research (CVR) and Novavax.

According to a study published by the Public Library of Science in the Jan. 30 issue of PLoS ONE, the vaccine produced a strong immune response in mice and protected them from death following infection with the H5N1 virus. The vaccine is being tested in humans in an early-phase clinical trial.

Recent outbreaks of avian flu around the world have prompted health officials to warn of its continued threat to global health and potential to trigger a flu pandemic.

Ted M. Ross, lead author of the study and assistant professor at CVR, said, “While worldwide avian flu control efforts have been mostly successful, avian flu, like seasonal influenza, mutates year to year, creating new subtypes and strains that could easily and quickly spread among humans. To stem the spread of a potential pandemic, we need stockpiles of vaccines available that can be readily adapted to enhance the immune system’s response to new strains.”

Unlike other avian flu vaccines, which are developed in part from live viruses, the vaccine uses a virus-like particle, or VLP, that is recognized by the immune system as a real virus but lacks genetic information to reproduce, making it a potentially safer alternative for a human vaccine.

Given the evolving nature of H5N1, the vaccine was engineered to encode genes for three influenza viral proteins to offer enhanced protection against possible new strains of the virus.

Researchers gave the vaccine to mice in one- and two-dose regimens. Mice immunized twice developed protective antibodies against H5N1 and were protected from disease and death when directly exposed to the virus.

The researchers also compared vaccine injections to nasal administration. Both were equally effective, but mice injected with the vaccine developed more antibodies in the blood, while mice that received the nasal administration had more antibodies in their lungs.

“VLPs may be advantageous over other vaccine strategies because they are easy to develop, produce and manufacture,” said Ross. “Using recombinant technologies, within 10 weeks, we could generate a vaccine most effective toward the current circulating strain of virus, making it a cost-effective counter-measure to the threat of an avian influenza pandemic.”

The study was funded by Rockville, Md.-based Novavax.

Co-authors from CVR included Donald M. Carter, Corey J. Crevar, Franklin R. Toapanta, Jonathan D. Steckbeck and Kelly Cole.


Drug-coated stents perform better

The use of drug-coated stents in patients with complex heart disease is associated with a lower rate of repeat procedures without an increased risk of death or heart attacks compared to bare-metal stents, report School of Medicine researchers in the New England Journal of Medicine.

The report is the largest and most detailed analysis comparing the safety and efficacy of drug-coated and bare-metal stents when used for patients with complex disease.

Using data from the National Heart, Lung and Blood Institute Dynamic Registry, the study’s lead author, Oscar C. Marroquin, assistant professor of medicine and director of the Center for Interventional Cardiology Research at UPMC’s Cardiovascular Institute, and colleagues analyzed records from 6,551 patients who were treated with either drug-coated stents or bare-metal stents and whether the use was standard or off-label.

Patients were followed for adverse cardiac events and death for one year after their procedures. Off-label use occurred in 55 percent of all bare-metal stent patients and 49 percent of drug-coated stent patients.

Compared to bare-metal stent patients, drug-coated stent patients had a higher prevalence of diabetes, hypertension, renal disease, prior percutaneous coronary intervention and coronary artery bypass graft, and multi-vessel coronary artery disease. At one year, however, there were no significant differences in the adjusted risk of death and heart attack in drug-coated stents compared to bare-metal stent patients. Repeat procedures to restore blood flow also were significantly lower in drug-coated stent patients.

“This study shows that drug-coated stents, even when used for patients with complex disease (off-label fashion), is a more effective strategy in reducing re-narrowing of the coronary arteries, without an increased risk of heart attacks or death at one year compared to bare-metal stents,” said Marroquin. “Furthermore, we feel that our study supports the continued use of drug-coated stents for patients with these complex heart issues.”

Stents are tiny metal mesh tubes implanted during cardiac catheterizations to prop open coronary arteries that have been narrowed by the buildup of cholesterol plaque.

Even when the procedure is successful, the stented area can re-narrow over time due to the formation of excess scar tissue in response to the stent. The risk of re-narrowing is higher in higher-risk patients than when they are used in patients with fewer medical complications. The drug-coated stents often preferred by cardiologists reduce the amount of scar tissue formation, resulting in a lower likelihood of artery re-narrowing over time compared to bare-metal stents.

The study was conducted in response to an FDA call for more data on what has become common practice by cardiologists worldwide: using stents, particularly drug-eluting stents, in high-risk patients with complex conditions.

The study was funded by the National Heart, Lung and Blood Institute.

