University Times

Autoimmune link to COPD found

Pulmonary specialists at the School of Medicine are reporting in the American Journal of Respiratory and Critical Care Medicine solid evidence that chronic obstructive pulmonary disease (COPD) is an autoimmune disease in many patients. Speculation on an autoimmune contributor to COPD previously had been unproven.

The finding holds particular relevance regarding possible future treatments, including a Pitt clinical trial of inhaled cyclosporine, which typically is used to suppress the immune system in transplant patients.

The fourth-leading cause of death and second-leading cause of disability in the United States, COPD is a lung disease commonly related to smoking that diminishes breathing capacity over time and includes conditions such as chronic bronchitis and emphysema.

“COPD damages the lung tissue, expanding and breaking down the walls of air sacs, which hinders air flow out of the lungs and the transfer of oxygen into the blood,” said Steven R. Duncan, a senior author of the study and professor in the School of Medicine. “This new work shows that in some patients with COPD, immune system antibodies attack the cells that line the airways and air sacs of the lungs called epithelial cells.”

The Pitt researchers tracked immune system antibodies in 55 smokers or former smokers (47 with COPD) compared to 21 healthy people who never had smoked. Abnormal antibodies were found in 68 percent of smokers and former smokers with COPD but in only 13 percent of former smokers without COPD and 10 percent of those who never had smoked.

“COPD is responsible for 120,000 deaths a year,” said Frank C. Sciurba, a study senior co-author, professor of medicine and director of Pitt’s Emphysema Research Center. “Available treatments, including inhaled bronchodilators, have little effect on disease progression. New information learned may help us to develop better treatments and perhaps even halt disease progression.”

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Team develops nano-level electrical switching technique

A research team led by physics and astronomy professor Jeremy Levy has developed a process that allows electrical conductivity to be turned on and off at nanoscale dimensions.

This capability holds promise for more powerful and compact information technologies, including ultra-high density information storage, reconfigurable logic devices, single-electron devices and quantum computers.

The researchers found a way to switch, at will, the interface of two readily formed insulating materials from an electrical conductor to an insulator and back. The research’s considerable technological applications stem from this adjustability, Levy said.

The findings were published online March 2 in Nature Materials with the print version scheduled for April.

The process works like a microscopic Etch A Sketch toy, Levy said. The interface lies between a crystal of strontium titanate and a 1.2 nanometer-thick layer of lanthanum aluminate, both of which are insulators. Using the sharp conducting probe of an atomic-force microscope, the team created wires less than 4 nanometers wide at the interface of the two materials. These conducting nanostructures can subsequently be erased with a reverse voltage or with light, rendering the interface an insulator once more.

“This work is not only potentially useful for technological applications, but also fascinating from a fundamental perspective,” Levy said. “The prospect of making both logic and memory devices with the same material is very intriguing, and at this small of a scale, it’s almost unheard of.”

The physical model still needs testing, but provides an important framework for future research directions, Levy said. The interface also acted as a transistor — an essential part of electronic devices that regulates electron flow — when the atomic-force probe served as a gate; further research will include creating devices that utilize single electrons for logic or storage.

The idea originated from a visit Levy made to the University of Augsburg in Germany where co-authors Jochen Mannhart and his student Stefan Thiel showed Levy how the entire interface could be switched between a conducting and insulating state. Levy thought of adapting the process to nanoscale dimensions and his student, Cheng Cen, the paper’s first author, brought the idea to fruition. Research by C. Stephen Hellberg from the Naval Research Laboratory contributed to the theoretical understanding of the project. The work was supported by the Defense Advanced Research Projects Agency and the National Science Foundation.

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Anesthesia research grant extended

The National Institute of General Medical Sciences (NIGMS) has awarded Yan Xu a five-year MERIT award extension for the project, “NMR Studies of Mechanisms of General Anesthesia.” Xu is a professor of anesthesiology, pharmacology and structural biology and vice chair for basic sciences in the School of Medicine’s Department of Anesthesiology.

The goal of the study is to use modern biophysical approaches such as nuclear magnetic resonance (NMR) techniques, combined with computer modeling, mutagenesis and structural biology to determine the underlying molecular and cellular mechanisms of general anesthesia.

Despite over 150 years of clinical practice, Xu noted in the funding request, the way general anesthetics work in the central nervous system continues to be among the greatest mysteries of the modern science.

In the previous funding period, Xu and co-PI Pei Tang, also of the anesthesiology department, developed a new paradigm to examine the way anesthetics modulate receptor protein functions. They seek to identify the structure-function and dynamics-function relationships with direct binding and dynamics analysis at the sub-molecular and atomic levels. Their focus has been on the trans-membrane domains of the alpha 1 subunit of the human glycine receptor (the primary inhibitory receptor in the spinal cord and the brainstem) and several related protein targets.

