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March 3, 2005

Research Notes

Risk of herpes infection rises with oral sex

The first clinical study to document risk of acquiring herpes simplex virus type 1 infection based on sexual activity has linked oral sex and vaginal intercourse with a demonstrably higher rate of infection, particularly in young women, researchers from the University reported in the February issue of Sexually Transmitted Diseases, the journal of the American Sexually Transmitted Diseases Association.

Genital herpes is one of the most common sexually transmitted diseases in the United States. Nationwide, at least 45 million people ages 12 and older – or one out of five adolescents and adults – have had a genital herpes infection. Between the late 1970s and the early 1990s, the number of Americans with genital herpes infection increased by 30 percent, according to the U.S. Centers for Disease Control and Prevention. While there is no cure, antiviral medications can shorten and prevent outbreaks. Daily suppressive therapy can reduce, but not eliminate, risk of transmission to non-infected partners.

Medical students traditionally have been taught that herpes simplex type 1 (HSV-1) infections most often take place above the waist, while herpes simplex type 2 (HSV-2) predominates below the belt. More recent evidence, however, suggests that HSV-1 also is an important pathogen in genital herpes infections, especially in younger women. HSV-1 is more commonly known to cause infections of the mouth and lips, often called fever blisters or cold sores. Viral shedding and disease transmission is possible even in the absence of a visible outbreak.

“Receptive oral sex and vaginal intercourse were found to be significant risk factors for the acquisition of HSV-1,” said Thomas Cherpes, an infectious diseases fellow at the University’s School of Medicine and the study’s first author. “Because oral HSV-1 infections are less frequent in childhood and adolescence, future prevention strategies will need to consider increased susceptibility for HSV-1 among young adults, and the important contribution of HSV-1 to the growing genital herpes epidemic.”

Researchers enrolled 1,207 non-pregnant women ages 18 to 30 at three Pittsburgh-area health clinics between 1998 and 2000. Participants were asked to return for three follow-up visits at four-month intervals. At each study visit, blood samples were tested for HSV-1- and HSV-2-specific antibodies, and surveys of sexual behavior and demographic information were completed.

Initially, HSV-1 was found in 38 percent of women aged 20 or younger. During the follow-up period, analysis found that women who had vaginal intercourse had a more than six-fold higher risk of acquiring HSV-1 than sexually inactive women, or 6.8 versus 1.2 cases. For those who had only receptive oral sex without vaginal intercourse, however, the risk was even greater – 9.8 versus 1.2 cases.

“The low frequency of infection we detected at enrollment is consistent with other research indicating a reduction in HSV-1 prevalence among younger people,” said Sharon Hillier, professor in the departments of obstetrics, gynecology and reproductive sciences and molecular genetics and biochemistry at the School of Medicine and the study’s senior author. “As a result, a significant number of young adults are now susceptible to oral or genital HSV-1 infection.”

This is important because most current research on genital herpes vaccine development focuses on HSV-2, added Hillier, who also is a senior investigator at the Magee-Womens Research Institute.

The falling rate of childhood HSV-1 infections is complicating the scenario by leaving larger numbers of young people susceptible to genital infection with HSV-1, according to Cherpes, particularly since surveys show a high rate of participation in sexual activities that put them at higher risk.

“Lifetime prevalence of receptive oral sex among sexually active women is 75 percent,” he said. “In our group, more than 90 percent of study participants reported a history of such activity.”

Cherpes and Hillier note that future vaccine development should include HSV-1 targets to reduce susceptibility.

In addition to Cherpes and Hillier, Leslie A. Meyn, Magee-Womens Research Institute, contributed to the study, which was funded by the National Institutes of Health.

Patients active in their health care may have lower risk for heart disease

Middle-aged women who take an active role in their health care may be less likely to develop cardiovascular disease as they transition through menopause, according to research done at the University.

The results, presented today at the American Psychosomatic Society Annual Meeting, suggest women who believe they should take charge of their health, rather than rely solely on treatment by doctors, have fewer signs of pre-clinical atherosclerosis.

“Our findings provide evidence that women who believe they should be engaged in the maintenance of their health, rather than women who would rather put the responsibility for their health into someone else’s hands, somehow translate those attitudes into better health through behavioral and psychological mechanisms,” said Wendy Troxel, predoctoral fellow in psychology at Pitt, and the study’s lead author.

