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Patient quality of life assessments should be used in conjunction with clinician evaluations of the severity of voice problems because both approaches provide related but unique information, according to a study by Columbia University Medical Center and University of Michigan researchers.

The study, led by Thomas Murry, Ph.D. and Jonathan E. Aviv, M.D., both professors of otolaryngology and head and neck surgery at P&S, compared a patient quality of life scale with a clinician evaluation scale. They found the results from the scales were correlated but not redundant. "We conclude that both scales should be used in evaluating patients and guiding the course of treatment, including the right amount of treatment," Dr. Murry says.

Characteristics such as age, employment status, and occupation are likely important factors in quality of life assessments. "For example, a retiree's or a mailman's quality of life may not be affected much by a voice disorder and they may not want much treatment," Dr. Murry says. "But any voice problem is a big deal to an opera singer or a schoolteacher because it affects his or her livelihood."

The researchers enrolled 50 patients with voice disorders and 45 patients without voice problems in the study. All study participants completed the 10-question Voice-Related Quality of Life Measure exam. Voice clinicians then assessed each of the participants using a clinical scale called GRABAS, widely used since 1981, that measures the overall grade or severity, roughness of the voice, breathiness, asthenia (weakness), and strain. Quality of life scales are a relatively new development in the field of otolargynology, which validated its first quality of life scale in 1997. The study was published in the June issue of the Journal of Voice.

—Matthew Dougherty

research title - Arsenic Exposure

A recent study of children exposed to arsenic-tainted water in Araihazar, Bangladesh, found that water arsenic was significantly associated with reduced intellectual function. Naturally occurring arsenic in well water has led to the exposure of millions of people in South Asia, and Bangladesh in particular. The new study is the first systematic look at the effects of this toxic element on children's intellectual abilities. The complete findings of the study will be published in the September issue of Environmental Health Perspectives and summarized in the Environs News Section.

Carried out in 201, 10-year-old children of parents participating in an ongoing study examining health effects of arsenic exposure, this most recent endeavor is the result of collaboration among the New York State Psychiatric Institute, Columbia University's Mailman School of Public Health and Lamont-Doherty Earth Observatory, and researchers in Bangladesh.

The children in the study were assessed using the WISC III, a battery of tests adapted by Gail Wasserman, Ph.D., a child psychologist at the Psychiatric Institute, to make them more culturally relevant. The tests evaluate intellectual abilities such as comprehension and problem-solving.

After adjusting for sociodemographic covariates such as parents' education, occupation and housing type, as well as water manganese content (also elevated in many Bangladesh wells), the researchers determined that the widespread use of water contaminated by arsenic had a deleterious effect.

"We believe that our finding is both important and tragic and adds urgency to the need for effective remediation in Bangladesh and other regions of south Asia where consumption of arsenic contaminated water is prevalent," the authors say.

Joseph Graziano, Ph.D., professor of environmental health sciences and associate dean for research at the Mailman School, says: "A staggering number of people are affected. While we do not know if a reduction in exposure would be associated with improved functioning in children already exposed, a better understanding of the relationship could be obtained by tracking exposures and outcomes regularly. We are working closely with our Bangladeshi colleagues to curb the exposure to arsenic. The findings are also highly relevant in the United States, where water arsenic concentrations sometimes exceed the WHO standard of 10 ug/L."

According to the researchers, approximately 30 to 40 million Bangladeshis have been exposed to contaminated water supplied by approximately 10 million wells. Since arriving in 2000, the investigators have seen to the installation of low-arsenic private and community wells in their 10-square-mile study region and implemented a village education program to reduce exposure. New support from Columbia's Earth Institute will allow the investigators to expand their remediation efforts.

This work was supported by NIEHS grants, the Mailman School of Public Health, and the Earth Institute at Columbia University.

research briefs title - Novel Brain Chemotherapy Trial Begins

Chemotherapy, an effective weapon against most cancers, is almost useless for patients with tumors in the brain, but it may not be due to the drugs' efficacy. Instead, the problem lies, at least partly, with the brain's blood-brain barrier, which stops the drugs from ever reaching the cancer.

Now CUMC researchers in neurological surgery are, for the first time, bypassing the blood-brain barrier and delivering a proven chemotherapy agent directly into tumors with a new technique called convection enhanced delivery. Other methods of delivering chemotherapy to brain tumors are also being tested in clinical trials around the country, giving researchers hope that a treatment to extend the lives of brain tumor patients may soon spring from one of these trials.

Brain tumors that develop from brain tissue are rare, arising in 15,000 to 20,000 people in the United States every year, but they are extremely aggressive. Radiation and surgery may remove the initial mass, but the cancer almost always comes back. Patients typically survive for only one to three years after diagnosis.

Developed about 10 years ago by NIH researchers, convection enhanced delivery sends cancer drugs straight to the tumor through catheters inserted into the brain. A slow steady flow of chemotherapy delivered through the catheters builds up pressure in the brain, which pushes the drug into the tumor's cells. The method not only avoids the blood-brain barrier, but also allows the delivery of higher doses of drugs to the patient without nausea or other typical side effects of intravenous chemotherapy.

