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An experimental approach that looks for the DNA leaking out from dead and dying cells may provide a route to a blood test for breast cancer, U.S. researchers reported on Tuesday.

An initial study showed the test detected 70 percent of breast cancer cases, and correctly cleared 100 percent of women who did not have breast cancer, the team at Chronix Biomedical, a privately-owned company in San Jose, California, said.

The experimental test is not ready to develop into a product but provides a basis for further research, they wrote in the journal Molecular Cancer Research.

“It is based on finding the unique DNA fingerprints from dead and dying cells,” Chronix CEO Howard Urnovitz said in a telephone interview.

Technological advances in DNA sequencing made the test possible, Urnovitz said. His team sequenced the entire genomes of 26 breast cancer patients and of 67 apparently healthy women.

They were looking for extra DNA in the blood of the breast cancer patients that would come from cells dying because of the tumors.

“If a breast cell is injured, it will overexpress the genes that make it a breast cell,” Urnovitz said. In theory, if a patient has excess DNA from breast cells that are dying, there is something going on that is killing breast cells.

The search is not easy. “The entire genome can be found in the blood,” Urnovitz said. And billions of cells die every day in the human body.

But eventually the Chronix team found what they believe is tell-tale DNA from dying breast cells.

“This study supports the potential of an entirely new approach to identifying cancer at its earliest stages when therapies may be most effective,” Dr. William Mitchell of Vanderbilt University School of Medicine in Tennessee, who worked on the study, said in a statement.

SCREENING AND MONITORING

“Laboratory tests using this approach may have the potential both to screen large populations for cancer before symptoms appear and to monitor patients for the recurrence of cancer once treated,” Mitchell added.

Much more testing needs to be done, Urnovitz said. But so far the test seems to specifically home in on breast cells. Unpublished data shows, for instance, that the DNA signature is not found in men with prostate cancer.

The cost of genetic sequencing will have to come down more before the test would be practical, Urnovitz added.

His team used Roche AG’s 454 sequencer at a cost of thousands of dollars per person, but companies are working to speed up sequencing and get the costs down.

The tests might be used to screen women for breast cancer and to tailor treatments, Urnovitz said.

“Imagine we can come in and say ‘you have damage to the protein kinase gene that would preclude you from these 10 cancer drugs, but here are 20 others that should work’,” he said.

“You would be selecting drug treatment based on each person’s lesions. This would be a really good example of personalized medicine.”

Urnovitz also hopes such a test could monitor patients who have completed treatment for cancer. Instead of coming to a cancer center to undergo a PET scan to check for tumors that may have returned, patients could get a blood test at their convenience and have it sent in for analysis.

“You could have one blood test for everything that is going on,” he said.

To overcome such obstacles, the study team developed a computational approach called cell specific significance analysis of microarrays (csSAM).

“What csSAM does is marry the concepts of cell separation with the ease of analyzing large families of genes on a microarray,” explains Dr. Butte. “Using a mathematical approach, we can virtually separate out the different cell types found in blood, determine the gene expression patterns of these cell types, and identify which changes in gene expression are due to actual disease and which are simply due to variations in the cell proportions.”

Investigators first tested the csSAM approach using liver, brain and lung cells from rats. They began by analyzing the gene expression patterns in the three separate cell populations. Then they mixed the cells together in different known ratios and used the new mathematical approach to pick out the individual gene expression patterns of each cell subset in each mixture. Once they had confirmed that this analytical approach correctly identified the gene expression patterns of each individual cell subset in the mixtures, they tested csSAM on blood from kidney transplant patients who were either undergoing kidney rejection or who were stable.

Using a traditional approach to analyze the gene expression from blood, the investigators did not observe any differences between people undergoing transplant rejection and people with stable transplants. However, using the csSAM approach, they were able to pull out and measure from the mixture the gene expression patterns of five specific subsets of immune cells — monocytes, basophils, neutrophils, eosinophils, and lymphocytes, known as T and B cells. The researchers were able to identify more than 300 differences in monocyte gene expression between the two groups and more than 100 genes that were significantly increased. Because monocytes make up a smaller proportion of immune cells in the blood, compared to neutrophils or lymphocytes, the traditional analysis approach could not distinguish these differences in monocyte gene expression amongst all the other gene signals.

