University Times

Mutant mice model major depression

School of Medicine researchers have developed a mouse model of major depressive disorder (MDD) that is based on a rare genetic mutation that appears to cause MDD in the majority of people who inherit it. The findings, published online in the American Journal of Medical Genetics Part B: Neuropsychiatric Genetics EarlyView, could help to clarify the brain events that lead to MDD, and contribute to the development of better means of treatment and prevention.

Lead  author  George Zubenko, a faculty member in psychiatry, said, “Major depressive disorder is a leading cause of suffering, disability and premature death from all causes including suicide. While the cause currently is unknown, twin and adoption studies indicate that genetic factors account for 40-70 percent of the risk for developing this common disorder. In this report, we describe how we constructed a laboratory mouse strain that mimics the brain mechanism that leads to major depression in humans, rather than symptoms,” he said. “Nonetheless, in our initial characterization the mutant mice exhibited several features that were reminiscent of the human disorder, including alterations of brain anatomy, gene expression, behavior, as well as increased infant mortality.”

The findings support the role of the genetic variant in the development of MDD, and affirm the mutant mouse strain as a model of MDD worthy of further study, Zubenko said.

Previous studies of families with a severe and strongly familial form of MDD revealed a mutation in the control region of CREB1, a gene that orchestrates the expression of many other genes that play important roles in normal brain functioning. Mice have a CREB1 gene that is very similar to the human version and, with the aid of genetic engineering techniques, the researchers were able to establish a mutant mouse strain that bore the same genetic error.

Since the control regions of corresponding human and mouse genes often have regions of high similarity, the methods described in this report may be useful in creating mouse models of other human diseases.

Hugh B. Hughes III of the Zubenko lab was a co-author.

The research was supported by  the National Institute of Mental Health, the Provost’s Fund for Research Development and the Shane Richard Brown Fund.

MRI data were collected at the Pittsburgh NMR Center for Biomedical Research at Carnegie Mellon University and were analyzed with support from the Office of the Senior Vice Chancellor for Health Sciences and the National Center for Research Resources, a component of the National Institutes of Health and NIH Roadmap for Medical Research.

Thoracic research presented

Researchers from the School of Medicine and UPMC recently presented early findings from studies of asthma, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, critical care medicine and other areas at the American Thoracic Society 2011 international conference.

Highlights included:

New form of asthma identified?

Sally Wenzel, a faculty member in the Division of Pulmonary, Allergy and Critical Care Medicine and director of the UPMC Asthma Institute, and her colleagues have identified what could be a new kind of asthma in a subset of patients with severe symptoms, primarily women, who do not readily improve with conventional treatments, including steroids.

Lung biopsies indicate that inflammation resembling a mixture of hypersensitivity pneumonitis and asthma is present in these patients and that many improve dramatically following treatment with alternative anti-inflammatory drugs, including azathioprine, instead of steroids.

Oral corticosteroid use studied

Wenzel and colleagues studied the long-term use of oral corticosteroids (OCS) by people with severe asthma and found that more than 60 percent of patients who were treated with oral steroids such as prednisone at their initial evaluation remained on OCS four years later, which could be predicted by a high degree of airway obstruction and inflammation. These results suggest alternate treatments to OCS are needed in many patients with severe asthma.

Premenstrual asthma

Wenzel and colleagues found that premenstrual asthma is a condition characterized by high frequency of symptoms, exacerbations and general severity. Premenstrual asthma is strongly associated with asthma-like reactions to aspirin; lower levels of IgE antibody, which typically play a role in allergy; smaller lung volumes, and gastroesophageal reflux disease, suggesting this may be a different and hormonally driven asthma variant.

Monocyte genetics a factorin IPF prognosis

Naftali Kaminski, a faculty member in the Division of Pulmonary, Allergy and Critical Care Medicine and director of the Dorothy P. and Richard P. Simmons Center for Interstitial Lung Diseases, and colleagues found that patterns of gene activity in white blood cells called monocytes reflect patients’ prognosis in idiopathic pulmonary fibrosis, a progressive lung-scarring disease.

