|March 2000 |
New noninvasive cancer screening tool
Aware that early cancer detection increases survival, researchers at Johns Hopkins have developed a new, easier approach to screening for lung, bladder, and head and neck cancers. The process involves analyzing body fluids for genetic mutations in mitochondrial DNA, found outside the cell's nucleus. The nucleus contains only two copies of DNA, one from each parent, while the mitochondria contains many copies, making it easier to find mutations. Until now, finding cancer-specific mutations in bodily fluids was like looking for a needle in a haystack," said lead researcher Dr. David Sidransky, professor of otolaryngology and oncology. "Finding mitochondrial mutations is much easier. With additional research, we expect to be able to identify mitochondrial mutations through a simple blood test."
The team examined urine, saliva and other fluids from 20 cancer patients. They found mutations in samples from all of the bladder and lung cancer patients, and in fluids from six of the nine head and neck cancer patients. The mitochondrial mutations in the body fluids were identical to changes in the primary tumors. Results of the National Institutes of Health funded research were reported in the journal Science.
Sidransky foresees the day when doctors can screen for cancer using mitochondrial DNA as easily as they can order mammography to look for breast cancer. The team plans to begin additional trials early next year using the new detection method to look for several different human cancers. "Someone at higher risk of developing lung cancer because of a history of smoking could provide a sputum sample," Sidransky said. "That sample would be analyzed to obtain a base line description of the individual's mitochondrial genome. In subsequent visits, new sputum samples would be collected and compared to the base line for changes. If new mutations are observed, we would be in a better position to intervene while the cancer is in an early and curable stage."
Vaccine may improve melanoma survival
In animal studies, a vaccine administered with superantigens to boost its effectiveness proved beneficial in the fight against melanoma, an aggressive form of skin cancer. Mice receiving the combined therapy lived longer than untreated mice after scientists at the University of Florida exposed both sets of animals to active melanoma cells. "If we just vaccinate mice with inactivated tumor cells, we get very little protection," said project leader Howard Johnson. "But if we vaccinate the mice with inactivated tumor cells and then give them superantigens, we significantly extend the survival of the mice."
Superantigens are proteins that stimulate the immune system and can improve response to the vaccine. Doctors routinely vaccinate people against diseases such as flu, pneumonia and whooping cough, but immunotherapy is a relatively new concept in the war against cancer. Normally, the immune system does not quickly recognize the need to battle cancer because the cells are not alien invaders like a bacteria or virus. "We do not have a mind set for vaccinating against cancer," Johnson said. "But the studies we're doing indicate that in cases where tumors have a clear-cut antigen associated with it, we would immunize people for cancer the way we immunize them to protect against things like polio." The scientists will present the results at the national conference of the American Association for Cancer Research in San Francisco. About 47,700 people are diagnosed with and 7,700 people die of melanoma annually, according to the American Cancer Society.
"The possibility of preventing this cancer through immunization would be a fantastic way of reducing both morbidity and mortality associated with melanoma," said Dr. Robert Skidmore, at Shands Hospital at the University of Florida. "It will put me out of business, but that's fine. I'll find something else to do."
Chemotherapy pump aids in treating liver metastases from colon cancer
Based upon successful results from two recent studies, physicians at Fox Chase Cancer Center in Philadelphia recommend modifying the conventional surgical approach to treating liver metastases from colorectal cancer. Of the nearly 129,000 patients diagnosed with colorectal cancer in the United States each year, 60 percent will develop metastases to the liver. In 15 to 20 percent of the cases, the cancer has spread to the liver before the diagnosis was made.
Following the Fox Chase recommendations, a surgeon would implant a pacemaker-size chemotherapy pump under the skin during surgery to remove the cancerous tissue. The pump allows for postoperative delivery of chemotherapy drugs directly into the liver through the main artery feeding the organ. Surgical patients receiving chemotherapy through the pump lived longer than those who only had surgery, the current standard treatment. After three years, 58 percent of the pump patients did not have a recurrence, compared with 34 percent of the patients who had surgery but no chemotherapy.
"This has dramatically changed the outlook for thousands of patients," said Dr. Elin R. Sigurdson, director of Surgical Research at Fox Chase. "At Fox Chase Cancer Center, the chemotherapy pump has been used routinely for several years." The researcher told fellow physicians at the Society of Surgical Oncology's 53rd Annual Cancer Symposium that an immediate change in the disease's treatment protocol was needed.
In a separate study, doctors compared results from surgery including the implanted pump with surgery plus traditional intravenous chemotherapy. After two years, 85 percent of the pump patients remained disease free, but only 69 percent of patients receiving a traditional chemotherapy infusion did not have a recurrence.
Drug to control inflammation may increase odds of surviving heart failure
More than four million Americans suffer from congestive heart failure (CHF); about half will survive five years. Researchers now say chronic inflammation may play a role in the disease. When the body senses it is under attack from foreign substances, the immune system releases complement proteins, antibodies and white blood cells to fight the invader. Tissues not receiving enough blood can also cause activation of complement proteins. Complement activation results in a series of reactions known as the complement cascade, byproducts of which can lead to destruction of tissue.
A recent study of 36 patients with severe CHF showed elevations of the harmful complement proteins have been associated with worsening symptoms and a higher rate of hospitalization and death from CHF. Researchers at Yale and Alexion Pharmaceuticals measured the level of harmful inflammatory complement and the incidence of cardiac events, such as inpatient care for CHF, the need for an urgent heart transplant or death. Patients with high complement levels had a 44 percent event-free, six month survival rate, while patients with lower complement levels had an 83 percent event-free, six month survival rate. In addition, higher complement levels were associated with more severe symptoms.