Methods that separate out specific cell populations from blood can lead to changes in expression of genes that are not due to disease but to the experimental manipulations. The csSAM approach circumvents these additional measures that may create even more noise in the samples.

Another advantage of the csSAM approach is that it could be applied to other high-throughput analyses of genes, proteins or other cellular products of any complex mixture of cells or tissues.

“In recent years, NIAID has placed increasing emphasis on supporting human immunology research, such as this study,” says Daniel Rotrosen, M.D., of NIAID’s Division of Allergy, Immunology, and Transplantation. “We are very encouraged that our investment has helped to develop this new analytical approach, which has the potential not only to define the parameters of the healthy human immune system, but also to help identify biomarkers of disease and develop more effective vaccines.”

Part of the National Institutes of Health, the National Heart, Lung, and Blood Institute (NHLBI) plans, conducts, and supports research related to the causes, prevention, diagnosis, and treatment of heart, blood vessel, lung, and blood diseases; and sleep disorders. The Institute also administers national health education campaigns on women and heart disease, healthy weight for children, and other topics. NHLBI press releases and other materials are available online at www.nhlbi.nih.gov.

Investigators have developed a new mathematical approach to analyze molecular data derived from complex mixtures of immune cells. This approach, when combined with well-established techniques, readily identifies changes in small samples of human whole blood, and has the potential to distinguish between health and disease states.

Led by Mark Davis, Ph.D., and Atul Butte, M.D., Ph.D., of Stanford University, Calif., the team of investigators received support from the National Institute of Allergy and Infectious Diseases (NIAID), as well as the National Heart, Lung, and Blood Institute and the National Cancer Institute, all part of the National Institutes of Health. Details about their work appear online at Nature Methods.

“Defining the status of the human immune system in health and disease is a major goal of human immunology research,” says NIAID Director Anthony S. Fauci, M.D. “A method allowing clinicians to accurately and quickly characterize the many different immune cells in human blood would be a valuable research and diagnostic tool.”

Over the past 15 years, the technology for gene expression microarrays, which allow investigators to identify and measure relative amounts of many different genes in parallel, has advanced tremendously. Today researchers can measure nearly every gene in the human genome using very small amounts of blood. However, blood contains numerous types of immune cells, such as lymphocytes, basophils and monocytes, and when microarray analysis is performed on this mixture, the interpretation of the results becomes problematic.

“Current methods that examine gene expression differences in mixtures of immune cells in blood do not take into account that, even among healthy individuals, there is a wide range of variation in the proportion of each cell type,” says Dr. Davis. “This creates so-called noise that masks many differences in gene expression. Even when you do observe a difference, you do not know if this is due to a real difference or a reflection of the varying number of cell types in the mixture.”

Until now, scientists had to separate out the cell types from a mixture prior to analysis to verify that actual changes in gene expression had occurred. But cell separation is time-consuming and costly, and requires large samples of blood, Dr. Davis adds.

Migraines are more common in women with multiple sclerosis (MS) than in those without the disease, new research shows.

The study looked at close to 117,000 U.S. women participating in the Nurses’ Health Study II, including 18,000 who had been diagnosed with migraine at the start of the study. The women were assessed every two years over a 16-year period. Of the 375 women who developed MS during the study, 82 had been diagnosed with migraine when the study began.

The researchers determined that women with a migraine diagnosis at the start of the study were 47 percent more likely to develop MS than other women. The risk was the same regardless of age, vitamin D levels, body mass index, smoking status or where the women lived.

This is the first large-scale study of its kind to examine the association between migraine and MS. The findings were released online Feb. 16 and are scheduled to be presented at the American Academy of Neurology’s annual meeting in Toronto in April.