Funding for the project, which started in 2004, will extend into 2014. Funding for the initial five years was set at $2.05 million. The budget for the second five years is $2.38 million, although the actual award level will be determined by the NIGMS budget.

“We proposed a new protein theory of general anesthesia on the basis of protein global dynamics, and believe that this theory will potentially unify the action of a diverse range of anesthetics on a wide array of proteins,” they wrote in their request for renewed funding, adding that they expect the new studies eventually to relate the receptor-specific molecular events to the functional consequences of the action of general anesthetics.

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New meds, CBT may aid depressed teens

For depressed adolescents who have not responded to initial treatment with selective serotonin reuptake inhibitors (SSRIs), the combination of cognitive behavioral therapy (CBT) and a switch to another antidepressant had better clinical results than a change in medication without CBT, according to a study by School of Medicine researchers published in the current issue of the Journal of the American Medical Association.

However, a switch to another SSRI was just as effective as a switch to serotonin and norepinephrine reuptake inhibitor (SNRI) venlafaxine and resulted in fewer adverse side effects.

“Current clinical guidelines for the acute management of adolescent depression recommend SSRIs coupled with CBT,” noted David A. Brent, academic chief of child and adolescent psychiatry at Western Psychiatric Institute and Clinic and professor of psychiatry, pediatrics and epidemiology in the School of Medicine. “While these treatments alone or in combination have been shown to be effective, previous studies have shown at least 40 percent of adolescents with depression do not respond sufficiently to these treatments. Despite the high percentage of non-response and the serious consequences of persistent depression in this age group, until now there have been no empirical studies to guide clinicians regarding the management of this population. With these results, doctors now have the guidelines to properly respond to and treat their adolescent patients.”

Brent and his team of researchers created a six-site, National Institutes of Mental Health funded study, the Treatment of SSRI-Resistant Depression in Adolescents (TORDIA), in order to focus on non-response to an SSRI, rather than on non-response to psychotherapy, because SSRIs have been the predominant method of treatment for adolescent depression.

The study involved 334 depressed 12-18 year olds who were followed for a period of 12 weeks. The effectiveness of four treatment strategies was evaluated in patients who had not responded to a two-month initial treatment with an SSRI. Those treatments included a switch to a second, different SSRI such as paroxetine, citalopram or fluoxetine; a switch to a different SSRI in addition to CBT; a switch to venlafaxine, or a switch to venlafaxine in addition to CBT. Results showed CBT plus a switch to either medication regimen showed a higher response rate than a medication switch alone. However, there was no difference in response rate between venlafaxine and a second SSRI.

The researchers chose to compare SSRIs with the SNRI venlafaxine because prior studies on adults have shown it to be more effective than an SSRI in managing treatment-resistant depression. And, unlike similar studies on adolescent depression, TORDIA included actively suicidal teens so that the study would mirror real-world treatment situations to ensure its findings would be readily applicable to community settings.

“These findings should be encouraging for families with a teen who has been struggling with depression for some time,” said Brent. “Even if a first attempt at treatment is unsuccessful, persistence will pay off. Being open to trying new evidence-based medications or treatment combinations is likely to result in improvement.”

Other Pitt co-authors were Satish Iyengar, chair of statistics; Boris Birmaher, Neal Ryan and Nadine Melhem, psychiatry; Giovanna Porta, WPIC systems analyst; Matthew Onorato, WPIC clinician; Kaleab Abebe, statistics graduate student, and Jamie Zelazny, Institutional Review Board.

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Metals detection system licensed

Luminos has signed an exclusive license agreement to use Pitt’s patented technology to develop and sell kits containing a new fluorescent sensor that detects the rare metals palladium and platinum. The fluorescent molecule was developed in Kazunori Koide’s lab in the Department of Chemistry. The technology allows the end user to detect palladium or platinum quantitatively in samples quickly and easily using the generated fluorescent signal.

One application the Ann Arbor, Mich.-based company plans to pursue is development of a kit to measure the metals in pharmaceutical products at the lab bench during the chemical synthetic process.

The fluorescent sensor can detect platinum-containing chemotherapeutic agents, such as cisplatin, in patient serum allowing for correct therapeutic dosing. Company representatives also see applications for businesses that use the metals in the manufacturing of goods such as catalytic converters, jewelry and dental products.

Luminos plans to have the first products using the technology on the market by late summer.

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Recidivism study released

A study by Pitt’s Center on Race and Social Problems (CRSP) shows that providing services to Allegheny County Jail (ACJ) inmates while they are incarcerated and after their release dramatically reduces the chance of the inmates returning to jail.

Hide Yamatani, associate dean of research in the School of Social Work, launched the project in 2004. He studied a group of 300 male inmates who were among those receiving in-jail services such as drug and alcohol treatment, GED preparation, anger management and vocational training, through the ACJ Collaborative, whose 25 members represent the ACJ, the Allegheny County Department of Human Services and the Allegheny County Health Department. The collaborative aims to reduce recidivism by offering direct in-jail services and transitional reintegration assistance to inmates after release.