"While current therapies for heart failure patients are directed at attempting to improve cardiac performance via improving control of blood pressure and fluid status, an increasing number of recent observations have suggested that chronic inflammation may contribute to the underlying clinical illness in patients with severe heart failure," said Dr. John F. Setaro, director of Cardiovascular Disease Prevention at Yale University.
At the American College of Cardiology conference, the researchers reported that a drug produced by Alexion Pharmaceuticals may be beneficial in treating congestive heart failure because it blocks production of a harmful complement protein during complement cascade. "These results raise the exciting possibility that control of inflammation via inhibition of the complement cascade may provide a novel and effective therapy for patients with severe heart failure," Setaro said.
Brain site may be responsible for triggering overeating
Collaborating researchers at the Oregon Health Sciences University in Portland, Oregon and the University of Alberta in Edmonton, Alberta (Canada) have identified an area in rat and mouse brains that may control eating. Located within the hypothalamus, the area of the brain that controls many aspects of behavior including food intake, the study unearthed individual neurons that are believed to serve as an "adipostat" or fat thermostat. Since dieting, starvation, and other eating patterns have seemed to affect the body's fat storage, metabolic rate, and energy output, experts have long believed that there must be a mechanism that regulates food intake and weight.
To find the neurons that they believed might be linked to eating behavior, the researchers injected neuropeptide Y (NPY) into the rats' hypothalamus, a peptide known to cause the animals to eat much more and gain weight, in order to trace its pathway. Apparently, the peptide is also held responsible for prompting the body to store more fat, use less energy, and become more efficient in its metabolism. Then they injected a second peptide, melanocyte-stimulating hormone (MSH), into the hypothalamus as well and traced its pathway. MSH has been found to inhibit feeding, as well as maintaining metabolic rates. Following these separate routes for feeding and appetite suppression led the way to the discovery of the specific neurons involved in processing the feeding signals and regulating metabolism. Working together, the neurons are responsible for controlling food intake by respectively inducing the urge to eat or suppressing appetite as required. Researchers believe that a malfunction of this process could be sending wrong signals to the brain, which may result in overeating. These findings, they hope, may lead to new ways to treat obesity, such as a drug treatment that could lower the body's adipostat setting.
Blood test targets patients most likely to benefit from platelet inhibitors
A simple blood test has helped Duke University Medical Center doctors determine which patients are most likely to benefit from a class of intravenous drugs known as super aspirins. The drugs are designed to prevent platelets from clumping and forming clots in patients suffering from unstable angina (unpredictable chest pain), or who are at risk for a second heart attack.
Overall results of the study, presented at the American College of Cardiology's annual meeting, showed lamifiban offered only modest, insignificant benefit compared with an inactive placebo. All 5,225 patients also received aspirin and the blood thinner heparin. Within 30 days, 11.8 percent of those treated with lamifiban suffered from a second heart attack, recurrent ischemia or died, as did 12.8 percent of the patients receiving placebos. The rates were similar to other glycoprotein IIb/IIIa platelet inhibitor drugs (super aspirins) already on the market.
The drug primarily helped patients testing positive for the protein troponin T, a marker of dying muscle tissue, lowering their risk of adverse events by 49 percent. Between 25 and 40 percent of unstable angina patients admitted to the hospital test positive for the protein. Eleven percent of the troponin T patients who received lamifiban died, suffered a second heart attack or experienced recurrent ischemia within 30 days, compared with 19.4 percent of the placebo patients. "It shows us that we can potentially refine the use of IIb/IIIa inhibitors and direct them to the patients who can really benefit from them," said lead investigator Dr. Robert Harrington of the Duke Clinical Research Institute. "This shows us that troponin T-positive patients are at much increased risk of adverse events, and that they are also the patients who benefit most from what lamifiban or other GP IIb/IIIa drugs can offer."
Drug cuts angioplasty-stent death and heart attack rate by 37 percent
Duke University physicians boldly predict a new drug will alter the practice of coronary medical care. Eptifibatide significantly lowered death and heart attack rates during a recent trial involving patients undergoing an angioplasty and receiving a mesh stent to prop the artery open. Nearly half a million patients with coronary artery disease have the procedure annually to open clogged blood vessels. But artery wall trauma often prompts formation of blood clots, which eptifibatide helps prevent.
Eptifibatide costs about $400, compared to $1,500 for Reopro, the only other clot-preventing drug effective during such procedures. Doctors routinely hold off using Reopro until a clot begins to form, due to its expense. But researchers showed administering the less costly eptifibatide as a routine, preventative treatment was beneficial.
More than 2,000 patients at 92 North American medical centers participated in the random, double-blind study. The drug was given before, during and 18 hours after the procedure. During the first two days, eptifibatide cut the rate of post-procedure complications by 37 percent and reduced heart attack and death rates by 40 percent, compared to patients receiving a placebo with no active ingredient. Doctors noted the drug increased the risk of minor and major bleeding, mostly at the site where doctors inserted the catheter during the procedure. An Independent Data and Safety Monitoring Committee halted the trial early due to the beneficial results.
"This could make a dramatic difference in the outcomes of patients treated with a stent angioplasty procedure," said Duke cardiologist Dr. James Tcheng, who presented his findings at the annual meeting of the American College of Cardiology. "Now only about 20 percent of patients being treated with a coronary stent receive platelet inhibitor therapy. The main reason more patients are not being treated with these drugs is the high cost of treatment."