“While having a history of migraine diagnosis was linked to MS, women with migraine need to know that over 99 percent of them will never develop MS, thus having migraine should definitely not be a reason to worry about getting MS,” study author Dr. Ilya Kister, of the New York University School of Medicine, said in a news release from the American Academy of Neurology.

“More research is needed since it’s still not known whether migraine is a risk factor for developing MS or if it is a condition that occurs at the same time as MS,” Kister added.

SOURCE: American Academy of Neurology

An implantable heart monitor that uses a new computation method is highly accurate in detecting a common heart rhythm problem called atrial fibrillation, according to a new study.

More than 2 million Americans have the condition, in which the heart’s two upper chambers quiver instead of beating effectively. This causes blood to pool and clot, leading to increased risk for stroke. About one in seven strokes occurs in people with atrial fibrillation, according to the American Heart Association.

Many people with the disorder have no symptoms, making it crucial to detect and treat the condition, Dr. Gerhard Hindricks, a professor at the Heart Center at the University of Leipzig, in Germany, and the study’s lead author, said in a news release from the American Heart Association.

The study included 247 people who were implanted with the Reveal XT leadless heart monitor and followed for 46 hours. The monitor, which is about the size of a camera memory stick, is placed under the skin.

The researchers found that the monitor correctly detected atrial fibrillation in 96.1 percent of those who had it. The study, published online Feb. 16 in Circulation: Arrhythmia and Electrophysiology, was funded by Medtronic, which makes the device.

Further studies are needed to assess the long-term accuracy of the monitor, according to Hindricks.

“The device has a limited data storage capacity (49.5 minutes of data), and this may be a limitation during longer follow-up periods — especially since the presence of false positive episodes may exceed the storage capacity in some patients,” he said. “Thus, long-term performance and validation studies are needed to find the optimal way of handling the device.”

SOURCE: American Heart Association

Hospital and nursing-home employees who are infected with latent tuberculosis may often decline drug therapy to prevent the disease from becoming active, a new study suggests.

The study, which followed patients with latent TB at 32 U.S. and Canadian medical clinics, found that 22 of 53 healthcare workers who were offered treatment declined to take it.

Of all 720 patients in the study, 17 percent refused drug therapy to ward off active TB.

Compared with other study patients, healthcare workers — all employees of a hospital or nursing home — were nearly five times as likely to decline treatment, according to findings published in the medical journal Chest.

Latent TB refers to a chronic, but symptomless and non-contagious, infection with TB bacteria; it is detected through tuberculin skin testing. Such TB infections are common throughout the world because in most people, the immune system is able to suppress TB bacteria. Up to 15 million Americans are estimated to have latent TB infection.

The danger with latent TB is that it can become active; active TB usually attacks the lungs, causing symptoms such as a severe cough, chest pain and weight loss. It can also spread through the air from person to person.

The U.S. Centers for Disease Control and Prevention (CDC) recommends treatment of latent TB in people who are at high risk of progressing to active infection, including people whose immune systems are compromised — due to HIV or immune-suppressing medications, for instance.

Treatment is also recommended for people who could easily spread the disease if it becomes active — such as prison inmates and patients and employees at hospitals and nursing homes.

It’s not clear why healthcare workers in this study were more likely than other people to decline drug treatment. One possibility is that they felt their risk of developing active TB was not significant, according to lead researcher Dr. C. Robert Horsburgh Jr., of the Boston University School of Public Health.

The average risk of developing full-blown TB disease is roughly one in 20, Horsburgh told Reuters Health in an email.

“It may also be that they are more concerned about side effects of the medicines used to treat latent TB,” he said, “since they see side effects of medications every day in the patients they take care of.”

Treatment of latent TB lasts for months. The standard therapy is a drug called isoniazid, usually prescribed as a nine-month course. Another option is a four-month regimen of a medication called rifampin.

The more common side effects of isoniazid include stomach upset and diarrhea; the drug has also been linked to cases of sometimes severe liver damage. Rifampin may cause symptoms such as stomach upset, nausea and headache.