The research team followed 370 middle-aged women from the Healthy Women Study, a prospective investigation of health during and following the critical menopausal transition led by Lewis H. Kuller, professor of public health at the University’s Graduate School of Public Health.

Participants’ involvement in their health care was measured using the Krantz Health Opinion Survey. Active participants would tend to agree with a statement such as “Except for serious illness, it is generally better to take care of your own health rather than to seek professional help,” while less active participants would agree with the statement “If it costs the same, I would rather have a doctor or nurse give me treatments than to do the same treatments myself.”

Then, using a type of imaging called B-mode ultrasound, the researchers took measures of two reliable signs of pre-clinical cardiovascular disease, intima-media thickness (IMT) and plaque buildup.

IMT is a measurement of the thickness of the artery wall and may be a factor in the later formation of plaques. Increased IMT has been shown to be a risk factor for heart attack and stroke.

Women who scored as active participants in the opinion survey had lower IMT and plaques in their arteries compared to non-active participants, which translates into a lower risk of developing heart disease or suffering a heart attack or stroke.

The results showing lower IMT in women who reported greater involvement in their health care persisted after statistically controlling for education, age during follow-up, pulse pressure, smoking history and triglycerides, and were independent of a general personality measure.

“This study supports the present trend in health care to encourage patients to take an active role in their health and well-being,” said Troxel.

Hard choices: When to accept organs for transplantation

A transplant is the only option for someone with end-stage liver disease, but patients face difficult questions when choosing the best time to receive a transplant. Recently, in a panel discussion at the 2005 American Association for the Advancement of Science (AAAS) Annual Meeting in Washington, D.C., a Pitt researcher presented findings on how his mathematical models can help patients make the right decision.

Andrew Schaefer, an assistant professor and the Wellington C. Carl Faculty Fellow in Pitt’s Department of Industrial Engineering, uses engineering techniques to examine the decision-making process facing potential recipients of livers from both living and cadaveric donors.

The liver is a unique organ in that it can regenerate itself: If a living person donates a part of his or her liver, the livers of both donor and recipient typically grow to normal size within two weeks of the surgery.

Livers from cadaveric donors are difficult to come by, and, as a result, numerous patients die waiting for a life-saving organ. Nonetheless, many patients prefer to remain on the national waiting list, preferring not to put someone they know through a living-donor operation, which involves a small but real risk to the donor.

According to Schaefer, patients should use up the capacity of their current liver first, but waiting too long could be dangerous. So the questions are: In the case of a living donor, how long should the patient wait before accepting the transplant? And in the case of a cadaveric donor, what criteria should one follow in deciding to accept a potential offer?

The answers to these questions are not at all obvious, and Schaefer and his colleagues Mark S. Roberts, associate professor of medicine in Pitt’s Division of General Internal Medicine, and Oguzhan Alagoz and Lisa M. Maillart of Case Western Reserve University, have been able to show that mathematical models can provide insight. “We’re actually able to model decisions that real patients face all the time,” Schaefer said. “These mathematical models can give answers that make sense to doctors and can answer questions for which other standard techniques aren’t as well suited.”

Schaefer and his colleagues are the first to study living donors, as well as the first to explicitly model patient physiology. “Our models are much more physiologically realistic than previous research,” said Schaefer. “We are actually tracking the levels of various laboratory values in the patient’s blood.”

Their next step is to make the model better represent both the biology and the quality of life of organ recipients. In addition to their work on organ transplantation, Schaefer, Roberts, and several Pitt graduate students also are working on other decision-making scenarios, such as modeling the optimal time to switch HIV medications or to discharge a patient from intensive care.

Schaefer and his team plan to work with the clinical team at the University’s Thomas E. Starzl Transplantation Institute to put their research to clinical use.

Environmental lead may cause violent crime 

Exposure to lead may be one of the most significant causes of violent crime in young people, according to one of the nation’s leading researchers on the subject.

“When environmental lead finds its way into the developing brain, it disturbs neural mechanisms responsible for regulation of impulse. That can lead to antisocial and criminal behavior,” reported Herbert L. Needleman, professor of psychiatry and pediatrics at Pitt, at the 2005 American Association for the Advancement of Science (AAAS) Annual Meeting. “The government needs to do more to eliminate sources of lead in the environment.”