Starting from more than 2,500 genes, the researchers identified certain gene expression patterns in an immune signaling pathway to measure with a gene microarray or chip, and found that decreased expression among specific genes is associated with a greater likelihood of death from the disease. The findings indicate that a simple blood test can reveal disease prognosis, which could help guide treatment planning, such as when to pursue lung transplantation.

ICU patients’ families more optimistic than docs

Critical care medicine faculty member Douglas White, who directs the department’s program on ethics and decision-making in critical illness, and his colleagues studied caregivers who were surrogate decision-makers for patients and their doctors in four intensive care units.

The researchers found that surrogate decision-makers were unduly optimistic about prognoses compared to physicians. This discordance seemed to come from disbelief rather than misunderstanding of the physicians’ prognostications.

Tropical droughts predicted

A 2,300-year climate record recovered from an Andean lake reveals that as temperatures in the northern hemisphere rise, the planet’s densely populated tropical regions likely will experience severe water shortages as summer monsoons become drier.

A Pitt research team found that equatorial regions of South America already are receiving less rainfall than at any point in the past millennium.

The researchers report in the Proceedings of the National Academy of Sciences that a nearly 6-foot-long sediment core from Laguna Pumacocha in Peru contains the most detailed geochemical record of tropical climate fluctuations yet uncovered. The core shows pronounced dry and wet phases of the South American summer monsoons and corresponds with existing geological data of precipitation changes in the surrounding regions.

Paired with these sources, the sediment record illustrated that rainfall during the South American summer monsoon has dropped sharply since 1900 — exhibiting the greatest shift in precipitation since approximately 300 BCE — while the Northern Hemisphere has experienced warmer temperatures.

Study co-author Mark Abbott, a geology and planetary science faculty member who also co-designed the project, said that he and his colleagues did not anticipate the rapid decrease in 20th-century rainfall that they observed.

“This model suggests that tropical regions are dry to a point we would not have predicted,” Abbott said. “If the monsoons that are so critical to the water supply in tropical areas continue to diminish at this pace, it will have devastating implications for the water resources of a huge swath of the planet.”

The sediment core shows regular fluctuations in rainfall from 300 BCE to 900 CE, with notably heavy precipitation around 550. Beginning in 900 CE, however, a severe drought set in for the next three centuries, with the driest period being 1000-1040. This period correlates with the demise of regional Native American populations, Abbott explained, including the Tiwanaku and Wari that inhabited present-day Bolivia, Chile and Peru. After 1300, monsoons increasingly drenched the South American tropics.

The wettest period of the past 2,300 years lasted from roughly 1500 to the 1750s during the timespan known as the Little Ice Age, a period of cooler global temperatures.

Around 1820, a dry cycle crept in briefly, but quickly gave way to a wet phase before the rain began waning again in 1900.

By July 2007, when the sediment core was collected, there had been a steep, steady increase in dry conditions to a high point not surpassed since 1000.

To create a climate record from the sediment core, the team analyzed the oxygen isotope delta-O-18 ratio in each annual layer of lake-bed mud. Low delta-O-18 indicates a wetter season, while levels are high when monsoon rain is light.

The team then established a connection between rainfall and Northern Hemisphere temperatures by comparing their core to the movement of the intertropical convergence zone (ITCZ), a stormy area near the equator where winds from the Northern and Southern hemispheres meet. Abbott and his colleagues concluded that warm northern temperatures such as those currently recorded lure the ITCZ — the main source of monsoons — north and ultimately reduce the rainfall on which tropical areas rely.

Abbott worked with geology and planetary science faculty member Mike Rosenmeier; Broxton Bird and Nathan Stansell, who received their PhD degrees in geology from Pitt in 2009, and researchers from Union College and the State University of New York-Albany.

Graphs illustrating the sediment core’s correlation with climate data are available at www.news.pitt.edu/news/tropical-monsoon-drought-climate-change.

