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January 20, 2011

Research Notes

Otitis treatment studied

Antibiotics are an effective treatment for young children with acute middle ear infections, according to a clinical trial at Children’s Hospital. The findings add important new evidence to the best treatment for ear infections and could have major implications on treatment guidelines in the United States.

Results of the study were published in the Jan. 13 issue of The New England Journal of Medicine.

The researchers, led by pediatrics faculty member Alejandro Hoberman, found that in children ages 6 months-2 years with acute otitis media (AOM), or middle ear infection, treatment with antibiotics for 10 days reduced the severity and duration of the infections more effectively than a placebo.

Children in the study who received antibiotics also were less likely to have evidence of clinical failure (persistent signs of acute infection) that required further treatment, said Hoberman, who also is chief of the Division of General Academic Pediatrics and vice chair of clinical research and the Jack L. Paradise Endowed Professor in Pediatric Research at Children’s.

“Based on these findings, there is strong evidence in favor of treating children younger than 2 years of age with antibiotics, irrespective of the severity of the ear infection,” he said. “To some degree, this is contrary to current clinical guidelines, which include an option for watchful waiting rather than prompt treatment for young children with apparently mild symptoms. We expect our study to have an impact on treatment guidelines for the United States that currently are being revised.”

Hoberman said the current recommendations are based on studies with many important limitations, most notably, a lack of strict diagnostic criteria. “In other words, many of the children studied merely may have had fluid in the middle ear instead of an actual ear infection. Other limitations were the inclusion of few very young children, in whom the infection tends to be more stubborn, and the use of antibiotics that had a limited effectiveness or were given in doses that were ineffective.”

Hoberman’s study randomly assigned 291 children to receive either the antibiotic amoxicillin-clavulanate or a placebo for 10 days. An improvement in symptoms occurred earlier in children who received antibiotics. Mean symptom scores over the first seven days were lower at each time point in the antibiotic group than in the placebo group. Larger differences between children receiving the antibiotic and children receiving the placebo were observed in rates of clinical failure: 4 percent vs. 23 percent on day four or five; and 16 percent vs. 51 percent on days 10-12.

The key to optimal management of AOM remains an accurate diagnosis, according to Hoberman. “Young children with a certain diagnosis of AOM are more likely to recover when treated with an appropriate antibiotic, and their symptoms will subside more quickly,” he said. “Provided the diagnosis of AOM in children younger than 2 years of age is certain, we favor treatment with antibiotics.”

Antibiotic resistance research planned

Alejandro Hoberman also is the principal investigator for a six-year, $8.2 million contract (pending the availability of appropriations) at the School of Medicine and Children’s Hospital, awarded by the National Institutes of Health (NIH) to address antibiotic resistance in children.

Children’s Hospital is one of four institutions to be awarded these recent contracts related to antimicrobial research from NIH’s National Institute of Allergy and Infectious Diseases (NIAID).

The Children’s clinical trial will compare a short-duration treatment strategy with standard duration treatment to determine the efficacy of short-course antibiotic therapy and its impact on antimicrobial resistance in young children with acute otitis media (ear infections).

Hoberman said: “Ear infections affect the vast majority of children, yet they can be difficult to diagnose and clinicians do not always agree on what constitutes adequate treatment. Experts remain divided between the so-called ‘watchful waiting’ approach and treatment with antibiotics.”

The new trials are part of a two-pronged NIAID approach to antimicrobial research: learning how to make better use of the drugs available today in order to protect their usefulness, while facilitating the development of new drugs.

In a prepared release, NIAID director Anthony S. Fauci stated, “Many infectious diseases are increasingly difficult to treat because bacteria and other microbes have developed resistance to commonly used antimicrobial drugs. Research to preserve the effectiveness of licensed antibiotics is a critical priority for the institute.”

UPJ project receives grant

The Pitt-Johnstown nursing department’s caregiver education, training and advocacy (CETA) project recently was awarded a $5,000 grant from the Community Foundation for the Alleghenies.

The CETA project, which could become a model for other communities that need to contain health care costs, will address critical needs of local individuals caring for elderly family members in the home setting.

Synthesis of elastin studied

Bioengineering research on synthesizing elastin in engineered arterial tissue is slated for publication in the Proceedings of the National Academy of Sciences.

The paper, by bioengineering faculty member Yadong Wang and Keewon Lee, a postdoctoral fellow in Wang’s lab, examines mature elastin synthesis in small-diameter arterial constructs.

Elastin is a protein that provides elasticity in the walls of blood vessels. “Mature elastin synthesis is a key challenge in arterial tissue engineering,” Wang stated. “Most engineered vessels lack elastic fibers in the medial layer and those present are poorly organized.”

Researchers cultured adult baboon smooth muscle cells they had seeded in porous tubular scaffolds made from the biodegradable elastomer poly(glycerol sebacate).

The researchers found that the cells produced a substantial amount of mature elastin within three weeks and the elastic fibers had a similar orientation as did those in native arteries. They tested the effect of pore sizes and found a 25-32 micrometer pore size supported cell organization and elastin synthesis more than larger pore sizes.

