University Times

Researchers study effects of clot-busting drug outside the hospital

Pitt's Department of Emergency Medicine is participating in a multi-center study on the use of a standard heart attack drug, usually administered inside the hospital, that will be given for the first time by paramedics outside the hospital.

Retavase is a U.S. Food and Drug Administration-approved, clot-busting drug used to treat heart attacks. Paramedics will administer the drug after an EKG assessment with portable equipment and consulting with a physician by telephone at a participating hospital. The time saved may reduce the number of deaths and the amount of heart muscle damaged by a heart attack.

"Previous research has shown that the earlier clot-busting drugs are administered, the better the outcome will be for the patient," said Vincent Mosesso, assistant professor of emergency medicine, medical director of pre-hospital care at UPMC Health System and principal investigator of the Pittsburgh study.

Paramedics employed by Mutual Aid EMS in Greensburg, Fayette County EMS and Frick Hospital Response Team will administer the drug with direction by the Medical Command Physicians at Westmoreland, Frick, Brownsville, Highlands, Jeannette and Uniontown hospitals.

When paramedics arrive on the scene where a person is suffering a heart attack, they will identify themselves as participating in the Pitt study. While paramedics assess the patient, they will briefly explain the study and how Retavase is used for the treatment of heart attacks.

After the paramedics and consulting physician have determined if the person is eligible for the study, the patient will be asked to provide his or her consent to participate and receive Retavase, which will be administered intravenously. There is no cost to the patient. People with a history of stroke, severe hypertension or recent surgery are ineligible.

Approximately 2,000 people from 20 centers throughout the United States and Canada will be selected for the study.

To be eligible, participants must be 18 years of age or older, have chest pain lasting 30 minutes or more, and have EKG evidence of a heart attack.

One thousand participants will receive Retavase outside the hospital. Results will be compared with those of another 1,000 patients who received the drug in the hospital to determine if there are differences in the patients' outcomes.

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Depression, not high blood sugar, predicts heart disease among Type 1 diabetics

Symptoms of depression –not high blood sugar — predict coronary heart disease (CHD) among people with Type 1 diabetes, according to researchers at Pitt's Graduate School of Public Health (GSPH) in a report published in the January issue of Atherosclerosis.

"We believe this is the first study to show that depressive symptomology is linked to coronary heart disease in Type 1 diabetes," said Trevor J. Orchard, professor of epidemiology at GSPH and principal investigator. "These results also provide further evidence that blood sugar levels fail to strongly predict the likelihood of this complication."

Investigators say they were not surprised to identify increased depressive symptoms as a risk factor, since depression is emerging as a risk factor for cardiovascular disease in the general population. "But the strength of the link was surprising," said Orchard, adding, "In addition, these results suggest that the high blood sugar association with the development of coronary heart disease among Type 1 diabetics is complex."

The study looked at risk factors for CHD and lower extremity arterial disease (LEAD), both common complications of Type 1 diabetes, and found that these two vascular disorders have different sets of risk factors, although both are thought to be due to the same disease process — atherosclerosis.

"We were particularly surprised to find no relationship between high glycemic levels and CHD, despite the fact that blood sugar and LEAD are closely connected," Orchard said.

These findings open doors to potential new ways of helping Type 1 diabetics avoid the development of vascular diseases, according to Orchard. "Knowing the risk factors for CHD and LEAD could help physicians develop specialized prevention and treatment plans," he said, adding that watching for symptoms of depression could be particularly helpful in managing CHD in Type 1 diabetics.

The current analysis used data from the Pittsburgh Epidemiology of Diabetes Complications Study, an ongoing 10-year study of risk factors for complications of childhood-onset Type 1 diabetes. A total of 658 Type 1 diabetic participants (332 men and 326 women) were initially examined from 1986 through 1988, and then every two years, for diabetes complications and their risk factors. CHD was defined as the presence of angina or a family history of heart attack or death from CHD. The researchers measured LEAD using a comparison of blood pressures from the leg and arm.

Results showed that factors leading to CHD in Type 1 diabetics include hypertension, depressive symptoms, kidney disease and low levels of HDLc (good) cholesterol. Besides high blood sugar, risk factors for LEAD are smoking and high levels of LDLc (bad) cholesterol. A longer duration of the Type 1 diabetes condition is a factor for both CHD and LEAD, and men tend to develop CHD slightly more often than do women, while women have a slightly higher incidence of LEAD.

The Pitt study is supported by a grant from the National Institutes of Health.

