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June 23, 2005


$9 million grant to develop biomedical research tools may aid drug discovery efforts

The School of Medicine has received $9 million from the National Institutes of Health (NIH) to establish the University of Pittsburgh Molecular Libraries Screening Center (UP-MLSC).

The center is one of nine in the nation that will create the most sophisticated methods for rapidly assessing hundreds of thousands of compounds for their biological activities and therapeutic potential — a capability that has until now been limited almost exclusively to pharmaceutical companies. Moreover, to help speed the use of promising targets for drug development, all information collected by the centers will be available freely to the entire scientific community through PubChem, a comprehensive database that has been established by the NIH.

As part of NIH’s Roadmap, which has as its overarching theme “New Pathways to Discovery,” NIH has allocated $88.9 million over the next three years to create the Molecular Libraries Screening Centers Network (MLSCN). NIH selected nine outside institutions as pilot centers to be included in the network, as well as NIH’s Chemical Genomics Center. Each center will work to develop the necessary tools conducting so-called high throughput screenings of molecules — which by the third year will allow each center to screen up to 100,000 molecule compounds using 20 different approaches, or assays, that help determine how these compounds interact with molecular targets, within cells, and how they are involved in regulating events that may be the root cause of different diseases.

Pitt’s center takes advantage of close ties between the School of Medicine’s Department of Pharmacology and the School of Arts and Sciences’ Department of Chemistry, along with new facilities devoted to drug discovery in the newly constructed Biomedical Science Tower 3. It also represents a collaboration with neighboring Carnegie Mellon University and Sandia National Laboratories in Albuquerque, N.M., and provides the UP-MLSC unique expertise in design and development of novel probes that use fluorescence and other optical imaging techniques.

John S. Lazo, the Allegheny Foundation Professor of Pharmacology at the School of Medicine, is principal investigator of the UP-MLSC.

“As a pilot center in the Molecular Libraries Screening Centers Network, we will be able to exploit and expand our existing strengths for developing and implementing methods for the detection, characterization and refinement of small molecules that have attractive biological and pharmacological properties and may eventually be further developed as therapeutic approaches to treating various diseases and conditions,” said Lazo, who also will direct a core devoted to assay implementation.

Andreas Vogt, research assistant professor of pharmacology in the School of Medicine, will focus on high throughput screening, which will exploit Pitt’s existing expertise in screening compounds in the context of whole cells.

Peter Wipf, University Professor in the chemistry department, School of Arts and Sciences, and co-principal investigator, will lead the synthetic chemistry core. The focus of that core will be to further improve and refine compounds designated as being the most promising to better target the specific errors that occur on the smallest of scales yet have profound effects on the development of disease. Mark D. Rintoul, manager of computational biology at Sandia National Laboratories, will direct the informatics core.

An NIH steering committee for the MLSCN, of which Lazo will be a member, will determine which of the most promising methods for screening molecules will be pursued and select from among its network of funded pilot centers those that will develop and implement these particular assays.

All information collected on assays and high throughput screenings of compounds will be included in NIH’s new database, PubChem, to ensure that resources developed from the MLSCN will be made available to the scientific community.


Heinz grant funds research on childhood obesity

Western Psychiatric Institute and Clinic (WPIC) recently received a $200,000 grant from the Heinz Endowments to collaborate with partners at the Pennsylvania Department of Public Welfare and the UPMC Health Plan in a project to address pediatric obesity in high-risk children of parents with type 2 diabetes.

Pediatric obesity has increased dramatically over the past two decades, with as many as 15 percent of American children now classified as overweight and an additional 15 percent at risk for being overweight. The problem is serious because children who are overweight are at risk for developing diabetes, cardiovascular disorders and other life-threatening and costly conditions. However, there have been few projects conducted to study how promising interventions developed by researchers can impact the daily lives of families.

The HEALTH (Healthy Eating and Activity as Life Time Habits) for Families program, designed collaboratively by WPIC faculty, members of the public welfare department’s Pediatric Obesity Workgroup and obesity experts at the UPMC Health Plan, will work directly with diabetic parents to support their ability to develop a home geared toward healthy eating and increased physical activity levels for the whole family.

“There is some evidence that a pediatric obesity program that focuses on parents alone may be more feasible to put into practice than one that works with both parents and children,” said Patricia Cluss, associate director, WPIC behavioral health medicine program and director, Prevention and Health Outcomes, UPMC Health Plan. “This grant will allow us to implement a plan that takes a pediatric care management approach from within a health plan. If we can coach parents in effective ways for encouraging children to form healthy eating and activity habits, the whole family can benefit.”