In their study, Horsburgh and his colleagues found that healthcare workers, besides being more likely to decline treatment, were at increased risk of failing to complete treatment. Of the 209 prescribed treatment, 125 did not finish the full course.

Residents of congregate settings — nursing homes, shelters and prisons — were also at increased risk of not completing drug treatment.

One factor that did boost treatment compliance overall, however, was shorter therapy.

Most study patients who accepted treatment were placed on nine months of isoniazid, but those given four months of rifampin were more likely to complete treatment — about 65 percent did, versus roughly 45 percent of those on isoniazid.

The implication, according to Horsburgh’s team, is that shorter courses of therapy would encourage more patients to comply. They point out, though, that the effectiveness of the four-month rifampin therapy has not yet been tested in large clinical trials.

An ongoing clinical trial is testing the effectiveness of a three-month course of isoniazid plus another drug, rifapentine.

“I hope that new regimens of three months…or less will be shown to be effective and will replace the current regimens,” Horsburgh said.

The study was funded by the CDC; one of the co-researchers has received grants from Pfizer, which makes the TB drug Mycobutin (rifabutin), and Oxford/Immunotec, which makes a blood test for TB.

A new clot-busting drug, Brilinta, may soon take the place of Plavix in treating patients with acute coronary syndrome, which includes angina and heart attack.

In a new trial, the upstart drug, ticagrelor (Brilinta) reduced the risk of second heart attacks and death without raising the risk of bleeding, as clopidogrel (Plavix) can do.

“For people with acute coronary syndrome, this very well may replace Plavix,” said study author Dr. Christopher Cannon, a cardiologist with Brigham and Women’s Hospital and an associate professor of medicine at Harvard Medical School, both in Boston. “This is pretty compelling evidence from this trial that ticagrelor is better without any increased risk of bleeding.”

An accompanying editorial concurred, while also pointing out that, as always, a “personalized approach to drug selection should be used.”

The study is published in the Jan. 14 online edition of The Lancet.

Approval for Brilinta from the U.S. Food and Drug Administration could come late this year, although it’s difficult to predict the timing of such decisions, Cannon noted.

The study was funded by AstraZeneca, which makes Brilinta. Earlier results from the trial were presented at several major medical conferences last year. These published results seem to be the final step in solidifying the ascendancy of the new drug over the mainstay, Plavix.

Combined with other blood-thinning therapies now in the pipeline, these findings may also mark the dawn of a new generation of blood thinners, experts say.

Plavix is used with aspirin to prevent blood clots that can lead to heart attacks, stroke and death. It has been the standard of treatment for heart patients for about a decade, Cannon said.

But the drug has its share of problems, namely a lag time between when it is administered and when it takes effect, and variability in how different individuals respond to it. And because of an increased risk of bleeding, Plavix must be discontinued before surgery, Cannon said.

In this study of more than 13,000 patients with acute coronary syndrome, Brilinta, which appears to be more potent than Plavix, emerged with several advantages over the old standby.

Because it is processed as soon as it’s swallowed (meaning it doesn’t have to go through the liver), Brilinta kicks in faster than Plavix, Cannon explained.

“It’s a more reliable level of anti-clotting effect. There’s less variability,” he stated. “At the dose we’ve chosen, it has about twice the level of anti-clotting effect, hence its benefit in preventing heart attacks and stent thrombosis [closure].”

And unlike Plavix, Brilinta is quickly reversible: When you stop taking it, it stops working, whereas Plavix binds to platelets for as long as they are around, Cannon noted. This means patients could have surgery with a lower risk of bleeding.

The authors estimated that for every 1,000 patients using Brilinta instead of Plavix for one year, there would be 11 fewer deaths, 13 fewer heart attacks and six fewer cases of blocked stents.

Drug maker Sanofi-Aventis, which markets Plavix in a partnership with Bristol-Myers Squibb, stood by the safety record of its product.

“Ticagrelor is an investigational drug, and has not been approved by any regulatory authorities,” the company said in a statement released Wednesday. “Ticagrelor’s efficacy and safety have been studied in a clinical trial setting in the ACS [acute coronary syndrome] population, and in the real-world setting the efficacy and safety is still unknown.”