According to the U.S. Environmental Protection Agency, humans can encounter lead through deteriorating paint and dust, air, drinking water, food and contaminated soil. Sources of lead are plentiful – until the 1970s lead was used in paint, gasoline and older water pipes. Today, much of that lead is still out there – on old window frames, in the soil of the vegetable gardens and in the drinking water of many American cities.

In the 1970s, Needleman was the first to discover cognitive effects in children who had been exposed to lead. Though the children had no visible signs of lead poisoning, they had significantly lower scores on IQ tests. As a result of these studies and others, lead has been removed from gasoline, paint and numerous other products.

Such measures have resulted in sharply lower levels of lead in children born today, compared to those born 30 years ago. Yet, Dr. Needleman’s latest research shows that even very low levels of lead found in bone, as measured by a technique called X-ray fluorescence, can affect brain development.

In a 1996 Pitt study of 301 children, those with the highest concentrations of lead – still below government-recommended safe levels – had tests scores showing more aggression, attentional disorders and delinquency. In 2002, those findings were extended to show that the average bone lead levels in 190 adjudicated delinquents were higher than normal controls. The results indicated that between 18 and 38 percent of all delinquency in Pennsylvania’s Allegheny County, which includes Pittsburgh, could be due to lead. Additionally, a number of recent studies have shown a strong relationship between sales of leaded gasoline and rates of violent crime.

“The brain, particularly the frontal lobes, are important in the regulation of behavior,” said Needleman. “Exposure to lead, at doses below those which bring children to medical attention, is associated with increased aggression, disturbed attention and delinquency. A meaningful strategy to reduce crime is to eliminate lead from the environment of children.”

Research sheds more light on the link between estrogen, lung cancer

New and effective treatments for lung cancer may rest on their ability to hinder the action of estrogen in lung cancer cells, according to two studies published in the current issue of Cancer Research. The Pitt studies build on current knowledge about the relationship between estrogen and lung cancer growth and suggest that blocking estrogen may be vitally important to improving survival from the disease.

Since 1930, a 600 percent increase in death rates from lung cancer has been reported in women in the United States, leading some experts to suggest that women may be more susceptible to lung cancer than men. The current research contends that this could be due to the effects of estrogen on the lungs.

“Our studies continue to show that lung cancer cells grow in response to estrogen and that stopping or slowing the spread of the disease may be dependent on blocking the action of estrogen,” said Jill Siegfried, a professor in Pitt’s Department of Pharmacology and co-leader of the Lung and Thoracic Malignancies Program in the University’s Cancer Institute. “In fact, in previous studies, we have observed that lung tumor cells contain estrogen receptors at levels comparable to breast cancer cells.” A receptor is a structure on the surface of a cell that selectively receives and binds substances.

In the first study, Laura Stabile, instructor in the University’s Department of Pharmacology, and colleagues examined methods to block the action of estrogen in human lung tumors grafted in mice. They compared the effect of blocking the estrogen receptor (ER) pathway alone to blocking it in combination with another receptor pathway – the epidermal growth factor receptor (EGFR). The investigators combined an agent approved for inhibiting the EGFR pathway, gefitinib (Iressa(r)), with an anti-estrogen agent, fulvestrant (Faslodex(r)) – a treatment commonly used to manage breast cancer in women with ER positive tumors, but not yet approved for clinical lung cancer treatment. They found that the combined treatment resulted in a tumor volume decrease of 59 percent, compared to a 49 percent decrease for gefitinib treatment alone and a 32 percent decrease for fulvestrant treatment alone. They also found that lung tumors in the combined treatment group were comprised mainly of dead and dying cells, while the number of these cells in the single treatment groups was significantly lower. The study suggests that an interaction between treatments that target both ER and EGFR may enhance the anti-tumor effects of therapy over the use of each agent alone. A pilot clinical trial is already underway testing the combination therapy in women with advanced lung cancer.

“Evidence from our study confirms what has been described for breast cancer – that blocking the estrogen receptor and the epidermal growth factor receptor pathways together is more effective,” said Stabile.

