Hope for improved HIV/AIDS drug therapy?

A team led by Pitt’s  Center for Vaccine Research (CVR)  recently obtained the first direct proof of a long-suspected cause of multiple HIV-related health complications. The finding supports complementary therapies to antiretroviral drugs as significantly slowing HIV progression.

The study, which will be published in the June issue of the Journal of Clinical Investigation and is available online, found that a drug commonly given to patients receiving kidney dialysis significantly diminishes the levels of bacteria that escape from the gut and reduces health complications in non-human primates infected with the simian form of HIV. The study was funded by the National Institutes of Health (NIH).

“We now have direct evidence of a major culprit in poor outcomes for some HIV-infected people, which is an important breakthrough in the fight against AIDS,” said Ivona Pandrea, a faculty member in the pathology department and at the CVR. “Researchers and doctors can now better test potential therapies to slow or stop a key cause of death and heart disease in people with HIV.”

Chronic activation of the immune system and inflammation are major determinants of progression of HIV infection to AIDS, and also play an important role in inducing excessive blood clotting and heart disease in HIV patients. Doctors believed this was due to microbial translocation, which occurs when bacteria in the gut gets into the body through intestinal lining damaged by HIV. However, no direct proof of this mechanism existed.

Pandrea and her colleagues showed blocking the bacteria from leaving the intestine reduces the chronic immune activation and inflammation. They did this by giving the drug Sevelamer, also known by the brand names Renvela and Renagel, to monkeys newly infected with simian immunodeficiency virus (SIV), the primate form of HIV.

Sevelamer is an oral drug approved by the U.S. Food and Drug Administration to treat elevated levels of phosphate in the blood of patients with chronic kidney disease.

The gut bacteria bind to Sevelamer, making it much more difficult for the bacteria to escape into the body and cause serious problems, such as heart disease, while further weakening the immune system and allowing HIV to progress to full-blown AIDS.

In SIV-infected monkeys treated with Sevelamer, levels of a protein that indicates microbial translocation remained low. However, in the untreated monkeys the levels increased nearly four-fold a week after SIV infection.

The treated monkeys also had lower levels of a biomarker associated with excessive blood clotting, showing that heart attacks and stroke in HIV patients more likely are associated with chronic immune system activation and inflammation, rather than HIV drugs.

“These findings clearly demonstrate that stopping bacteria from leaving the gut reduces the rates of many HIV comorbidities,” said Pandrea.

Since most interventions in people infected with HIV begin after the person has reached chronic stages of infection when the gut is already severely damaged, Pandrea notes, “These treatments may not be as effective later in the infection. Clinical trials in HIV-infected patients were not yet successful in reducing microbial translocation in chronically infected patients. Our study points to the importance of early and sustained drug treatment in people infected with HIV.”

Other approaches, such as coupling Sevelamer with antibiotics, anti-inflammatory drugs, probiotics or supplementation of existing HIV/AIDS drugs could further reduce the likelihood of microbial translocation. Clinical trials are underway to assess these strategies.

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Research shows how Huntington’s protein could cause brain cell death

Scientists in the School of Medicine have identified a key molecular mechanism by which the abnormal protein found in Huntington’s disease can cause brain cell death. The results of these studies, published in Nature Neuroscience, could one day lead to ways to prevent the progressive neurological deterioration that characterizes the condition.

Huntington’s disease patients inherit a gene that contains too many repeats of a certain DNA sequence, which results in the production of an abnormal form of a protein called huntingtin (HTT), explained senior investigator Robert Friedlander, chair of neurological surgery. But until now, studies have not suggested how HTT could cause disease.

“This study connects the dots for the first time and shows how huntingtin can cause problems for the mitochondria that lead to the death of neurons,” Friedlander said. “If we can disrupt the pathway, we may be able to identify new treatments for this devastating disease.”

Examination of brain tissue samples from both mice and human patients affected by Huntington’s disease showed that mutant HTT collects in the mitochondria, which are the energy suppliers of the cell. Using several biochemical approaches in follow-up mouse studies, the research team identified the mitochondrial proteins that bind to mutant HTT, noting a particular affinity for TIM23, a protein complex that transports other proteins from the rest of the cell into the mitochondria.

Further investigation revealed that mutant HTT inhibited TIM23’s ability to transport proteins across the mitochondrial membrane, slowing metabolic activity and ultimately triggering cell-suicide pathways. The team also found that mutant HTT-induced mitochondrial dysfunction occurred more often near the synapses, or junctions, of neurons, likely impairing the neuron’s ability to communicate or signal its neighbors.