Pitt collaborators on the study were Helen A. Vlachos, Faith Selzer and Sheryl F. Kelsey of the Graduate School of Public Health and William D. Anderson, Joon Sup Lee, Suresh R. Mulukutla and A. Conrad Smith of Pitt’s Cardiovascular Institute.


Meditation eases back pain

Older adults with chronic lower back pain can benefit from a mindfulness meditation program, according to a study by Pitt researchers in the February issue of the journal PAIN.

“Almost a quarter of older adults live with chronic lower back pain,” said Natalia Morone, professor of general internal medicine at the School of Medicine, who led the study.

“Since chronic pain is associated with depression, decreased appetite, impaired sleep and overall decreased quality of life, complementary medical techniques are a welcome addition to traditional treatments.

“Previous studies have noted mindfulness meditation’s benefits for those with chronic pain but its effects had not been noted in older adults exclusively and low back pain specifically. With so many people seeking alternative therapies, we felt it was our responsibility to study it scientifically.”

Mindfulness meditation is a mind-body technique described as paying attention on purpose and staying in the present moment to experience each unfolding event.

Study participants were taught three mindfulness meditation techniques: a body scan in which participants lie down and are asked to place their attention non-judgmentally on each area of the body; sitting practice, which focuses on breathing while sitting in a chair, and walking meditation, which is mindful slow walking with focused attention on body sensation and/or breathing.

“Mindfulness meditation focuses on letting go of struggle and accepting one’s condition without judgment. Participants have noted that the practice has a quieting effect and find that while practicing meditation they can reduce their chronic pain by deflecting it and focusing on other parts of the body,” said Morone.

At the conclusion of the eight-week program, those with chronic low back pain noted an improved ability to cope with pain and improvement in physical function.

At the three-month followup the majority of patients still were practicing meditation, suggesting that they had incorporated it into their daily lives because they had experienced an ongoing benefit.

Morone was supported by a primary care faculty development training grant and by the Roadmap Multidisciplinary Clinical Research Career Development Award Grant from the National Institutes of Health.

Other study authors were Carol M. Greco and Debra K. Weiner of the School of Medicine.


Ring favored over patch for birth control

In the first study to compare directly a contraceptive vaginal ring and skin patch, more women indicated overall satisfaction with the vaginal ring, Pitt-led researchers report in the current issue of Obstetrics and Gynecology.

The products, which use the same combination of hormones as prescription birth control pills, became available in 2002 as an alternative to daily pills. The ring and patch are left in place for three weeks at a time.

The multi-center study evaluated 500 women randomly assigned to use the ring or patch for four consecutive menstrual cycles in 2005 and 2006. “What we found is that more women are happier with the ring than the patch,” said study first author Mitchell Creinin, professor of obstetrics, gynecology and reproductive sciences in the School of Medicine.

“On the whole, they report fewer complications, and a significant majority preferred the ring to their pill.”

In November 2005, the U.S. Food and Drug Administration issued a warning regarding estrogen levels in the contraceptive patch and related risk of blood clots. The study participants all were given standard, written information about the warning. Five who used the patch said the FDA labeling change influenced them to discontinue use at the end of the study.

“Overall, however, patch users were twice as likely to discontinue using the product by the end of the third cycle, and seven times more likely to say they had no wish to continue once the study was over,” said Creinin, who also is director of family planning at Pitt and a senior investigator at Magee-Womens Research Institute (MWRI). The adverse effects most commonly cited as reasons for discontinuation included longer periods, cramps, nausea, mood swings, skin irritation or problems with the patch falling off. Those who used the ring most commonly cited discomfort and more frequent vaginal discharge as reasons for discontinuation.

“Although oral contraceptives are the most commonly used reversible form of contraception in the United States, continuation rates are only 40 percent at six months of use,” the authors wrote. In addition, prior studies have shown that in the third month of use, about half of women miss three or more pills each cycle, likely decreasing contraceptive effectiveness.

“The two alternative delivery systems for combined hormonal contraceptives had not been evaluated in a single randomized trial, making it difficult for clinicians to compare and contrast these options for their patients,” Creinin said. “But now we can provide more accurate counseling to patients who might be interested in a non-daily birth control method.”

Leslie A. Meyn of MWRI was among the Pitt co-authors involved in the study.

Additional participating centers were Boston University, Columbia, Eastern Virginia Medical School, Johns Hopkins University, Oregon Health and Science University, UCLA, the University of Chicago and the University of Wisconsin.


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