Aspirin Is Safer Than Warfarin And Just As Effecive For Treating Blocked Arteries In Brain

"Comparison of warfarin and aspirin for symptomatic
intracranial arterial stenosis." "NEJM", March 31,2005, Vol.352., No.12, pp.1305-1316.

To reduce the risk of stroke, partial blockage of arteries in the brain (intracranial stenosis) has for decades been treated with drugs such as aspirin and warfarin that reduce blood clotting. However, doctors have never had good evidence for choosing one therapy over the other. Now, results of a double-blind, randomized clinical trial show for the first time that aspirin works as well as warfarin with fewer side effects. The study was funded by the NINDS, part of the NIH.

"This trial is good news. A simple low-cost drug works just as well as one that requires complicated and expensive monitoring and dose adjustments," says John R. Marler, M.D., the Associate Director for Clinical Trials at NINDS.

Intracranial stenosis is caused by atherosclerosis - fatty deposits that build up on the inner walls of the arteries and restrict blood flow. Intracranial stenosis causes about 10 percent of the 900,000 strokes and transient ischemic attacks (TIAs) in the United States each year. TIAs are transient strokes that last only a few minutes and occur when the blood supply to part of the brain is briefly interrupted. People with a stroke or TIA due to intracranial stenosis have a greatly increased risk of a second stroke - as much as 15 percent per year. Studies in the 1950s suggested that anticoagulants (a class of drugs that reduce blood clotting), such as warfarin, can reduce the risk of stroke in people with this disease.

In the new study, called the Warfarin Aspirin Symptomatic Intracranial Disease (WASID) trial, investigators at 59 medical centers across the United States, led by Marc I. Chimowitz, M.D., of Emory University in Atlanta,
compared warfarin to 1300 milligrams (mg) per day of aspirin in a total of 569 patients for an average of 1.8 years. All of the patients had a greater than 50 percent blockage of a major intracranial artery and had experienced a TIA or non-disabling stroke within the 90 days prior to their enrollment in the study.

The investigators found that about 22 percent of the patients had a subsequent ischemic stroke, brain hemorrhage, or death from other blood vessel-related causes, regardless of whether they received aspirin or warfarin. However, the rates of major hemorrhage and death from all causes were significantly higher in the patients treated with warfarin (event rates for aspirin compared to warfarin, respectively, were 3.2 percent vs. 8.3 percent for major hemorrhage and 4.3 percent vs. 9.7 percent for death). Enrollment in the study was terminated earlier than originally planned on the recommendation of an independent Data and Safety Monitoring Board because of concern for the safety of the patients given warfarin.

Since warfarin treatment is a more expensive and complicated therapy than aspirin, not using warfarin and preventing the bleeding complications associated with it would save more than $20 million per year in the United
States, Dr. Chimowitz estimates.

"The results of this study are only relevant to people with intracranial stenosis," Dr. Chimowitz notes. People who are receiving warfarin for other conditions, such as an irregular heart rhythm (called atrial fibrillation) or clots in the legs or lung, should not stop taking the drug, as studies have found that it is the best option in those conditions, he cautions.

The dose of aspirin used in this study - 1300 mg - is much higher than the daily doses typically prescribed, which range from 81 to 325 mg. While there is some concern that doses of 1300 mg aspirin may increase the risk of
gastrointestinal bleeding, the investigators chose this dose because it was the only amount for which earlier studies had provided good preliminary data. "This is the only dose we know is as effective as warfarin for this disease, since it was the only dose studied. We just don't know how other doses of aspirin would stack up," says Dr. Chimowitz. The major bleeding risk on high dose aspirin in WASID was similar to the major bleeding risk in other stroke trials that have evaluated lower doses of aspirin (e.g. 325 mg per day), he adds. Most experts believe there are no advantages to aspirin doses greater than 325 mg for stroke prevention, and the U.S. Food and Drug Administration-approved dose of aspirin for prevention of vascular events is 50-325 mg. Patients should consult their physicians before beginning any long-term or high-dose aspirin treatment regimen.

