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May 29, 2008


Lung research presented

Pitt researchers were among the presenters of research at this month’s International Conference of the American Thoracic Society.

* ARDS biomarkers ID’d

Researchers in the School of Medicine have identified a panel of genes that appears to be strongly predictive of acute respiratory distress syndrome (ARDS). Diagnosis of ARDS can be a challenge because the disorder often is associated with other illnesses such as pneumonia and sepsis, as well as chemical exposure and traumatic injury.

“A total of 11 genes were found to be strongly predictive of ARDS — especially p21 and p57 — genes associated with stress response and tumor suppression,” said Judie Ann Howrylak, a fellow in the Division of Pulmonary, Allergy and Critical Care Medicine. “Using this gene signature, we were able to distinguish patients with ARDS and sepsis from patients with sepsis alone with a high degree of accuracy.”

To find biomarkers for ARDS, Howrylak and her colleagues evaluated blood samples collected from 12 patients with ARDS and sepsis and 23 patients with sepsis alone over a period of nearly two years. Individual samples were collected within 48 hours of admission to medical intensive-care units at UPMC and subjected to genetic analysis.

Other Pitt authors were Michael Donahoe, Lorrie Lucht and Jigme Sethi of the Division of Pulmonary, Allergy and Critical Care Medicine.

* Men, women differ in pneumonia cases

A Pitt study of 1,136 men and 1,047 women with pneumonia symptoms who were treated at 28 hospital emergency departments found that the men generally came to the hospital sicker and had a higher risk of dying over the next year in spite of aggressive medical care.

“It is well known that women live longer than men. We have always assumed that these differences occur because men engage in riskier behaviors and have a greater burden of chronic diseases,” said Sachin Yende, study co-author and assistant professor in the Department of Critical Care Medicine.

“Our study showed that men were more likely to die up to a year after pneumonia, despite adjusting for health behaviors and chronic conditions. Further, our findings indicate this may be linked to differences in immune response.”

On average, men arrived at the emergency departments with poorer vital signs, were more likely to be smokers and had a greater variety of complicating health conditions.

After hospitalization, men received timely antibiotic treatments more often than women and were twice as likely to be admitted immediately to intensive-care units.

Investigators adjusted results for age, race, tobacco use, other demographic characteristics, chronic health conditions, health behaviors and levels of treatment.

First author Michael Reade, a former fellow in Pitt’s Department of Critical Care Medicine now on the faculty at the University of Melbourne, said, “Even so, men had a 30 percent higher risk of death, and the social factors we examined were not sufficient to explain the differences we observed.”

The researchers found significant differences between men and women in substances important to the body’s immune response to infection including tumor necrosis factor, interleukin-6, interleukin-10, antithrombin III, Factor IX, plasminogen activator inhibitor-1 and D-dimer.

Gender differences in immune response to infection are an area of intensive research, with investigations into the role of X chromosomes, which encode genes for several important immune system mediators. “Some investigators have suggested that the immune response may differ because women have two copies of the X chromosome,” said Yende. “Sex hormones are another area of inquiry.”

Other Pitt authors were Gina D’Angelo, Eric Milbrandt, John Kellum, Amber Barnato, Florian Mayr, Lisa Weissfeld and principal study investigator Derek Angus, all of the School of Medicine.

The study was funded by the National Institute of General Medical Sciences.


Best HIV drug combination confirmed

In the largest study of its kind, researchers at the School of Medicine confirmed that one of the most frequently prescribed triple-drug combinations for initial HIV infection is the most effective at suppressing HIV and that a two-drug regimen performed comparably to triple-drug regimens.

Published in the May 15 issue of the New England Journal of Medicine, the study looked at nucleoside reverse transcriptase inhibitors (NRTIs) and a two-drug regimen that did not include NRTIs. Although effective and commonly prescribed, NRTIs can produce severe side effects in some patients.

The study of 753 participants at 55 centers found that the popular three-drug combination of efavirenz plus NRTI therapy was more effective at achieving and maintaining reduction of the virus than another commonly prescribed drug combination of lopinavir-ritonavir plus NRTI.

Interestingly, a two-drug combination of lopinavir-ritonavir plus efavirenz had a similar level of effectiveness as each of the triple-drug regimens that included NRTIs. HIV levels in 24 percent of the participants in the efavirenz group returned to detectable levels during the almost two-year study compared to 33 percent of participants in the lopinavir-ritonavir group and 27 percent of those in the NRTI-sparing group. All three treatment regimens produced substantial improvements in immune responses.

Sharon Riddler, lead author of the study and associate professor of medicine in the Division of Infectious Diseases, said, “Although all three regimens were well-tolerated and effective, our results showed that efavirenz with NRTIs should still be considered the gold standard regimen for initial HIV treatment.

“The results from the NRTI-sparing regimen have given us valuable reassurance that we can utilize a two-drug therapy regimen based on lopinavir-ritonavir plus efavirenz for patients who are unable to take NRTI due to side effects.”

John Mellors, senior co-author and professor in the School of Medicine and Graduate School of Public Health, said, “This study not only establishes the best initial therapy for HIV infection, it opens the way toward simpler regimens that contain fewer drugs.”

The study was conducted as part of the AIDS Clinical Trials Group with funding from the National Institute of Allergy and Infectious Diseases.


Effects of lead exposure seen decades later

Older workers with past occupational exposure to lead face an increased risk for recirculation of lead into their bloodstreams later in life, according to a study by Pitt researchers published in the current issue of Archives of Environmental and Occupational Health.

“The neurotoxic effects of lead have been documented for over a century,” noted Lisa A. Morrow, lead author and associate professor of psychiatry and psychology at Western Psychiatric Institute and Clinic. “Our study found that even workers with no current workplace exposure to lead — but who have had considerable past exposure — show increasing levels of lead in their blood as they age.”

While state and federal standards that constitute safe exposure have continued to be lowered over the last decade or so, lead exposure continues to be widespread in the United States, with more than 1.4 million industrial workers having potential lead exposure.

Previous studies have shown that the amount of lead in the body increases throughout the life span, with 90 to 95 percent of that lead stored in the bones. With aging, bones demineralize and stored lead can be recirculated into the bloodstream.

The Pitt researchers studied 58 men with prior workplace exposure to lead. The men, aged 40-76, had not worked with lead, on average, for the preceding 10 years.

Correlations between blood lead and bone lead were highest in the older men, meaning the combination of age and bone lead significantly predicted an increase in current blood lead levels. This suggests that lead from the bones is an important source of lead circulating in the blood. Older workers with prior exposure to lead may therefore face an additional neurotoxic hazard long after exposure has ended.

“Lead is a powerful neurotoxin that affects people of all ages. Recent studies have shown impairment in both children and adults at concentrations previously thought to be safe. Lead attacks many systems in the body. The most important target is the central nervous system. Increased measures to prevent exposure will be necessary to achieve the optimal goal of zero blood lead in the U.S. in the next decade,” said Morrow.

Pitt co-authors of the study were Herbert Needleman of psychiatry and pediatrics, Christine McFarland and Michael Tobin of psychiatry and Kim Metheny of neurology.

Morrow was supported by funding provided by the National Institute for Occupational Safety and Health.


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