Aggressive treatment of second heart attacks increases survival rates
Patients suffering a second heart attack while recovering in the hospital from their first heart attack do not always receive optimum medical care, according to a study by Duke University Medical Center researchers. They found aggressive treatment with clot-dissolving drugs or reopening the artery using angioplasty or coronary artery bypass surgery nearly tripled survival rate, compared with conservative treatment. But only two-thirds of Americans receive such care. "The results of our analysis show that instead of taking a conservative approach, physicians should to be treating these patients more aggressively," said Dr. Michael Hudson, at the Duke Clinical Research Institute. "Patients treated with either aggressive treatment strategy had a mortality rate after 30 days of about 10 percent, compared to 28 percent for those treated conservatively."
The researchers reviewed data from two large international trials. In the United States, repeat use of clot-dissolving drugs to treat the second heart attack dropped from 29 to 19 percent, but the use of procedures or surgery to reopen the artery increased from 33 to 48 percent. Scientists still need to determine which method is most beneficial. Results of the study were presented at the annual scientific sessions of the American College of Cardiology.
"Many doctors do not have much experience in the readministration of clot-busters, so they are hesitant in using them in these situations because of the potential for bleeding complications," Hudson said. "Our analysis of the data shows that under two percent of these patients will suffer from a stroke, less than one percent will have an intracranial bleed after readministration of the drug, and survival will be comparable to an emergency revascularization strategy. Compared to the benefits provided by this therapy, these findings should give physicians the confidence to take this approach for their patients."
Drug may combat memory loss in Parkinson's and other disorders
An experimental drug taken for a short period of time has been shown to reverse drug-induced "working" memory loss in monkeys, according a study published in the journal Science. Working memory enables people to briefly hold information while thinking and comprehending information. Drugs used to treat psychotic conditions can alter dopamine receptors in the brain, resulting in working memory impairments.
Yale University School of Medicine researchers sought to stimulate dopamine D1 receptor function with an experimental drug, called ABT 431. The team worked with six, female monkeys and taught them to perform memory-intensive tasks. When given the antipsychotic drug haloperidol at levels similar to the typical human dose, five of the monkeys made errors related to their inability to remember. One monkey refused to leave her cage. Scientists administered AMT 431 in blocks of five days followed by a two week washout period without the drug. After each treatment with ABT 431, the monkeys showed significant improvement. Following repeated exposure, the benefits lasted through the washout period and have persisted for more than a year.
"What's remarkable about this particular drug is that patients would only need to use it for a short period of time to achieve long-lasting effects," said author Patricia S. Goldman-Rakic. "By stimulating D1 receptors, the medication might also prove useful to people with other conditions characterized by low dopamine levels, such as Parkinson's disease, or memory loss related to aging. In these diseases, long-term treatment often becomes part of the problem because of unwanted side effects."
Goldman-Rakic said in the future, doctors may be able to improve patients' working memory with pills or periodic injections of the drug or a similar compound. "What's needed now are clinical trials," Goldman-Rakic said. "This could help so many people."
Gene treatment may treat cirrhosis complication
A new gene therapy treatment offers possibilities for reversing portal hypertension, a major complication of cirrhosis of the liver. Hepatitis C, hepatitis B, chronic alcohol abuse and other conditions can cause the disease, the world's tenth leading cause of death. Cirrhosis produces liver scarring and shrinkage. Pressure increases in the portal vein as blood meets resistance passing through the diseased organ. Portal hypertension can weaken gastrointestinal blood vessels to the point that they break, leading to serious bleeding.
"In humans, for example, about 30 percent of patients will die in the hospital after the first bleeding complication from portal hypertension," Dr. Don Rockey, director of the Duke Liver Center at Duke University Medical Center. "The one year mortality rate after diagnosis is about 60 percent. This is a very difficult condition to treat successfully."
That's because no effective medical or surgical remedies exist. Scientists have noted livers with cirrhosis produce less nitric oxide, a chemical that is known to relax blood vessels within the liver. Working with rats, researchers inserted a nitric oxide-producing gene into a modified adenovirus, known to frequently infect the liver. As the virus moved through the organ, it lost some of its effectiveness, but enough of the gene reached the designated liver cells. The genes continued to yield nitric oxide for 10 to 14 days. "Once the virus infected the target cells, the genes produced nitric oxide, which opened up the vessels and significantly reduced the hypertension," Rockey said. Results of the National Institutes of Health and the American Digestive Health Foundation-funded study were published in the Journal of Clinical Investigation.
"To have a targeted therapy would be of immense help to physicians who take care of these patients," Rockey said. "Further studies will determine whether or not this approach will be feasible in humans."
Scientists discover two processes involved in breast cancer
Researchers have discovered two cellular processes that trigger the spread of breast cancer. University of Iowa researchers showed that aberrant cytosine methylation and chromatin condensation shut off maspin (mammary serine protease inhibitor), a gene that suppresses tumor development in healthy breast tissue. When maspin is silenced, tumor cells grow and spread. The scientists indicated the discovery is an important step toward development of drugs that prompt maspin expression.
Maspin prompts several changes to the surface of cancer cells, inhibiting cell motility, invasion and metastasis. Previous research has shown that mutations in tumor-suppression genes can cause cancer growth. But with breast cancer, maspin hasn't been eliminated or rearranged, which led the scientists to look for mechanisms that might turn off its protective activity.
Comparing cultures of normal human mammary epithelial cells with cultured human breast cancer cell lines, the team found seven of nine cancer cell lines had no detectable maspin expression, and six of the seven had an aberrant pattern of cytosine methylation of the maspin promoter. This deviation was associated with an altered chromatin configuration, making the genetic material inaccessible to proteins needed for gene expression. The researchers were able to reactivate maspin expression by introducing a DNA demethylating agent.
In an article reported in the International Journal of Cancer, the authors concluded that aberrant cytosine methylation occurs with a frequency of approximately 80 percent in human breast cancers. They theorized that forced re-expression of the maspin gene could effectively inhibit metastatic disease. "These new findings provide critical information regarding the regulatory mechanisms of maspin, which allows us to examine the potential of maspin re-expression in cancer therapies," said investigative team member Mary J.C. Hendrix, Ph.D.