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Pitt team first to illustrate mechanisms of chromosome missegregation in cancer cells

Pitt researchers have provided the first graphic illustration of mechanisms by which chromosomes are distributed unevenly during cancer cell division. Results were published last month in the Proceedings of the National Academy of Sciences.

"This is really the first paper showing a mechanism by which chromosome segregation can go awry in cancer cell division, leading to genetic defects such as abnormal or missing chromosomes," said William Saunders, principal investigator on the study, assistant professor of biological sciences and an investigator in Pitt's Oral Cancer Center. "By witnessing these events, we can now target for study those activities within a cancer cell that become deranged during cell division. In this way, we can focus on ways to interrupt these abnormal processes with the potential to curb cancerous growth."

During normal cell division, coils of genetic material called chromosomes align neatly in the middle of the cell into 23 pencil-shaped pairs of parallel strands called chromatids. At the same time, two centrioles form at opposite poles of the cell. Thread-like microtubules attach each of the chromatids to the centrioles, forming the spindle. When the cell divides, the chromatids separate and are pulled by the microtubules to opposite poles. Thus, two identical pools of chromatids, the inherited genetic instructions of the future daughter cells, form at the poles.

The interior of the cell separates in barbell-like fashion with a narrow bridge that eventually pinches in two to form the two daughter cells.

Using fluorescent markers to label cell structures involved in the division of oral cancer cells, the Pittsburgh team is the first to capture the unusual activities that account for well-recognized genetic derangements characteristic of cancer cells.

In one set of experiments, the researchers found that an oral cancer cell could produce not two but three or four spindle poles, each with its own set of microtubules, thus forming bizarre, Y-shaped or cruciform spindle structures. Specifically, the researchers found in the cancer cells that a protein within each spindle pole, called the nuclear mitotic apparatus protein (NuMA), split apart in renegade fashion, generating new poles in an apparently haphazard way. As a result, chromatids migrated to various parts of the cell. During cell division, the haphazard alignment of chromosomes will lead to daughters with different numbers and types of chromosomes.

"For years, scientists have recognized these bizarre mitotic spindle structures in pathology specimens, and we've known for some time that NuMA is involved in organizing the spindle poles. However, this study is the first to show how multiple spindles form, how NuMA may be involved and thus why cancer cells contain too few or too many chromosomes," said Susanne Gollin, senior author of the paper and associate professor of human genetics, otolaryngology and pathology at Pitt's School of Medicine.

The research was supported by an oral cancer center planning grant from the National Institute of Dental and Craniofacial Research, which has since awarded Pitt an $11.2 million grant to establish a comprehensive oral cancer center, the only such designated comprehensive center in the country.

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Biological reason found for greater risk of smoking related lung cancer in women

A gene for a protein that fuels lung cancer growth is more active in women than in men, according to a report by a Pitt-led research team, which also discovered that nicotine found in cigarettes induces gene activity.

Their report, published in the Journal of the National Cancer Institute, offers the first biological explanation for the greatly increased risk women face versus men in developing lung cancer.

If substantiated in future studies, this research could provide a valuable marker for predicting which women are most likely to develop the disease or dangerous pre-cancerous changes.

The research team found in women an increase in the expression of the gene for gastrin-releasing peptide receptor (GRPR), which is found on the surface of cells lining the lung. When stimulated by its hormone, gastrin-releasing peptide, GRPR triggers cell proliferation typically seen in lung cancer. The Pittsburgh-based research team also discovered that nicotine found in cigarettes stimulates expression of the GRPR gene in lung cells.

"Our research strongly suggests that women are likely to develop lung cancer after much less smoking exposure than men and much earlier in life, regardless of their smoking history," said Sharon Shriver, principal investigator on the study, who is now an instructor of biology at Penn State University.

"Prior reports have suggested various molecular markers associated with an increased risk in women smokers; however, ours is the first study to provide a mechanism for cancer promotion in this population," said Jill Siegfried, senior author on the paper, Pitt professor of pharmacology and co-director of the University of Pittsburgh Cancer Institute's Lung Cancer Center. "This study also validates previous population studies suggesting that women are at substantially increased risk of smoking-related lung cancer."

The scientists looked at normal lung tissue samples from 38 women and 40 men, including 58 patients with lung cancer. They found that 55 percent of the non-smoking women and 75 percent of women with less than 25 pack-years of smoking expressed GRPR mRNA (a precursor of the GRPR protein).

A pack-year is one package of 20 cigarettes smoked each day for one year.

By contrast, none of the male nonsmokers and only 20 percent of men with a 25 pack-year or less smoking history expressed GRPR mRNA.

The research study was supported by grants from the National Cancer Institute, the American Lung Association and the University of Pittsburgh Cancer Institute.