In the new phase I trials at CUMC, Jeffrey Bruce, M.D., professor of neurological surgery, selected the drug, topotecan, based on his findings from cell culture and animal studies. Topotecan was the most effective in reducing tumor size among two dozen different drugs Dr. Bruce tested.

"Topotecan actually cured rats of their brain tumors, but curing tumors in rats is one thing, curing them in humans is another," Dr. Bruce says. "We would love to cure brain cancer, but that's still a long way off. More realistically we think we can slow the growth of the tumors, improve quality of life and lengthen survival."

Five patients so far have received topotecan and none have experienced any side effects associated with standard, intravenous chemotherapy. Other side effects, such as weakness or seizures, caused by the drug's effect on normal brain tissue have been temporary.

About 35 to 50 patients are needed to complete the trial. To participate, patients must have a single, recurrent tumor under 60 cc in size located in the cerebral cortex and have already undergone standard surgery and/or radiation. For more information contact Joanne Loughlin at 212-305-7056.

This research is supported by the NIH.

—Susan Conova

CUMC researchers have identified a gene in owl monkeys that prevents infection by HIV-1, the virus that causes most cases of AIDS.

The gene – TRIMCyp – is unique to owl monkeys, but it is a fusion of two genes, TRIM5 and cyclophilin A (CypA), each of which is found separately in all primates, including humans. These molecules constitute an innate defense system that stops viruses from replicating and infecting primates. The research appeared in the July 29 issue of Nature.

Since 1993, the researchers, led by Jeremy Luban, M.D., associate professor of microbiology, have been attempting to understand how the cellular protein CypA regulates HIV-1 replication. In previous studies they demonstrated that CypA protects HIV from an antiviral activity in human cells. Last year, Dr. Luban and his associates made the paradoxical observation that, in owl monkeys, CypA was part of a potent antiviral defense system.

Dr. Luban and graduate student David Sayah have now discovered the explanation for these seemingly contradictory findings. In the course of evolution, owl monkeys acquired a gene called TRIMCyp which was created by a "retrotransposition" event, whereby a copy of the CypA gene jumped into a new location in the TRIM5 gene.

The discovery of TRIMCyp has excited HIV researchers for three reasons. First, the new gene is related to one discovered earlier this year – TRIM5alpha – in Asian rhesus macaques. TRIM5alpha in macaques also stops HIV infection, and both TRIM5alpha and TRIMCyp can prevent HIV replication in human cells when introduced into those cells in culture.

Also, TRIMCyp should shed light on how HIV-1 is thwarted in monkey cells. The fact that the two genes have fused in owl monkeys suggests that in other primates where the two genes are separate, TRIM5alpha and CypA work together to prevent HIV-1 infection. CypA may guide TRIM5alpha to the HIV-1 virus, or it may help TRIM5alpha inactivate the virus. Experiments to determine how the two genes work together are now under way.

Last, TRIMCyp sheds light on how genes evolve. Our genes are composed of modular units called exons. One theory holds that the exons of one gene can be fused to create a single unit that then jumps to a new location, creating a new exon within another gene. TRIMCyp demonstrates that this in fact occurs in the real world.

The work was supported by the NIH, the Medical Scientist Training Program, and the American Foundation for AIDS Research.

—Susan Conova

Research Briefs article title - Study Connects Prenatal Flu and Schizophrenia

A new study indicates that prenatal exposure to influenza may increase the risk for development of schizophrenia years later. The study, which evaluated archived sera from pregnant women who participated in a large birth cohort called the Child Health and Development Study (CHDS) from 1959-1966, was conducted by researchers at the New York State Psychiatric Institute and the Mailman School of Public Health in collaboration with the Kaiser Foundation for Research. The study appeared in the Aug. 2 issue of the JAMA publication, Archives of General Psychiatry.

The findings are part of a larger team study known as the Prenatal Determinants of Schizophrenia (PDS), which examines prenatal infection, nutrition, chemical exposure, paternal age, and a range of other prenatal factors that influence schizophrenia risk. The study shows, for the first time, that serologically documented prenatal exposure to influenza is associated with schizophrenia. The risk of schizophrenia was increased threefold when influenza occurred during the first half of pregnancy; however, when influenza occurred during the second half of pregnancy, no increased risk was observed.

"It is an exciting time for research that combines serologic documentation of infectious diseases during pregnancy, long-term follow-up, and careful assessments for schizophrenia and other disease outcomes," says Alan Brown, M.D., lead author and associate professor of clinical psychiatry at P&S and epidemiology at the Mailman School. "Because the individuals whom we are studying have only recently passed through the age of risk for schizophrenia, it has become possible only in the last few years to analyze archived prenatal serum specimens in order to address the question of whether schizophrenia is related to prenatal risk factors such as viruses, as well as nutritional factors and toxins, during pregnancy."

"These findings represent the strongest evidence thus far that prenatal exposure to influenza plays a role in schizophrenia," said Ezra Susser, M.D., D.P.H., senior investigator of the PDS study, chairman of the Department of Epidemiology at the Mailman School and head of epidemiology of brain disorders at the Psychiatric Institute. "Although the findings may ultimately have implications for prevention, we strongly caution against making any public health policy recommendations until these links have been confirmed through further study."

This study was funded by the National Institute of Mental Health, the National Alliance for Research on Schizophrenia and Depression, and the Lieber Center for Schizophrenia Research.


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