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May 15, 2014

Research Notes

$10 million NIMH grant funds center

The National Institute of Mental Health (NIMH) has awarded a $10 million, five-year grant to establish the Silvio O. Conte Center for Translational Mental Health Research in the  School of Medicine’s Department of Psychiatry. The center will focus on cortical cells, brain circuits, neuronal connectivity and cognition in schizophrenia.

Schizophrenia is a major public health problem and devastating illness, affecting 0.5-1 percent of the world’s population. Symptoms can include hallucinations, delusions, disorganized thinking and mood disturbances. Current treatments for schizophrenia have limited effectiveness, and all medications currently used to treat schizophrenia and related disorders were discovered by serendipity rather than goal-oriented, rigorous science.

“There is an urgent need for a new approach to treatment development to address these problems,” said David A. Lewis, chair of Pitt’s Department of Psychiatry, and director of the center. “This innovative center will initiate drug development methodically by first identifying molecular targets that could influence the course of the illness, a strategy that has been successful in other areas of medicine.”

The center’s research activities will test the hypothesis that molecular disturbances in certain triangular-shaped “pyramidal” cells, which are found in the outer layers of the brain’s cerebrum known as the neocortex, alter cortical circuitry within and between brain regions, impair functional connectivity and neural signaling and disturb the processes of working memory and attention in individuals with schizophrenia.

Five research projects and clinical and diagnostic cores will take convergent approaches to examine these molecular changes with the aim of making laboratory findings readily relevant to clinical treatment of schizophrenia. The center’s work is directed at identifying pathophysiology-based molecular targets for new treatments and at developing biomarkers that can be used to monitor their impact.


Regenerative medicine helps muscle strength, function in leg injuries

Damaged leg muscles grew stronger and showed signs of regeneration in three out of five men whose old injuries were surgically implanted with extracellular matrix (ECM) derived from pig bladder, according to a new study conducted by researchers at Pitt’s School of Medicine and the McGowan Institute for Regenerative Medicine. Early findings from a human trial of the process and from animal studies were published in Science Translational Medicine.

When a large volume of muscle is lost, typically due to trauma, the body cannot respond sufficiently to replace it, explained senior investigator Stephen F. Badylak, a faculty member in surgery and deputy director of the McGowan Institute, a joint effort of Pitt and UPMC. Instead, scar tissue can form that significantly impairs strength and function.

Pig bladder ECM has been used for many years as the basis for medical products for hernia repair and treatment of skin ulcers. It is the biologic scaffold that remains behind after cells have been removed. Previous research conducted by Badylak’s team suggested that ECM also could be used to regenerate lost muscle by placing the material at the injury site, where it signals the body to recruit stem and other progenitor cells to rebuild healthy tissue.

“This new study is the first to show replacement of new functional muscle tissue in humans, and we’re very excited by its potential,” Badylak said. “These are patients who can’t walk anymore, can’t get out of a car, can’t get up and down from a chair, can’t take steps without falling. Now we might have a way of helping them get better.”

For the study, which is sponsored by the U.S. Department of Defense and is continuing to enroll participants, five men who had at least six months earlier lost at least 25 percent of leg muscle volume and function compared to the uninjured limb underwent a customized regimen of physical therapy for 12-26 weeks until their function and strength plateaued for a minimum of two weeks.

Then, study lead surgeon J. Peter Rubin, chair of plastic surgery in the School of Medicine, surgically implanted a “quilt” of compressed ECM sheets designed to fill into their injury sites. Within 48 hours of the operation, the participants resumed physical therapy for up to 26 additional weeks.

The researchers found that three of the participants, two of whom had thigh injuries and one a calf injury, were stronger by 20 percent or more, six months after the surgery. One thigh-injured patient improved on the “single hop test” by 1,820 percent, and the other had a 352 percent improvement in a chair lift test and a 417 percent improvement in the single-leg squat test. Biopsies and scans all indicated that muscle growth had occurred. Two other participants with calf injuries did not have such dramatic results, but both improved on at least one functional measure and said they felt better.

“This work represents an important step forward in our ability to repair tissues and improve function with materials derived from natural proteins,” Rubin said. “There will be more options to help our patients.”

He added: “We think it’s remarkable that this approach was able to improve function among patients who were all well past the acute injury response phase and were not helped by the standard surgical procedures they had already had.”

The study also showed six months after an injury, mice treated with ECM showed signs of new muscle growth while untreated mice appeared to form typical scars.


Prophylactic antibiotics prevent UTI recurrences in kids with vesicoureteral reflux

A study led by researchers at Children’s Hospital demonstrated that children diagnosed with an abnormal flow of urine from the bladder to the upper urinary tract, called vesicoureteral reflux (VUR), can avoid recurrent urinary tract infections (UTI) by taking daily low-dose antibiotics, although the treatment didn’t reduce their risk for UTI-induced kidney scarring. The results of the multicenter study were presented at the Pediatric Academic Societies annual meeting in Vancouver. The study was published in the New England Journal of Medicine.

Alejandro Hoberman, a faculty member in pediatrics and chief, Division of General Academic Pediatrics at Children’s, said: “Our study provides a clear message that recurrences of UTI in children with vesicoureteral reflux can be prevented; some of these children appear pretty sick when they have a UTI with fever. VUR is present in one-third of children presenting with UTI accompanied by a fever and has been associated with a heightened risk of kidney scarring. One way to decrease infection risk is to give children antibiotics when they are well, called antimicrobial prophylaxis.”

Earlier randomized, controlled trials that compared antireflux surgery with antimicrobial prophylaxis showed no differences in rates of recurrent UTIs and renal scarring; however, the actual efficacy of either treatment could not be determined because the studies lacked a placebo or observation comparison groups. Recently conducted randomized trials have reported conflicting results about the effectiveness of antimicrobial prophylaxis in reducing recurrences.

“This study showed unequivocal evidence that antimicrobial prophylaxis reduced at least in half the likelihood of children having recurrent UTIs,” said Hoberman. “Some subgroups of children derived the most benefit, particularly those with bladder and bowel dysfunction at baseline, and those in whom the UTI occurred with fever.”

The goal of the two-year study was to determine if giving children low-dose trimethoprim-sulfamethoxazole would prevent recurrent UTIs, decrease kidney scarring and contribute to the emergence of bacterial resistance.

The study enrolled 607 children ages 2 to 71 months who were diagnosed with VUR following a first or second episode of UTI. Participants were recruited from 19 clinical trial centers in the United States and underwent kidney scans to determine if scarring was present. They then were randomized to receive trimethoprim-sulfamethoxazole or a placebo. Kidney scans were repeated at one and two years after study entry.

Results showed that 39 of 302 children (13 percent) receiving antimicrobial prophylaxis developed UTIs compared to 72 of 305 (24 percent) receiving placebo. Antimicrobial prophylaxis reduced the risk of infections by 50 percent compared with placebo.

“Rates of renal scarring at the outcome visit were low and not reduced by prophylaxis, perhaps because most children were enrolled after their first infection and because parents, instructed to be vigilant, sought early medical attention,” said Hoberman. “Not unexpectedly, recurrences that did occur in children who received prophylaxis were more likely to have been caused by a resistant pathogen.”

—Compiled by Alex Oltmanns


The University Times Research Notes column reports on funding awarded to Pitt researchers as well as findings arising from University research.

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