Researchers seek greener operating room

Pitt engineering and medicine researchers have received a $25,000 grant from Pitt’s Clinical and Translational Science Institute to help establish procedures and policies that hospitals can adopt to be more environmentally conscious.

The team includes civil and environmental engineering faculty members Melissa Bilec and Amy Landis, as well as medical school faculty members Noedahn Copley-Woods and Richard Guido of obstetrics, gynecology and reproductive sciences.

Using hysterectomy as a case study for the amount of waste generated during surgeries, the researchers will apply a life-cycle assessment, or LCA, which gauges the environmental effect of the entire procedure, from the raw materials and basic tools needed to the ultimate disposal of the implements and equipment used. Hysterectomies were selected because of the multiple procedures involved — the researchers will be able to conduct comparative LCAs of abdominal, vaginal, laparoscopic and robot-assisted surgery.

Once the entire footprint of these procedures is known, the team will be able to assess which areas could be more sustainable.

“Greening” the OR will contribute substantially to the researchers’ overall goal of helping hospitals reduce the amount of waste generated.

Energy research consortium formed

Pitt is one of seven research universities that have formed a new initiative to address the environmental impacts of the discovery, development, production and use of energy resources in Appalachia. The Appalachian Research Initiative for Environmental Science (ARIES), under the direction of the Virginia Center for Coal and Energy Research at Virginia Tech, will study both upstream and downstream issues related to the energy sector.

In addition to Virginia Tech, team members include Anthony Iannacchione of Pitt’s Department of Civil and Environmental Engineering and researchers from West Virginia University, the University of Kentucky, Ohio State University, Penn State and Penn.

The technical scope of the research ARIES will conduct includes:

• Evaluating the effects of coal mining on streams and biological communities in the region;

• Investigating methods for minimizing water discharges effectively through alternative water management practices and treating water prior to discharge;

• Developing analytical tools to allow mine planners to locate, isolate and manage strata that may generate releases of environmental concern, and

• Assessing improved placement designs and spearheading development of mining engineering systems and practices that can improve environmental performance and accountability.

ARIES is being funded with a five-year, $12.5 million grant from Alpha Natural Resources, International Coal Group, Massey Energy, Natural Resource Partners, TECO Coal Corp., Patriot Coal Corp., Cliffs Natural Resources, Mepco and Norfolk Southern.

For additional information, visit www.energy.vt.edu/ARIES.

Transplant research presented

The following studies were among the research presented by Pitt doctors during the 2011 American Transplant Congress in Philadelphia:

Lung transplants in the elderly

Yoshiya Toyoda, a faculty member in surgery at the School of Medicine and head of cardiothoracic transplantation at UPMC, presented findings from research exploring outcomes in lung transplant patients over age 70.

While many transplant centers will not perform lung transplants in patients older than 65, researchers found that single and double lung transplants can be offered to highly selected patients ages 70-74 with excellent outcomes.

Cancer & kidney transplantation

Christine Wu, a faculty member in the Department of Medicine, and Ron Shapiro, director of UPMC’s kidney, pancreas and islet transplantation, presented research on the incidence of cancer among deceased and living donor kidney transplant recipients who were given the antibody alemtuzumab.

Researchers looked at 1,350 transplants done between 2001 and 2008 and found that 52, or 3.85 percent, were diagnosed with cancer after their transplant. The most common type identified was lymphoma. Researchers did not find that use of alemtuzumab was associated with a higher risk of cancer.

PRES risks explored

Transplant surgeon Ruy Cruz of the Thomas E. Starzl Transplantation Institute presented findings into the understanding of posterior reversible encephalopathy syndrome (PRES), a rare complication that can occur after a liver transplant.

Cruz and his colleagues analyzed more than 1,800 adult liver transplant recipients between 2000 and 2010 and found 18 had been diagnosed with PRES.

Researchers found that low levels of magnesium and infection may put patients at risk for developing PRES.

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