Even with treatment, the rates of ischemic stroke in this clinical trial were substantially higher than in stroke prevention trials that have evaluated aspirin and warfarin in patients with other causes of stroke. This underscores that patients with intracranial stenosis are at particularly high risk for stroke and that better therapies are needed, the investigators note.

Complete reconstructed Neanderthal skeleton revealed

WHOLE at last. The first reconstruction of a complete Neanderthal skeleton reveals more clearly than ever the similarities and differences between us and them.

The reconstruction makes clear their larger, bell-like chest cavity and wider pelvis. Their bodies were also very compact and dwarf-like in shape, with effectively no waist, possibly as an adaptation against the cold.

Gary Sawyer of the American Museum of Natural History in New York city and Blaine Maley at Washington University in St Louis, Missouri, wanted to shed light on the anatomy and stature of this cousin of modern humans, which died out nearly 30,000 years ago. They assembled the skeleton by taking casts of the most complete skeleton available, the La Ferrassie 1 specimen found in 1909 in the Dordogne valley in France. Then they filled in the blanks using casts taken from other Neanderthal collections from the same period, approximately 60,000 years ago (The Anatomical Record, Part B: The New Anatomist, vol 283B, p 23). "It's the first time any human 'ancestor' has ever been fully reconstructed," says Sawyer.

Meanwhile, the oldest fossilised primate protein to have been sequenced, taken from a Neanderthal, was last week found to be identical to the human equivalent (Proceedings of the National Academy of Sciences, DOI: 10.1073/pnas.0500450102).

From issue 2491 of New Scientist magazine, 19 March 2005, page 14

Breakthrough In Medical Research: New Chemotherapy Gives Hope To Brain Tumour Patients

A large international study conducted by the European Organisation for Research and Treatment of Cancer (EORTC) in collaboration with the National Cancer Institute of Canada (NCIC) Clinical Trials Group demonstrated that the addition of a novel chemotherapy agent, Temozolomide (brand name: Temodal®) to radiation therapy increases survival in patients suffering from glioblastoma, a very aggressive form of a brain tumour. Further, molecular analyses of the tumour allowed for the identification of those patients most likely to benefit from this type of treatment. The findings are leading to a new standard of care for patients with this fast growing and devastating cancer. The results of this landmark trial are published in two companion papers in this weeks' edition of the New England Journal of Medicine (publication date: 10 March 2005).

Prior to the discovery of this new therapy, the average life expectancy of patients with glioblastoma was about 1 year. The results of this study demonstrate a clear improvement of survival. At 2 years only 10% of patients treated with radiotherapy alone were alive, compared to 26% of patients receiving the combination of both radiotherapy and temozolomide chemotherapy. If patients were to be selected according to their molecular profile - the investigators analysed the functionality of a gene responsible for DNA repair, the so called MGMT gene - the improvement is even more dramatic, as almost half of those patients whose tumours carry an inactivated MGMT gene are alive after 2 years. Importantly, the study also showed that this new combined therapy did not impact negatively on the patients' quality of life. Health-related quality of life has become an increasingly important endpoint in cancer studies.

"This landmark study represents the most important advance in the management of glioblastoma since radiotherapy was shown to be of benefit over 35 years ago", comments Dr. Warren Mason, a lead investigators in Canada and head of the neuro-oncology unit at the Princess Margaret Hospital in Torono, Ontario/Canada. "This study also identified MGMT the first clinically relevant molecular marker for glioblastoma which not only serves as a prognositic factor for survival, but also as a predictor for response to chemotherapy. This observation paves the way for using the unique tumor genetic signature as a guide for individualizing therapy and optimizing outcome."

From: European Organisation for Research and Treatment of Cancer

Study Reveals How Brain's Immune System Fights Viral Encephalitis

New York University biologists have uncovered how the innate immune system in mice's brains fights viral infection of neurons. The findings, published as the cover study in the latest issue of Virology, show that proteins in neurons fight the virus at multiple stages--by preventing the formation of viral RNA and proteins, and blocking the virus' release, which could infect other cells in the brain.