Study finds estrogen replacement does not slow heart disease
Hormone replacement therapy (HRT) may not protect older women's hearts as much as previously thought, according to a major study reported at the American College of Cardiology's annual meeting. During the three year Estrogen Replacement and Atherosclerosis (ERA) trial, researchers at several major medical centers assessed the status of 309 older women's coronary arteries. About half the participants had a history of surviving a heart attack. The women were randomly assigned either estrogen, estrogen combined with progestin or a placebo with no active ingredient. Scientists measured changes in the women's arteries and found coronary artery disease progressed at the same speed in all three groups. HRT lowered the women's cholesterol levels but that change did not result in less clogging of the arteries.
"This study provides additional evidence that HRT may not be as effective as we once thought in slowing heart disease," said Dr. David Herrington of Wake Forest University Baptist Medical Center. "The message for women and their physicians is to make full use of proven therapies, such as cholesterol-lowering drugs, and not assume that HRT is an effective alternative for treatment of heart disease."
This is the second study to show HRT may not offer significant cardiovascular benefits. The 1998 Heart and Estrogen/Progestin Replacement Study (HERS), involving 2,763 older women with histories of cardiac disease, showed women taking HRT had as many heart attacks and deaths from cardiac disease as women not taking hormones. "ERA supports the findings of HERS. In both studies, there was no clear-cut evidence of benefit in women with established heart disease," Herrington said. "Other studies, such as the Women's Health Initiative, are looking at the effects of HRT in younger women. These studies will further clarify what role, if any, HRT may play in the prevention of heart disease."
Pig cell transplants offer hope for Parkinson's
Parkinson's disease causes stiffness, tremors, poor balance and other neurological symptoms, partially due to a progressive loss of dopamine-producing cells. Drugs to boost dopamine levels help but may become less effective after five years. Pioneering research, reported in the journal Neurology, shows embryonic dopamine-producing pig cell implants have decreased symptoms in some patients. "This is the first study to use pig cells in a human brain," said study author and neurologist Dr. Samuel Ellias, at Boston University Medical Center. "Previous studies have shown that transplantation of human embryonic cells can be effective in alleviating some symptoms in Parkinson's disease patients. However, the limited availability of human tissue and moral and ethical concerns limit the widespread application of this approach."
Researchers surgically implanted pig cells, from specially screened donor animals, into three sites in the brains of 12 patients suffering from advanced Parkinson's disease. Rates of improvement varied, with initial progress taking up to three or four months. One year later, 10 patients experienced, on average, a 19 percent improvement in mobility and the ability to perform activities of daily living, as measured by a standard rating scale. Three patients showed improvements of 34 to 51 percent. Benefits lasted more than a year in some subjects. Brain scans, however, did not show cell growth or other changes in the patients' brains.
Pig brain tissue is quite similar to human brain tissue, but patients typically require drugs to prevent rejection. In this study, half the subjects received drugs to suppress the immune system, and the other half received pig cells treated with an antibody to protect against incompatibility. One patient who responded well received cells with the antibody. "This antirejection technique has been shown to permit graft survival without systemic immunosuppression in animals," explained Ellias. "This is the first experimental use of this technique in humans."
Cancer stopping protein discovered
Cancer experts have known for sometime that the gene p53 suppresses tumor growth and that mutations of the gene exist in more than half the people who have cancer. Now researchers have identified a protein enzyme, called Chk2, that activates p53. Without Chk2, cells with faulty DNA can multiply and form tumors, according to a report in the journal Science. "These findings that Chk2 mutations behave like p53 mutations in causing cancer is very important," said Stephen Elledge, Ph.D., at Baylor College of Medicine. "Chk2 is now a strong candidate for the gene mutation in the half of cancers that do not have mutations in p53."
In test tube studies, Elledge and scientists at the University of Toronto found that when cells without Chk2 were exposed to radiation they survived doses that normally would have caused p53 to trigger a suicide response. When the scientists reintroduced Chk2, p53 levels rose. "These studies showed that Chk2 is a strong regulator of p53, and is among its most important regulators," said Elledge. "There is also clinical evidence that it has a role in cancer because two cancer-prone families have recently been found that show a familial mutation in the Chk2 gene. The cancer in those families strongly resembles those caused by mutations in p53."
The loss of Chk2 may contribute to a range of cancers, but Elledge doubts it is equal in importance to the loss of p53, because p53's genetic properties make it more likely to cause tumors. "Chk2 may play an important role in inherited cancers in which both genes are mutated," said Elledge. "Cells from tumors that show loss of Chk2 may have new vulnerabilities not present in tumors that have mutations in p53. We may be able to exploit that vulnerability to selectively kill those cancers."
Heart patients don't take aspirin as often as appropriate
For just a penny per day, patients with coronary artery disease could drop their heart attack risk by one third. Yet nearly three quarters of patients with a history of angina or heart attack do not take aspirin on a regular basis. While aspirin use has increased, researchers at Massachusetts General Hospital say more heart patients could benefit from the inexpensive, effective drug. "A substantial number of patients are at higher than necessary risk of developing future heart problems because they are not taking aspirin," said study author Dr. Randall Stafford.
Researchers analyzed data from the National Ambulatory Medical Care Survey, an annual compilation of physician-reported information about patients' diagnosis and treatment by the National Center for Health Statistics. Reviewing 10,942 visits made to doctors offices by patients with coronary artery disease, the scientists found aspirin use increased from five to 26 percent between 1980 and 1996. "That was much lower than what might be expected," Stafford said. "It shouldn't necessarily be 100 percent because not everyone can take aspirin without developing complications; but it should be more than 26 percent."