To verify the findings, the researchers showed that producing more TIM23 could overcome the protein transport deficiency and prevent cell death. “We learned also that these events occur very early in the disease process, not as the result of some other mutant HTT-induced changes,” Friedlander said. “This means that if we can find ways to intervene at this point, we may be able to prevent neurological damage.”

Co-authors of the paper included other scientists from Pitt’s School of Medicine and Washington University School of Medicine.

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Students swayed by “fun” image of hookah smoking ignore health harms

Educational campaigns meant to dissuade college students from initiating hookah tobacco smoking may be more successful if they combat positive perceptions of hookah use as attractive and romantic, rather than focusing solely on the harmful components of hookah tobacco smoke, a School of Medicine study found.

The research examined the sequence of events around which university students first smoke tobacco from a hookah, also known as a water pipe, in an effort to determine the driving factors behind the decision. The report will be published in the June issue of the journal, Nicotine & Tobacco Research, and is online now.

Due to the fact that hookah tobacco smoking exposes the user to substantial amounts of toxicants such as carbon monoxide, nicotine, carcinogens and tar, initiation of this behavior is of concern.

“It was surprising to learn that college students, even when they were aware of the health dangers associated with hookah tobacco smoking at baseline, still went on to use a hookah for the first time,” said lead author Jaime Sidani of the Department of Medicine and a senior research specialist in the program for research on media and health (PROMH) at Pitt. “However, students who had less positive attitudes toward hookah smoking were significantly less likely to initiate. This suggests that countering positive attitudes may be at least as effective as emphasizing harm in preventing initiation of hookah tobacco smoking.”

Sidani and her colleagues analyzed a sample of 569 first- and second-year University of Florida students who were surveyed twice over a seven-month period about their attitudes, knowledge and behaviors regarding hookah smoking. During that time, 13 percent of the students initiated hookah tobacco use.

The students were more likely to initiate hookah use if they had positive attitudes toward hookah smoking — which is frequently promoted as relaxing, pleasurable, fun and sexual — and if they thought it was a socially acceptable practice among their peers.

Sidani said: “If educational programs can help students to cut through the positive portrayals and marketing of hookah smoking, it may be possible to make hookah smoking less attractive and socially acceptable, resulting in less initiation.”

Senior author Brian Primack, a faculty member in the Department of Medicine and director of PROMH, added that regulation of hookah tobacco smoking and marketing in the United States is confusing and less rigorous than laws meant to prevent cigarette smoking, which may contribute to misperceptions about hookah smoking.

“Clear policy measures addressing the sale and marketing of hookah products and regulation of hookah bars and cafes may be another way to counteract the positive attitudes young adults hold toward hookah smoking,” Primack said.

This research was supported by National Cancer Institute and the Steven Manners Memorial Fund at Pitt’s University Center for Social and Urban Research.

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State’s 1st test of wireless pacemaker conducted

UPMC electrophysiologists were the first in the state to implant a catheter-delivered, leadless pacemaker to treat life-threatening bradycardia, a slow heartbeat that reduces blood flow to the brain and body.

The Medtronic micra transcatheter pacing system is a wireless device that detects a slow heartbeat and sends impulses to the heart to maintain a normal rhythm. The procedure was performed at UPMC Shadyside last month on an 86-year-old man. UPMC is one of only six U.S. centers selected for participation in the international trial for patients who need a pacemaker.

Traditional pacemakers use a pulse generator unit that is implanted under the skin, usually in the upper chest, with one or more wires, known as leads, which are threaded through the veins to the right-side heart chambers. The miniaturized, leadless pacemaker is implanted directly into the right ventricle of the heart, gaining access via the femoral vein in the groin.

“One advantage compared to traditional pacemakers is that no incision is required,” said Andrew Voight, a faculty member in the Department of Medicine, lead surgeon for the procedure and electrophysiologist at the UPMC Heart and Vascular Institute. “That can help reduce infection complications. This pacemaker eliminates the need for a lead, which is more prone to failure over time than any other part of the pacemaker system.”

In the U.S., the Medtronic micra transcatheter pacing system will not be commercially available until the successful completion of this clinical trial and approval by the U.S. Food and Drug Administration.