Upon their release, the men were encouraged to seek support services from more than 60 community-based organizations. The former inmates were interviewed after 30 days, six months and one year. The study found those who received services had a lower recidivism rate (16.5 percent compared to 33.1 percent for other inmates of a similar age) one year after release from jail.

No statistically significant difference in recidivism rates between black and white participants was found. Half the study participants were black; half were white. Both racial groups had improved housing a year after their release and increased employment was found for white former inmates. No change was found for blacks.

The study estimated an annual savings to the county of more than $5.3 million with the greatest cost savings in increased public safety and reduced victimization among county residents.

“So often, people have the impression that money spent on inmates and former inmates to receive social services is wasted,” said Larry Davis, CRSP director, Donald M. Henderson Professor, and dean of the School of Social Work. “These findings argue strongly that efforts to help those who have been incarcerated result in significant positive returns for the larger society. We are sure that many of the men who participated in this study are now spending time parenting their children — something they would not be doing had they not been provided services by the ACJ Collaborative.”

More information can be found at www.alleghenycounty.us/dhs/jail.aspx.

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Relapse rare for substance abusers with transplants

Only about 6 percent of former alcoholics and 4 percent of former illicit drug users will relapse into their addictions in any given year following an organ transplant, according to a study by Pitt researchers published in the February issue of Liver Transplantation.

“Substance abuse can lead to serious organ diseases for which transplantation is increasingly considered an acceptable treatment,” noted senior author Mary Amanda Dew, professor of psychiatry and director of the clinical epidemiology program at Western Psychiatric Institute and Clinic. “Still, the transplant community remains concerned about these patients resuming their harmful behaviors once the transplant has been done.”

Studies have suggested vast disparities in the prevalence of addiction relapse after transplantation. By conducting a meta-analysis of 54 studies (all but four pertaining to liver recipients) published between 1983 and 2005, the researchers sought to establish more precise estimates of the rates of alcohol and drug relapse in individuals receiving liver or other solid organ transplants. They also looked for associations between relapse and many pre-transplant or psychosocial characteristics.

They examined post-transplant outcomes for more than 3,600 former substance abusers in the areas of alcohol relapse, heavy alcohol use, illicit drug relapse, tobacco use, non-adherence to immunosuppressants and non-adherence to clinic appointments.

The average rate for alcohol relapse was approximately six cases per 100 persons per year of observation (PPY). The average rate for relapse to heavy alcohol use was 2.5 per 100 PPY. The average relapse to illicit drug use was 3.7 per 100 PPY. Relapse rates for the other studied outcomes ranged from 2 to 10 cases per 100 PPY.

Due to the amount of data available, relapse risk factors could be assessed only for alcohol use. While demographics and pre-transplant characteristics showed little correlation with relapse, poor social support, family alcohol history and pre-transplant abstinence of less than six months showed small but significant associations with relapse.

“Future research should focus on improving the prediction of risk for substance abuse relapse, and on testing interventions to promote continued abstinence post-transplant. Interventions are important because, although the risk of relapse is small during any given year, as the years add up the likelihood of relapse increases,” Dew concluded.

Co-authors from Pitt were Andrea F. DiMartini, psychiatry and surgery; Annette DeVito Dabbs, nursing; Mark Unruh, medicine; Larissa Myaskovsky, medicine, psychiatry and the Center for Health Equity Research and Promotion at the VA Pittsburgh Health Care System, and Jennifer Steel, UPMC Liver Cancer Center.

Funding was provided by the International Transplant Nurses Society, Astellas Pharma and the National Institute for Mental Health.

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Refugee research funded

Simon Reich, director of the Ford Institute for Human Security in the Graduate School of Public and International Affairs, has been awarded $85,000 from Canada’s Department of Foreign Affairs and International Trade (DFAIT) Glyn Berry Program’s Global Peace and Security Fund.

Reich’s project will address the question of what makes an IDP (internally displaced persons) or refugee camp safe for children threatened with the possibility of abduction for use as child soldiers or human trafficking, and what the international policy community can do to address this problem.

Earlier Ford Institute research concluded that the abduction of children from IDP and refugee camps was a major contributory factor in explaining the enormous variation in child soldier participation rates between past and current African conflicts. Subsequent work by the Ford Institute, in a DFAIT-funded pilot study based on a sample of camps drawn from seven African conflicts, initiated research on the question of the determinants of camp security from external attack for the general camp population.

Reich sought the support of the Canadian government because of its expressed concern about the needs facing unprotected civilian populations, particularly children, consistent with norms established by the international community. Enforcement of the provisions established by these norms has proved elusive and data regarding this issue are limited and often unsystematic.

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The University Times Research Notes column aims to inform readers about funding awarded to Pitt researchers and to report briefly on findings arising from University research. We welcome submissions from all areas of the University, not only health sciences areas.

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