In the second study, Pamela Hershberger, assistant professor in the Department of Pharmacology, examined the effect of estrogen on the expression of genes in lung cancer cells. Using gene arrays, Hershberger and colleagues reported that some of the same growth genes induced by estrogen in breast cancer also are regulated by estrogen in lung cancer. In addition, the same estrogen inhibitor, fulvestrant, that was active against lung cancer in Stabile’s study also blocked the ability of estrogen to regulate lung cancer cell gene expression. Hershberger’s study further showed that other proteins needed for ER to act in breast cancer are found in lung cancer cells.

“Both of these studies clearly suggest that lung cancer cells respond to estrogen and that improving overall patient survival may be contingent upon identifying therapies that target specific pathways and put a halt to estrogen signaling,” said Siegfried.

The studies were funded by a Specialized Program of Research Excellence (SPORE) award in lung cancer from the National Cancer Institute to Pitt’s Cancer Institute.

Co-investigators on the first study included Jennifer S. Lyker, Christopher T. Gubish, Weiping Zhang, Jennifer R. Grandis and Siegfried. Co-investigators on the second study included Mark Nichols; A. Cecilia Vasquez; Beatriz Kanterewicz; Stephanie Land, department of biostatics, Pitt’s Graduate School of Public Health and Siegfried.

Researchers present results at maternal fetal medicine conference

The clinical and basic science research findings of several studies was presented recently by researchers from the Magee-Womens Research Institute at the 25th annual meeting of the Society for Maternal Fetal Medicine in Reno, Nev.

A study by Hyagriv Simhan, assistant professor of obstetrics, gynecology and reproductive sciences at the University’s School of Medicine and his colleagues found that immunologic changes in common bacterial infection maybe linked to higher risk for preterm birth.

Pregnant women with a common gynecological disorder called bacterial vaginosis (BV) had significantly lower levels of vital immune system proteins, indicating a possibly decreased ability to meet other immune-system challenges such as sexually transmitted diseases and infection-related preterm birth, according to the report.

“Bacterial vaginosis is known to alter many aspects of reproductive immunity,” said Simhan, the study’s first author who also is an assistant investigator at the Magee-Womens Research Institute. “A robust immune system response is needed to defend against infection that can carry grave consequences for pregnant women.”

Other study authors included Steve Caritis, Sharon Hillier and Marijane Krohn.

Another study presented at the conference found that concentrations of blood protein might point to higher risk of gestational diabetes.

Even as early as the first trimester, reduced blood levels of the protein adiponectin were associated with later development of gestational diabetes, according to Kristine Yoder Lain, assistant professor of obstetrics, gynecology and reproductive sciences at the University’s School of Medicine and her colleagues.

Levels of adiponectin, a protein specific to fat tissue that is known to be involved in obesity, diabetes and heart disease, were analyzed in blood samples taken early in pregnancy from 38 women who later developed gestational diabetes as compared to those from 30 women who did not develop the condition.

“Women with the lowest adiponectin concentrations were 11.2 times more likely to develop gestational diabetes, and this persisted after controlling for body mass index and race,” said Lain, who is first author of the study and also medical director of the Center for Diabetes and Pregnancy at Magee-Womens Hospital. “This suggests that women with glucose intolerance of pregnancy may have significant alteration in adiponectin levels long before a diagnosis of gestational diabetes is made.”

Additional authors from the University included Paul Speer, Stacy McGonigal and James M. Roberts.

Pitt prof to study lava flow on Mars and the Earth

Michael Ramsey, assistant professor in the Department of Geology and Planetary Science, has received a three-year grant from NASA to study lava flow surfaces on Mars and Earth. The goal of the study, titled “Mars Lava Flow Surface Morphology: An Avenue for Answering Fundamental Questions Regarding the Rates and Styles of Volcanism,” is to better interpret information on new volcanic surfaces in Hawaii and then to apply that knowledge to older geologic surfaces on Mars.

Ramsey will perform the research in conjunction with lead investigator Steve Anderson of Black Hills State University, in Spearfish, S.D., and colleagues at other institutions. This $160,000 research award dovetails with Ramsey’s other NASA-funded projects, which total more than $1.3 million.

Martian lava flows seen from orbit are strikingly similar to older lava flows seen in Hawaii. The scientists will study how underlying topography, interior structure and heat flow affect the final appearance of lava flows.

“Our hope is that by gaining a better understanding of the flows in Hawaii, we will be able to interpret the conditions on Mars, at the time the flows formed there,” said Ramsey.

This research is funded by NASA’s Mars fundamental research program.

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