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ED visits for TBI increase

The rate of visits to U.S. emergency departments (ED) for traumatic brain injury (TBI) rose nearly 30 percent in 2006-10, according to a study led by a Children’s Hospital physician. The rise might be attributable to a number of factors, including increased awareness and diagnoses.

Results of the study, led by Jennifer R. Marin, a faculty member in the Department of Pediatrics and an emergency medicine physician at Children’s Hospital, were published in the recent issue of the Journal of the American Medical Association. The researchers used data from the Nationwide Emergency Department Sample (NEDS) database to determine national trends in ED visits for TBI. NEDS is a nationally representative database and includes 25 million-50 million visits from more than 950 hospitals each year. Additionally, the authors used U.S. census data in order to determine incidence rates and the burden of traumatic brain injury on the country’s population.

“The reason for this increase may be because more people are sustaining head injuries, patients are more aware of TBI and more likely to seek emergency care, health care professionals are more vigilant about making these diagnoses, or a combination of these,” said Marin. “The findings underscore the need for more evaluation into why and how to reverse these trends so that we can minimize the incidence of traumatic brain injury and the consequences associated with these injuries.”

The team found that in 2010 there were an estimated 2.5 million ED visits for TBI, representing a 29 percent increase in the rate of visits for TBI during the study period. By comparison, total ED visits increased by 3.6 percent. The majority of the increase in the incidence of TBI occurred in visits coded as concussion or unspecified head injury. Children younger than 3 and adults older than 60 years had the largest increase in TBI rates. The majority of visits were for minor injuries and most patients were discharged from the ED.

“Traumatic brain injury is an important cause of morbidity and mortality each year,” Marin said. “There has been widespread attention to traumatic brain injury, specifically in terms of prevention, in the last decade by policymakers and health professionals. Large-scale studies that assess national statistics and trends are one of the few ways we have to understand the scope of the problem.”

The authors suggest that the increase in TBI among the very young and very old may indicate these age groups do not benefit as much from public health interventions, such as concussion and helmet laws and safer sports practices.

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Rhythmic bursts of electrical activity from cells in ear teach brain how to hear

A precise rhythm of electrical impulses transmitted from cells in the inner ear coaches the brain how to hear, according to a study led by researchers at Pitt’s  School of Medicine. They recently reported the first evidence of this developmental process in the online version of Neuron.

The ear generates spontaneous electrical activity to trigger a response in the brain before hearing actually begins, said senior investigator Karl Kandler, a faculty member in the Department of Otolaryngology. These patterned bursts start at inner hair cells in the cochlea, which is part of the inner ear, and travel along the auditory nerve to the brain.

“It’s long been speculated that these impulses are intended to ‘wire’ the brain auditory centers,” he said. “Until now, however, no one has been able to provide experimental evidence to support this concept.”

To map neural connectivity, Kandler’s team prepared sections of a mouse brain containing the auditory pathways in a chemical that is inert until UV light hits it. Then, the team pulsed laser light at a neuron, making the chemical active, which excites the nerve cells to generate an electrical impulse. It then tracked the spread of the impulse to adjacent cells, allowing the team to map the network a neuron at a time.

All mice are born unable to hear, a sense that develops around two weeks after birth. But even before hearing starts, the ear produces rhythmic bursts of electrical activity that cause a broad reaction in the brain’s auditory processing centers. As the beat goes on, the brain organizes itself, pruning unneeded connections and strengthening others. To investigate whether the beat is indeed important for this reorganization, the team used genetically engineered mice that lack a key receptor on the inner hair cells, which causes them to change their beat.

“In normal mice, the wiring diagram of the brain gets sharper and more efficient over time and they begin to hear,” Kandler said. “But this doesn’t happen when the inner ear beats in a different rhythm, which means the brain isn’t getting the instructions it needs to wire itself correctly. We have evidence that these mice can detect sound, but they have problems perceiving the pitch of sounds.”

In humans, such subtle hearing deficits are associated with central auditory-processing disorders (CAPD), difficulty processing the meaning of sound. About 2- 3 percent of children are affected with CAPD and these children often have speech and language disorders or delays, and learning disabilities such as dyslexia. In contrast to causes of hearing impairments due to ear deficits, the causes underlying CAPD have remained obscure.

“Our findings suggest that an abnormal rhythm of electrical impulses early in life may be an important contributing factor in the development of CAPD,” Kandler said. “More research is needed to find out whether this also holds true for humans, but our results point to a new direction that is worth following up.”

—Compiled by Alex Oltmanns

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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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