In addition to Cluss, other researchers involved in securing the grant include Linda Ewing, UPMC Health Plan and WPIC, and Deneen Vojta, Valerie Meya and Gwendolyn Poles from the public welfare department.


Researchers see electron waves in motion for first time with new imaging technique

Both the ancient art of stained glass and the cutting-edge field of plasmonics rely on the oscillation of electrons in nanosized metal particles. When light shines on such particles, it excites the electromagnetic fields on the metal’s surface, known as “surface plasmons,” and causes its electrons to oscillate in waves, producing the rich hues of stained glass.

But because electrons move nearly as fast as light, those oscillations have been difficult to observe and had never before been seen in motion. Now, in a paper published in the current issue of the journal Nano Letters, Pitt researchers have demonstrated a microscopy technique that allows the movement of the plasmons to be seen for the first time, at a resolution a trillion times better than conventional techniques.

Hrvoje Petek, professor of physics and astronomy, and Hong Koo Kim, professor of electrical and computer engineering, are co-directors of Pitt’s Institute of NanoScience and Engineering. Their paper, “Femtosecond Imaging of Surface Plasmon Dynamics in a Nanostructured Silver Film,” showed that it is indeed possible to achieve high-resolution imaging through a combination of ultra-fast laser and electron optic methods. This technique had never been demonstrated in practice.

Petek and Kim used a pair of 10-femtosecond (one quadrillionth of a second) laser pulses to induce the emission of electrons from the sample, a nanostructured thin silver film. Scanning the pulse delay, they recorded a movie of surface plasmon fields at 330 attoseconds (quintillionths of a second) per frame. The video is available on line at

The research is a boon to the emerging field of plasmonics. Currently, semiconductor chips each contain “about a mile” of wires, said Petek. When electrons carry electrical signals through such wires they collide about every 10 nanometers (10-8 m). In part, this causes problems because the chips give off too much heat. The solution may be to send the signal as plasmon waves, which would lead to faster chips and less dissipation of energy, Petek said.

Other researchers on the paper were Atsushi Kubo and Ken Onda, postdoctoral research associates in the Department of Physics and Astronomy, and Zhijun Sun and Yun S. Jung, doctoral students in the Department of Electrical and Computer Engineering. All are affiliated with the University’s Institute of NanoScience and Engineering.

Funding for this research was provided by the National Science Foundation.

Pitt’s Institute of NanoScience and Engineering is an integrated, multidisciplinary organization that brings coherence to the University’s research efforts and resources in the fields of nanoscale science and engineering.


Pitt researchers presented results and information on ongoing studies at the International Conference on Bipolar Disorder, held at the David L. Lawrence Convention Center, Downtown.

The conference was sponsored by Pitt’s School of Medicine and Western Psychiatric Institute and Clinic (WPIC). Here is a sampling of the Pitt research findings presented at the conference:


Treatment sequences evaluated for bipolar depression

After decades of relative neglect, research on the depressed phase of bipolar illness has again become topical. Such renewed interest reflects increasing evidence that it is the depressions, not the more colorful manias, that account for the greater proportion of the morbidity, disability and mortality associated with bipolar disorder, as well as the fact that none of the currently available antidepressant therapies are particularly effective treatments.

Michael E. Thase, professor of psychiatry, reviewed evidence pertaining to “mood stabilizer first” monotherapy treatment strategies, contrasted with treatment approaches that combine mood stabilizers and antidepressants or other multi-drug regimens.


2 therapies compared for those with bipolar I

The Maintenance Therapies in Bipolar Disorder study was a randomized trial of two psychosocial interventions for patients with bipolar I disorder: Interpersonal and Social Rhythm Therapy (IPSRT), an adaptation of Klerman and Weissman’s interpersonal psychotherapy, and intensive clinical management.

Ellen Frank, professor of psychiatry and psychology, found that although acute IPSRT treatment generally was associated with positive long-term outcomes, this was not true for patients entering the trial with substantial medical problems. Such patients may be less able to participate in a treatment that focuses on social rhythm stabilization and resolution of interpersonal problems than their physically healthier peers.

Alternatively, bipolar patients with substantial medical comorbidity actually may benefit from a treatment that focuses largely on physical concerns.

Other Pitt researchers contributing to the study were D.J. Kupfer, H. Swartz, A. Fagiolini, J. Scott and W. Thompson.


Recruitment, screening strategies presented for bipolar clinical trials

There has been little study of recruitment in bipolar clinical trials. Susan R. Berman, senior program coordinator, Mood Disorders Research Treatment Clinic, WPIC, examined demographic variables (age, gender and race) that may affect retention through the screening process and entry into a bipolar research study. Recruitment sources and cost per enrolled research subject were explored.