The study, reported in Circulation: Journal of the American Heart Association, showed cardiologists recommended aspirin more often than primary care physicians. Patients over 80 years of age were less likely to take aspirin than younger patients: 17 percent vs. 28 percent. Twenty-nine percent of the men took aspirin, but only 21 percent of the women. "Although aspirin therapy in the most elderly may carry an increased risk of complications, aspirin is likely to have the greatest absolute benefit in this population," Stafford said, adding that the gender difference is "consistent with the observation that women may receive less aggressive treatment for coronary artery disease."
The American Heart Association warns people to check with their doctors before taking aspirin on a regular basis.
Government stops blood pressure drug trial
After results showed the blood pressure drug Cardura prevented far fewer heart complications than a cheaper, more conventional water pill, the National Heart, Lung, and Blood Institute (NHLBI) prematurely halted that portion of a large cardiovascular drug study and urged patients taking the medication to consult their doctors. "Cardura was less effective at lowering blood pressure and at preventing cardiovascular complications, particularly heart failure," said study steering committee chairman Dr. Curt Furberg of Wake Forest University Baptist Medical Center. "It is also ten times more expensive than the diuretic."
Chemotherapy found as effective as bone marrow transplant for metastatic breast cancer
Bone marrow transplants offer no additional benefit in the treatment of metastatic breast cancer than a lengthy course of conventional chemotherapy, according to a recent high priority National Cancer Institute trial. Maintenance chemotherapy provided the same or better three year survival rates and fewer complications.
Atrial fibrillation complicates heart attack recovery
Approximately two million Americans suffer from atrial fibrillation, an irregular heart quivering more common in older adults. Researchers at Georgetown University Medical Center in Washington, D.C., found 22 percent of elderly heart attack patients experienced atrial fibrillation prior to or just after suffering a heart attack. Patients with both conditions experienced more disability and death than people who suffered a heart attack but no atrial fibrillation. "We didn't think atrial fibrillation would be as common as we found it to be," said senior author Dr. Allen J. Solomon. "When elderly heart attack patients have atrial fibrillation, they are at increased risk for having a stroke, congestive heart failure or a second heart attack. Their hospital stay is also longer."
Stress combined with low serotonin promotes heart disease
Depressed and angry people die more often from heart disease than other individuals. Researchers at Duke University may have discovered the reason why: low serotonin levels. In a recent study, scientists found that people with low levels of serotonin, put under emotional stress, experienced a significant elevation in cytokines, immune system proteins known to contribute to plaque buildup in the arteries. People with normal or high serotonin levels, exposed to the same stressful situations, did not show a rise in cytokine production.
Suarez presented the findings at the American Psychosomatic Society's annual meeting. He said The study presents the possibility that increasing serotonin levels might lower cardiovascular risk.
Exercise lowers leptin level
Exercise plays a key role in lowering levels of the fat hormone leptin, which when elevated has been linked to insulin resistance, high blood pressure, obesity and increased cardiac risk. Harvard School of Public Health researchers found physical activity could significantly lower leptin levels and, in turn, improve heart health. "We don't know yet if a high level of leptin is an independent risk factor for heart disease," said Dr. Nain-Feng Chu, who headed the study. "But we do know that obesity raises a person's risk of a heart attack and stroke, and our findings provide evidence that physical activity may reduce the chronic disease risk in men through changes in leptin levels."
Researchers assessed the dietary and lifestyle habits of 268 men, from 47 to 83 years old, who did not have cardiovascular disease, diabetes or cancer. Men with the highest leptin levels didn't exercise, weighed more and ate more fatty foods than the men with the lowest leptin levels. Normal and overweight men who regularly participated in vigorous physical activity experienced dramatically lower leptin levels. About three hours of jogging per week produced a 10 percent drop in leptin levels. The Harvard team presented the findings at the American Heart Association's 40th Annual Conference on Cardiovascular Disease Epidemiology and Prevention.
"As you get fatter, your body makes more leptin," said coauthor Eric B. Rimm. "But when you exercise, the amount of leptin in the blood decreases. Most of the time, you also lose weight, which means your risk of heart disease decreases too."
Five years ago, many scientists thought genetic manipulation held the key to lowering leptin levels and controlling obesity, but regulating humans' leptin levels has proven difficult. Old-fashioned exercise, once again, proves beneficial, giving people one more reason to get up and move.
Angiogenesis factor linked with heart attacks
Offering hope for future molecular treatments to limit damage from heart attacks, researchers for the first time have tied a cellular defense mechanism which kicks in when heart cells are deprived of blood and its marker hypoxia-inducible factor (HIF) to patients suffering from heart disease. HIF is a gene-stimulating factor, expressed when oxygen levels drop, causing ischemia. Cultures and animal studies have shown HIF activates genes that trigger vascular endothelial growth factor (VEGF), prompting new blood vessels to grow and increase oxygen supply to starving tissue.
"Knowing that HIF and VEGF are very strong angiogenesis genes, we sought to understand their role in myocardial ischemia. Through our findings, it is very clear that during a heart attack or ischemia, HIF and VEGF are active responses attempting to increase a decreasing blood flow," said Dr. Patricia Thistlethwaite at the University of California, San Diego School of Medicine.