Biochemical analysis showed that the constructs contained mature elastin equivalent to 19 percent of the native arteries. Mechanical tests indicated that the constructs could withstand up to 200 pounds of mercury burst pressure and exhibited elasticity comparable to native arteries.

Other Pitt authors of the study included Donna B. Stolz of cell biology and physiology.

NO loss in Alzheimer’s probed

A School of Medicine researcher, in collaboration with NIH scientists, has discovered that the deadly plaques of Alzheimer’s disease interact with certain cellular proteins to inhibit normal signals that maintain blood flow to the brain. Their findings, which could lead to new approaches to treat the dementia, recently were published in PLoS One.

Levels of nitric oxide (NO) —a signaling molecule that helps regulate blood flow and immune and neurological processes — are known to be low in the brains of people who have Alzheimer’s disease, but the reason for that hasn’t been clear, said study co-author Jeffrey S. Isenberg, a faculty member in the Division of Pulmonary, Allergy and Critical Care Medicine.

“Our research sheds light on how that loss of NO might happen, and reveals biochemical pathways that drug discoverers might be able to exploit to find new medicines for Alzheimer’s,” he said. “There is evidence that suggests enhancing NO levels can protect neurons from degenerating and dying.”

The researchers found in mouse and human cell experiments that amyloid-beta, the main component of the plaques that accumulate on brain cells in Alzheimer’s, binds to a cell surface receptor called CD36, which causes decreased activity of the enzyme soluble guanylate cyclase to reduce NO signaling. But that inhibitory effect required the presence of and interaction with CD47, another cell surface protein, indicating that additional steps in the pathway remain to be identified.

“It’s possible that an agent that could block either CD36 or CD47 could slow the progress of neuronal degeneration in Alzheimer’s by protecting the production of NO in the brain,” Isenberg said. “Importantly, we have already identified therapeutic agents that can interrupt the inhibitory signal induced by these interactions to maximize NO production, signaling and sensitivity.”

He and his colleagues currently are studying such blockers in a variety of disease models.

Stress, asthma linked

New research shows that parental stress, particularly depression, is an important risk factor for asthma problems among Puerto Rican children. In a study of 339 sets of twins from Puerto Rico, published online in the Journal of Allergy and Clinical Immunology, maternal and paternal depression were associated with children’s recurrent hospitalizations for asthma and poor control of asthma symptoms.

The study was led by Juan Celedón, the Niels K. Jerne Professor of Pediatrics and Medicine at the School of Medicine and chief of the Division of Pediatric Pulmonary Medicine, Allergy and Immunology at Children’s Hospital.

According to the study, children whose mothers had depression were at increased risk of asthma hospitalizations at 1 and 3 years of age, and an increased prevalence of asthma diagnosis at age 3. At 1 and 3 years of age, children whose fathers had depression experienced increased oral steroid use and there was an association between parental depression and hospitalizations.

“Our findings add to the growing body of evidence of a link between stress in the family and the development of asthma in children and subsequent poor symptom control,” Celedón said. “Addressing parental psychosocial stress, caused by factors such as violence and poverty, may improve rates of hospitalization and asthma symptom control in childhood.”

Asthma affects more than 6.8 million children in the United States, and Puerto Ricans have the highest lifetime prevalence of asthma. In addition to high rates of asthma, Puerto Ricans have a high prevalence of psychosocial stress, mostly related to exposure to violence and high levels of poverty, with 45 percent of the population living below the poverty level.

Aricept studied in depressed elderly people

A School of Medicine study published in the Archives of General Psychiatry finds that donepezil enhances language, memory and executive functioning in older, depressed adults to a greater extent than was evident from the use of an antidepressant medication alone. The medication, marketed under the trade name Aricept, is used to treat dementia in Alzheimer’s patients.

For the study, researchers compared 130 depressed adults over the age of 65 with 67 subjects receiving donepezil and 63 receiving a placebo. The participants were followed for two years while researchers explored the effects of donepezil and the placebo on five areas of neuropsychological functioning, including speed of information processing, memory, language, visuospatial functioning and executive functioning, or brain processes that are responsible for planning and abstract thinking.

The researchers noted two unexpected findings: donepezil seemed to delay the progression of mild cognitive impairment to frank dementia, and the use of the drug was associated with somewhat higher recurrence rates of clinical depression episodes, said Charles F. Reynolds III, lead author of the study and UPMC Endowed Chair of Geriatric Psychiatry. “So, there was both a benefit and a risk to adding donepezil to antidepressant pharmacotherapy in older adults. Fortunately, the majority of recurrent depressive episodes could be treated to remission,” he said.

Adding donepezil to maintenance antidepressant medication appears to be useful in the treatment of older, depressed patients with mild cognitive impairment but does not benefit those with normal cognition.