Professional methods of recruitment yielded more research subjects, according to the study. Of the direct methods, television advertisements and referrals from friends/family had the highest yield.

Other Pitt researchers involved in the study included E.S. Friedman, J.A. Callan, A.L. Fasiczka, M. McLean, D.M. Hunter, A. Fagiolini, D.J. Kupfer and M.E. Thase.


Sleep disturbances studied in remission phase of bipolar disorder

It is well known that insomnia and hypersomnia are very common during the acute episodes of mood disorders. For instance, the Diagnostic and Statistical Manual of Mental Disorders (DSM) reports that sleep EEG abnormalities may be evident in 40-60 percent of outpatients and in up to 90 percent of patients with a major depressive episode.

Andrea Fagiolini, assistant professor of psychiatry, evaluated the frequency of insomnia and hypersomnia in the remission phase of bipolar disorder.

Of 110 patients studied, 53 percent reported a sleep problem (difficulty falling asleep, sleep continuity difficulties, early morning awakening or hypersomnia), despite not currently experiencing a DSM-IV major affective episode.

Other Pitt researchers included E. Frank, A. Fasiczka, P.R. Houck, I. Soreca, D. Fleming, T. Denko, D. Spiker, E. Friedman, J. Callan, S. Berman, C. Spotts, M.E. Thase and D.J. Kupfer.


Seasonal changes could contribute to mood state instability

Edward S. Friedman, associate professor of psychiatry, examined 1,000 patients enrolled in the systematic treatment enhancement program for bipolar disorder (STEP-BD) for evidence of a seasonal effect on prevalence of different clinical mood states.

His study found there was a higher prevalence of depression in STEP-BD patients in northern sites; that seasonal changes in prevalence rates of illness differ for bipolar I and II patients, and that there is a peak rate of depression in the fall season in northern sites and in summer in southern sites.

The findings suggest seasonal effects contribute to mood state instability.

Other Pitt researchers contributing to the study were M. Bhargava, M. Landen, J.M. Foris, S. Wisniewski and M.E. Thase.


Cognitive functioning, daily living activities relationship examined in older adults with bipolar disorder

Limited research has focused on cognitive functioning in adults with bipolar disorder age 60 years and older. Ariel G. Gildengers, assistant professor of psychiatry, examined cognitive functioning of elderly, clinically euthymic (of normal mood) adults with bipolar disorder and the relationship between cognitive functioning and instrumental activities of daily living (IADLs).

In this small group of euthymic, elderly patients with bipolar disorder, researchers observed substantial dysfunctions in multiple cognitive domains, particularly in information-processing speed and executive functioning. Moreover, decrease in information-processing speed was associated with decrements in performance of IADLs. Cognitive dysfunction is likely an important and under-recognized component of disability in older adults with bipolar disorder, according to the research.

Other Pitt researchers involved in the study included M.A. Butters, D. Chisholm, M.B. Holm, J.C. Rogers, R.K. Bhalla, B.A. Schoderbek, P.R. Houck, D.J. Kupfer, C.F. Reynolds III and B.H. Mulsant.


Divalproex reduces cocaine use in patients with bipolar disorder, comorbid alcoholism

Ihsan M. Salloum, associate professor of psychiatry, tested the efficacy of divalproex sodium in reducing cocaine use among bipolar alcoholics. The results from a randomized, placebo-controlled trial showed an advantage of divalproex over placebo in reducing cocaine use.

The small sample and the secondary data analysis call for caution in interpreting these findings, researchers say. However, these results provide an encouraging lead to further evaluate divalproex efficacy in bipolar-cocaine comorbidity, they added.

Other Pitt researchers included J.R. Cornelius, A. Douaihy, D.C. Daley, L. Kirisci, T.M. Kelly and M.E. Thase.


Does comorbid substance use disorder increase risk for suicide attempt?

There have been conflicting reports in the literature regarding whether comorbid substance use disorder (SUD) in patients with bipolar disorder increases the risk of a suicide attempt.

Crystal R. Spotts, clinical research coordinator, Mood Disorders Research Treatment Clinic, WPIC, examined lifetime SUD and suicidal ideation.

Research findings included that subjects without an SUD were much more likely to have completed a suicide note than those with alcohol, other drug or nicotine use disorders.

However, those with an alcohol, other drug or nicotine diagnosis were much more likely to have made a suicide attempt. This also was true for those with more than one SUD compared to those without.

Other Pitt researchers included E.S. Friedman, A. Fagiolini, J.A.Callan, S.A. Berman, A.L. Fasiczka, M.E. Thase and D.J. Kupfer.

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