The researchers found HIF and VEGF in 37 diseased tissue samples taken from hearts of patients undergoing coronary bypass surgery but not in normal tissue biopsied from the same heart. HIF showed up in specimens displaying signs of acute ischemia, with an onset less than 48 hours, and early infarction, areas of tissue dying from lack of blood supply. Tissue samples with evidence of a heart attack in the distant past did not have detectable levels of VEGF or HIF. The New England Journal of Medicine published a report of the study. The findings offer potential for minimizing heart impairments through molecular level treatments. "We demonstrated that HIF is turned on in the early phases of myocardial ischemia, and that it in turn stimulates the production of VEGF in the heart," Thistlethwaite said. "Our next step is to deliver HIF by gene therapy into the heart to improve myocardial function, and limit the damage of a heart attack."
Longer heart surgery increases complication risk
During heart surgery, tiny fat particles enter the bloodstream and can block very small blood vessels, damaging the brain. Risk increases the longer a heart-lung machine performs natural body functions during such surgeries as coronary artery bypass and heart valve replacement. More than 50 percent of surgical patients requiring use of the machine suffer from neurologic or neuropsychological deficits during the first postoperative week. For 10 to 30 percent of the patients the deficits will become long-term or permanent, and one to five percent will die or suffer a severe disability, according to researchers at Wake Forest University.
The scientists counted the number of fat particles, called microemboli, present in 36 brain specimens from patients who had died within three weeks of surgery. All subjects had microemboli, often found in clusters where tiny arteries divide. The number of emboli increased with longer operations. They found for each hour spent on the heart-lung machine the number of fat particles increased by 90.5 percent. The rate was even higher for patients undergoing valve surgery, which tends to last longer. Although length of surgery has been suspected as a cause for brain complications, this is the first study to quantify the number and volume of microemboli. Findings from this National Institute of Neurological Disorders and Stroke-funded research were reported in the journal Stroke.
The team began studying the effects of heart surgery on the brain in 1990. They suggested that suctioning blood from the open chest and returning it through the heart-lung machine might cause microemboli formation, and thought that eliminating the practice, or removing fat emboli from the scavenged blood might reduce postoperative brain dysfunction.
Electron beam scan predicts heart attack risk
Noninvasive, high speed electron beam tomography scans proved more accurate in predicting heart disease risk than the evaluation of traditional factors such as cholesterol, obesity, high blood pressure, exercise and smoking. But combining data concerning these conventional factors with electron beam computed tomography (EBCT) provided more exact information about cardiac problems. Cooper Institute researchers reported the findings at the American Heart Association's 40th Annual Conference on Cardiovascular Disease Epidemiology and Prevention. "EBCT may add significant information to conventional risk factors for determining a patient's level of or risk for heart disease," said lead author Dr. Ming Wei, with the Dallas not-for-profit institute. "This could help physicians provide early treatment to patients at risk for a heart attack and possibly even prevent heart disease from progressing in those patients."
The researchers studied 1,133 men and women, conducting both a conventional risk factor assessment and an EBCT scan. They found 110 patients with coronary artery disease, and made a final diagnosis after patients suffered a heart attack or an angiogram confirmed the condition. An angiogram can determine the severity of blockages and evaluate arterial blood flow. EBCT scans quickly obtain high resolution images that show calcium deposits and the extent of calcification in coronary arteries. The more calcium in the arteries the greater the odds of heart disease. The scans cost $400 to $500 and could aid in making treatment decisions. "If people have a history of moderately elevated cholesterol, an EBCT scan is a great way to help them decide, along with their physician, whether to begin taking cholesterol-lowering medication," said coauthor Dr. Larry W. Gibbons, of the associated Cooper Clinic. "If they have no calcium in their arteries, then chances are they don't need to be on medication. But if they are accumulating calcium in their heart arteries, then the physician would probably decide on aggressive medication for that patient."
Depression after bypass surgery ups risk for future heart problems
About 20 percent of coronary artery disease patients undergoing bypass surgery to open clogged arteries become depressed in the hospital, but a new study indicates post-op blues may increase the risk for future cardiac problems. Researchers at the University of Maryland Medical Center and Columbia University College of Physicians and Surgeons studied 309 bypass patients, 207 men and 102 women, conducting a detailed psychiatric interview prior to discharge from the hospital and assessing for health changes one year later. Depressed patients were more than three times as likely to suffer from a heart problem such as a heart attack, or to require another cardiac procedure or hospital care, than patients who did not experience postoperative depression. And women's risk for cardiac problems within the year were three times greater than men's risk. Demographics and disease severity did not explain the odds. "We looked at many factors, including the patient's age, gender, marital status, smoking behavior, and depression," said Dr. Ingrid Connerney, at the University of Maryland Medical Center. "But it turned out that only depression, heart condition, and gender mattered, and they were of equal importance."
Forty seven percent of the depressed women suffered a serious cardiac problem within 12 months of bypass surgery, but only 18 percent of the nondepressed women experienced problems during the study period. Twenty one percent of the men who were depressed had additional cardiac difficulties, but only six percent of the nondepressed men did. "Based on our findings, we believe that physicians and patients need to be aware of the increased risks faced by patients suffering depression," Connerney said. "The next logical step is to investigate whether treatment of depression lessens the risk of future cardiac events."
Higher radiation improves prostate cancer cure rates
Increasing radiation doses with three dimensional conformal radiation therapy (3D-CRT) improves five year prostate cancer cure rates by 14 to 40 percent, according to researchers at Fox Chase Cancer Center in Philadelphia. External beam radiation using the new conformal method lets radiation oncologists direct the beams, limiting coverage to the tumor. Since the computer-assisted technique avoids irradiating nearby tissues and organs, doctors can administer higher doses. In a study of 618 patients, reported in the International Journal of Radiation Oncology, Biology and Physics, researchers found treating prostate cancer with 3D-CRT resulted in a cure rate of more than 80 percent for patients with an initial prostate-specific antigen (PSA) of 20 or less.