“Cognitive impairment is a core feature of depression in older adults and may foreshadow the development of dementia,” said Reynolds. “While treatment of depression usually benefits associated cognitive impairment, it does not completely regulate cognitive impairment and may not delay the progression to dementia. So, even in remission, older adults with past depression may still show residual cognitive difficulties, such as slowing of information processing speed and impairments in executive or language function. Our study showed that by adding donepezil, cognition can be improved beyond that which is seen simply with the treatment of depression itself.”

Pitt co-authors of the study included Meryl A. Butters, Mary Amanda Dew, Margo Holm, Joan C. Rogers, Jordan F. Karp, Mark D. Miller, Ellen M. Whyte, Ariel Gildengers, Katalin Szanto, Patricia R. Houck, Amy Begley, Jacqueline Stack and Salem Bensasi of the Department of Psychiatry; Oscar Lopez of neurology; Sati Mazumdar and Stewart Anderson of biostatistics, and M. Llyas Kamboh of the Graduate School of Public Health.

Measles gene, Paget’s linked

A gene from the measles virus plays a key role in the development of Paget’s disease (PD) of bone, according to a team led by School of Medicine researchers.

Their findings, recently published in Cell Metabolism, confirm a long-held speculation that the childhood infection is an environmental trigger for the disease and reveal how the viral gene contributes to the development of its characteristic bone lesions.

“Our earlier work showed that bone cells called osteoclasts in about 70 percent of these patients contain a certain measles virus protein,” noted senior investigator G. David Roodman, a faculty member and vice chair for research in the Department of Medicine. “Also, when we engineered normal osteoclasts in mice to contain, or express, the measles protein, pagetic bone lesions formed.”

Osteoclast abnormalities lead to imbalance in the normal processes of bone dissolution and rebuilding. According to the National Institute of Arthritis and Musculoskeletal and Skin Diseases, an estimated 1 million Americans have PD. Bones are enlarged but fragile, leading to pain and a greater likelihood of fracture. Arthritis, hearing loss and kidney stones can occur as a result.

In the new study, Roodman’s team sought to understand the roles of mutations in a gene called p62, which is common among PD patients, and measles virus nucleocapsid protein (MVNP) by examining the marrow of affected and unaffected bones of 12 PD patients and of eight people without PD. They also bred mice with the p62 mutation and MVNP.

The team found that marrow from eight of the 12 PD patients expressed MVNP; three patients expressed the protein in both affected and unaffected bone sites, and four patients did not make it at either type of site. Osteoclast precursor cells from PD patients who made MVNP formed pagetic osteoclasts in test tube experiments and displayed other typical PD responses. Osteoclasts appeared normal, though, when the precursor cells came from PD patients who didn’t make MVNP. “It’s not clear why this would happen,” Roodman said. “It could be that other viruses or genes are triggering PD in these patients.”

Mice with a p62 gene mutation and MVNP developed dramatic bone lesions. Other tests indicate that the presence of MVNP increases production of the cell-signaling protein interleukin-6, which in turn leads to osteoclast changes that are seen in PD.

The prevalence of Paget’s disease has dropped during the past 25 years, Roodman said. That could reflect the impact of measles vaccination or that another environmental factor involved in PD has changed.

Among the Pitt co-authors was Noriyoshi Kurihara of the Department of Medicine.

The study was funded by the National Institutes of Health and the Paget’s Foundation.

Volatility, volume raise stock prices

While savvy investors might say that a stock’s value is the determining factor for how much they’re willing to pay, Pitt researchers have shown that recent price trends and other aspects unrelated to a stock’s value are important in determining the price investors actually pay.

Mathematics faculty member Gunduz Caginalp said: “A basic rationale for price movement is due to changes in the value of the asset. In the absence of any insight into the motivations of investors and traders, one might stipulate that prices should fluctuate randomly about this basic valuation.”

Caginalp and one of his students, co-author Mark DeSantis, analyzed 111,356 records from 119 funds, corresponding with the daily closing prices of those funds Oct. 26, 1998-Jan. 30, 2008.

They found strong statistical evidence that a short-term price trend tends to increase trading prices in financial markets, to a magnitude of almost half that of valuation.

The researchers also found statistically significant positive impacts on the price with respect to the stock’s short-term volatility and volume trend, as well as to the nation’s money supply. According to the study, the findings about the money supply’s impact validate asset-flow theory, which holds that additional cash fuels trading price increases. Caginalp and DeSantis’s findings appear in Nonlinear Analysis: Real World Applications, available online at and slated for publication in the journal in April.

“Papers that discuss motivations beyond valuation rarely have direct contact with market data,” says Caginalp. “As such, it is easy for exponents of efficient market theories to dismiss them.”

Caginalp finds the positive correlation of stocks’ short-term volatility to price surprising. “In classical finance, the inverse risk-reward relationship stipulates that high volatility should be interpreted as greater risk, which should diminish the price that traders would pay for the stock,” he said. Caginalp hypothesizes that traders are attracted to high volatility because they foresee volatility as an opportunity for greater profits.


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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