"There is no magic bullet in fighting viral infections in neurons," said NYU Biology Professor Carol Shoshkes Reiss, the study's senior author. "However, these findings show the redundancy of the immune system--when one response fails to fight infection, others step in."

The study was also conducted at NYU, by a post-doctoral fellow, Mark Trottier, Jr., PhD, now at Michigan State, and Beth Palian, currently a doctoral student at the University of Southern California.
Recently, the West Nile virus has been responsible for a viral encephalitis outbreak in the northeast. The NYU researchers set out to determine how the body can fight viral encephalitis. Specifically, they examined how type I interferons--proteins made by the body that are released in response to stimuli, notably infection--work in neurons and to determine if nerve cells' response to interferons is similar to that of other cells.

Examining the effect of the virus in mice and in cell culture, the researchers found that neurons are sensitive to the protective effect of interferons, inducing pathways to fight the virus' spread. However, their findings showed that interferons fight the virus at different stages of the virus' life cycle. First, they inhibit viral RNA and protein synthesis. If this fails, interferons block the virus from forming particles which can be released and infect other neurons. This is critical, since the immune system does not kill infected precious neurons the way it does other cells, which can be replaced.

The researchers attributed the spread of viral encephalitis to the inability of lab mice to produce sufficient amounts of interferons to fight the virus.

TEST COULD IMPROVE DETECTION OF PRION DISEASE IN HUMANS

A highly sensitive post-mortem test could help scientists more accurately
determine if a person died of Creutzfeldt-Jakob disease (CJD), a human
neurological disorder caused by the same class of infectious proteins that
trigger mad cow disease, according to a new study supported in part by the
National Institutes of Health (NIH). The finding opens the possibility that
such testing might be refined in the future so it can be used to detect
prion disease in living people and animals before the onset of symptoms.

The test, called conformation-dependent immunoassay (CDI), was originally
developed to detect various forms of disease-causing proteins called prions
in cows, sheep, deer and other animals.

In the new study, researchers led by
Jiri Safar, M.D., Bruce Miller, M.D., Michael Geschwind, M.D., Stephen
DeArmond, M.D., and Nobel Laureate Stanley B. Prusiner, M.D., of the
University of California, San Francisco, found that CDI not only identifies
prions in human brain tissue but is faster and far more precise than the
standard immunological detection methods, which only detect a small fraction
of the infectious prions that may be in the brain.

The finding appears in the March 1, 2005 issue of the "Proceedings of the
National Academy of Sciences", <http://www.pnas.org>.

In the study, Prusiner and his colleagues extracted brain tissue from 28
people who had died of CJD. They tested these samples using CDI, which uses
highly specific antibodies that bind to all disease-causing prions in the
brain. They also used immunohistochemistry (IHC) to measure only the prion
proteins that are resistant to an enzyme called protease. Protease-resistant
prions are abnormal and usually infectious, meaning they can cause CJD and
other neurodegenerative diseases. CDI detected abnormal prions in all of the
sampled brain regions. In contrast, the researchers found that IHC detected
abnormal prions in less than 25 percent of the sampled brain regions. The
findings, according to the researchers, suggest that CDI could be used to
establish or rule out the diagnosis of CJD with greater accuracy than IHC,
particularly when a small number of samples are available. Prusiner and
colleagues are exploring the possibility of using CDI in living tissue, like
blood or muscle, to detect and diagnose prion diseases, such as CJD or
bovine spongiform encephalopathy (BSE, mad cow disease) while people or
animals are still alive.

"This research not only is an important advance for the detection and
diagnosis of prion diseases, but, with the identification of
protease-sensitive infectious prions, will lead to a better understanding of
the underlying disease processes," said Andrew Monjan, Ph.D., Chief of the
NIA's Neurobiology of Aging Branch.