Fox Chase physicians said only 40 percent of radiation oncology facilities were using 3D-CRT in 1998, the most recent statistic available. The American Society for Therapeutic Radiology and Oncology plans a series of programs to educate doctors how to use the new method. Previous studies found 3D-CRT as effective as transperineal permanent implantation for early-stage prostate cancer, but the newer technique caused fewer side effects. "Morbidity is very low if 3D-CRT is done," said Dr. Gerald E. Hanks. "We have the potential to cure more patients; it is essential that we take advantage of that potential."
According to the American Cancer Association, about 180,400 new cases of prostate cancer will be diagnosed in the United States this year, with the incidence of new cases declining after a peak in the early 1990s attributed to the use of PSA screenings. The organization expects close to 32,000 men will die from the disease. Prostate cancer survival rates have increased from 67 percent to 92 percent during the past 20 years, with more than half the men surviving 15 years after diagnosis.
Heat activated drug carriers stop tumor growth
Killing tumors without destroying healthy tissues has presented cancer treatment challenges. Duke University's newly developed submicroscopic, heat-activated drug carriers called liposomes stopped cancer growth by delivering higher doses of chemotherapy directly to the tumor. After injecting the liposome, researchers heated the tumor, causing portions of the liposome structure to start melting, releasing cancer-killing drugs. The liposome reseals when it leaves the artificially heated area, preventing the delivery of toxic drugs to healthy areas.
During two trials, Duke scientists implanted human squamous cell carcinoma tumors into mice, then injected the animals with one of several different treatments: chemotherapy alone, no drug, an old liposome, one that worked differently and the promising new liposome. The new drug carrier is smaller, about one-hundredth the size of a red blood cell, and activates at a lower temperature than previous liposomes. Reporting the findings in the journal Cancer Research Advances in Brief, scientists said the two molecule thick liposome can release 45 percent of the drug stored within it during one 20 second burst.
Tumors in six of nine mice receiving the new liposome in the first trial and in all eleven animals in the second trial disappeared and did not regrow during the sixty day study. Mice receiving the other liposomes showed some delay in tumor growth, dependent on the amount of drug released. Mice receiving no treatment experienced steady, rapid tumor growth, to five times the original size within ten days. The commonly used chemotherapy drug doxorubicin had no effect. "It's pretty unusual to see something work that well," said Dr. Mark Dewhirst. "It's not unheard of, but it's certainly unusual."
The Duke team plans to collaborate with a veterinary college to test the liposomes on dogs receiving treatment for cancer. They also will conduct toxicity studies before conducting human trials.
Estrogen protects brain, offers hope as stroke treatment
Many studies have touted estrogen's cardiovascular benefits. Postmenopausal women taking estrogen survive more strokes than women who don't use hormone replacement therapy. Now researchers at the University of Florida (UF) have shown that giving high doses of the female hormone to rats suffering from a stroke can prevent brain damage. Estrogen does not open the clogged artery. It offers the potential for keeping cells alive, thereby extending the amount of time clot-dissolving drugs can be administered.
For the study, reported in the journal Stroke, scientists surgically removed the rats' ovaries so they could not produce their own estrogen, and divided the animals into different groups. Some received no treatment, others a dose of estrogen twenty times what normally circulates in their bodies, at 30 minutes, one, two, three and four hours after researchers surgically induced a stroke. The team blocked the rats' middle cerebral artery, then injected the animals with the female hormone. When estrogen was given within 30 minutes, brain cell death rate dropped by 60 percent. Administered three hours after the stroke, 30 to 40 percent of the cells were saved.
"As time passed, the amount of tissue that was protected declined, which indicates that there is a window of opportunity to protect brain tissue. The earlier you are in that window, the better the outcome," said lead researcher James W. Simpkins, chairman of the university's College of Pharmacy. "If you were past four hours, you wouldn't expect to see any protection."
Previous UF research had shown estrogen offered protective benefits when given prior to a stroke. "Here we have confirmation that it has potential for treating a patient who comes into the emergency room with stroke symptoms," Simpkins said. Clinical trials still need to be conducted to determine safety and estrogen's effectiveness in treating human stroke patients.
Study shows serotonin-boosting drugs cause changes in some brain cells
Millions of Americans take serotonin-boosting drugs to combat depression or lose weight. Researchers at Jefferson Medical College in Philadelphia, working with rats, found high doses of the drugs caused brain cells to shrivel or take on abnormal corkscrew shapes, changes similar to the street drug Ecstasy, known to be a brain-cell toxin.
For four days, researchers gave different sets of animals high does of either Prozac, Zoloft, Meridia or Redux. The first two are prescribed to treat depression, the last two obesity. Redux was taken off the market in 1997 due to reports of heart valve damage. When researchers examined the rats' brains, they saw obvious changes in some nerve terminals that release the chemical serotonin. Low levels of serotonin, a neurotransmitter, are associated with depression, eating disorders and other conditions. The drugs, known as selective serotonin reuptake inhibitors (SSRIs), keep the neurotransmitter from being recirculated, so the chemical stays active longer. Rats used as control groups were given either the amphetamine-derivative Ecstasy or another drug that pushes serotonin out of brain cells. Rats receiving Ecstasy showed changes similar to those receiving the SSRIs. The scientists say the findings, reported in the journal Brain Research, raise concerns about long-term use of the popular drugs.
"We don't know if results with four days of drug treatment are clinically significant," said lead researcher Dr. Madhu Kalia. "We don't know if the cells are dying. That's the key question. We need to do more studies to prove cell death. These effects may be transient and reversible. Or they may be permanent."
Many patients take the drugs for extended periods, so the scientists plan long-term animal studies to determine if the effects persist and if they cause behavioral or neurological changes. "The problems with human studies is we can't do such experiments in controlled environment," Kalia explained.
Genetic marker helps predict breast cancer recurrence
Scientists often refer to p53 as the anticancer gene, because it causes cells to self-destruct when DNA becomes damaged, preventing cancer from taking hold. But a change or mutation in this important tumor-suppressor gene may serve as a marker for predicting a breast cancer recurrence.
Scientists at Jefferson Medical College and Yale University found larger amounts of the flawed p53 gene and its protein in women whose breast cancer returned within four years of initial diagnosis than in women who remained cancer free. Knowing the mutation exists may prompt doctors to alter treatment plans for these women, perhaps increasing radiation doses or ordering newer therapies designed to increase a cancerous tumor's sensitivity to treatment. "Women with a genetic change in this important gene may need to be treated with additional therapies necessary to prevent the development of recurrent breast cancer and minimize the risk of metastatic disease," said Dr. Bruce Turner, at Jefferson Medical College in Philadelphia. "The results provide the first evidence in humans that p53 gene changes are also associated with poor responses to radiation therapy treatments."
Researchers followed, for an average of more than 14 years, 121 women who had an early-stage cancerous lump surgically removed between 1973 and 1995 and had radiation therapy. Thirty-nine percent of women who experienced a recurrence within four years had higher levels of the altered protein, compared to nine percent of the women whose cancer did not return. Only 48 percent of the women who had high p53 levels lived 10 years disease-free, while 67 percent of those without the genetic change survived a decade without a recurrence. The study was reported in the journal Cancer.
Doctors fail to emphasize outpatient drug complications
Doctors order prescription drugs to treat a host of maladies, but sometimes the medications produce long-lasting complications, and some patients become dissatisfied with care and need additional medical treatment, according to a study reported in the Journal of General Internal Medicine. The study of outpatients, who obtain and administer their own drugs, showed complications were more common than medical records indicated. Patients reported the most problems with antibiotics, antidepressants and nonsteroidal anti-inflammatory drugs, often complaining about common side effects such as gastrointestinal ailments, sleep disruptions, mood changes and tiredness.
Doctors at Harvard's Brigham and Women's Hospital in Boston and San Francisco General Hospital surveyed 2,248 outpatients. Close to 400 patients reported a drug complication, but only 64 drug-related adverse effects were recorded in patients' medical charts. "Physicians often take these types of reactions for granted in the course of medical therapy. However, it is important to realize that these events are not minor to patients. Physicians may underestimate the impact of these events on patient satisfaction, health care utilization and quality of life," said lead author Dr. David Bates, at Brigham and Women's Hospital.
Bates expects many complications could be prevented if computerized prescribing systems were used to detect allergies and drug interactions, fewer unnecessary antibiotics were prescribed, and if doctors explained possible side effects to patients. "Patients who know in advance about potential side effects may handle them better or have less concern about them," he said.
Vitamin E and carotenes offer sunburn protection
Beta-carotene and vitamin E supplements may protect people from sunburn, according to a new German study. Scientists have know for some time that ultraviolet irradiation decreases plasma and skin concentrations of carotenoids, like beta-carotene, which has led to theories that beta-carotene supplements might be beneficial in preventing sun damage. Scientists suspect the protective benefits are related to the carotenoids' antioxidant properties.
Working with 20 healthy, fair-skinned nonsmokers, scientists initially exposed different sections of the subjects' backs to a blue-light solar simulator, measuring redness after multiple irradiation doses, which served as control measurements. Then for twelve weeks, the researchers gave the men and women, ages 20 to 57, either 25 mg total carotenoids or a combination of 25 mg carotenoids and 335 mg vitamin E with their main meal. Skin color was measured by chromatometry before and 24 hours after exposure to the ultraviolet light. Different areas of the skin were exposed to increasing doses of irradiation, starting at week zero of the antioxidant supplementation and at four, eight and 12 weeks. While both groups experienced less redness after taking the supplements, the addition of vitamin E seemed to offer some, but not significant, extra protection. The researchers concluded, in a report in the American Journal of Clinical Nutrition, that the antioxidant supplements may be beneficial as an aid to "diminishing sensitivity to ultraviolet light."
The study only evaluated redness, or sunburn, and did not address sun exposure and cancer risk. A recent large-scale, long-term Harvard Medical School study found that beta-carotene supplements did not prevent nonmelanoma skin cancer.
Sugar chain gene may suppress tumor growth
Canadian researchers, working with mice, identified a carbohydrate chain gene that causes cancer cells to proliferate. By eliminating the gene, they halted tumor growth and metastasis. The discovery, reported in the journal Nature Medicine, holds promise for new cancer treatments. "Cancer cells express sugars, allowing rapid tumor growth," said coauthor Dr. Jim Dennis, at the University of Toronto. "What we have done is look at how those sugars on the cell surface affect the growth and spread of cancer."
Researchers found that the carbohydrate chain Mgat5 was elevated in human breast, colon and skin cancers. Scientists used gene targeting to create mice without Mgat5. The mice looked normal but reacted differently when exposed to a powerful cancer-causing gene. The mice without Mgat5 had a stronger immune response and an 80 to 95 percent reduction in breast cancer growth and lung metastasis compared to other mice. The improved immune response may aid in limiting tumor growth. "Our study shows that the Mgat5 gene in cancers promote cell movement, which drives growth-signaling pathways inside the cells," said Dennis. "This is the first time that we have been able to show a direct involvement of carbohydrate chains in cancer growth. This study and ongoing investigations in the signaling pathways affected by Mgat5 will direct us to new approaches to control the spread of tumors."
GlycoDesign Inc., a Canadian biotechnology firm working with the university, is researching methods to inhibit Mgat5, which might boost cancer patients' immune response after chemotherapy.