“The effectiveness of Plavix has been proven, and the safety profile supported by four large clinical studies involving 81,000 patients across the entire spectrum of its approved cardiovascular indications,” the statement continued. “Plavix has been prescribed to more than 100 million patients worldwide during the 11 years it has been on the market. Plavix is recommended in national and international guidelines for heart attack, stroke and/or PAD [peripheral arterial disease] patients at risk for future atherothrombotic events, and is an important treatment option for millions of patients at cardiovascular risk.”

However, one expert was impressed by the latest findings on Brilinta.

“This were top-line results,” said Dr. Kirk Garratt, clinical director of interventional cardiovascular research at Lenox Hill Hospital in New York City. “It’s important that, for the first time, we have a drug that is not only more powerful in its ability to control platelet behavior but able to do that without increasing bleeding. That’s astonishing.”

Still, enthusiasm may need to be tempered, he said.

Garratt pointed out that the vast majority of participants in the trial came from Europe, the Middle East and Africa, not North America. “And in that group of North American patients there was no benefit for ticagrelor,” he said. “It could just be play of chance but you can’t get around the fact that when the population was [studied] separately, there was no benefit.”

Secondly, Brilinta needs to be taken twice a day to maintain its effect, not once daily as with Plavix.

“No matter how good you are about medicines, you’re going to miss some,” Garratt.

This, added to the fact that the drug stops working if you stop taking it, means that a person who forgets his or her medication at night could see their risk for heart trouble rise by the morning.

“When it’s morning again, you not only have made new platelets [which happens continuously] but the old platelets are springing back to life and people are most likely to form blood clots in the early morning hours,” Garratt said. “I’m a little concerned about a drug that could leave a patient really unprotected in the early morning hours when they’re most likely to form blood clots if they miss the evening dose, which will happen.”

SOURCES: Christopher P. Cannon, M.D., cardiologist, Brigham and Women’s Hospital, and associate professor, medicine, Harvard Medical School, Boston; Kirk Garratt, M.D., clinical director, interventional cardiovascular research, Lenox Hill Hospital, New York City;

Questioning the theory that prenatal exposure to the flu virus might be a risk factor for schizophrenia, a new study finds no link between the flu pandemic of 1957 and later schizophrenia rates.

In an analysis of studies from Europe, Australia, Japan and the U.S., researchers found no higher-than-normal risk of schizophrenia among people born in the nine months after the 1957 flu pandemic.

The findings, reported in the Schizophrenia Bulletin, conflict with those from some earlier studies linking the same pandemic to a heightened schizophrenia rate.

While the exact causes of schizophrenia are not clear, it is considered a disorder of disrupted brain development, and researchers have long believed that schizophrenia arises from a combination of genetic susceptibility and environmental factors.

Among the suspected environmental factors is fetal exposure to a mother’s infection during pregnancy, with the influenza virus being one of the potential culprits.

The first evidence came from a 1988 Finnish study that found an increased rate of schizophrenia among people who were in the womb at the time of the 1957-58 Asian flu pandemic that killed about 2 million people worldwide.

Since then, studies have come to conflicting findings as to whether prenatal flu exposure might contribute to schizophrenia. However, some smaller studies that have used mothers’ blood samples to measure flu exposure during pregnancy have supported a link.

One theory is that inflammatory substances released in the mother’s blood in response to the infection may cross the placenta and affect fetal brain development in a way that makes the child more vulnerable to developing schizophrenia later in life.

These latest findings, however, “do not support this hypothesis,” report the researchers, led by Dr. Jean-Paul Selten of the University Medical Center Utrecht in the Netherlands.

The results are based on 11 international studies that compared rates of schizophrenia among people who were in the womb during the 1957-58 pandemic with those of people born within the few years before and after the outbreak.

The researchers also analyzed two studies that included women who were pregnant and reported having the flu during the pandemic.

Overall, Selten’s team found no increased schizophrenia risk among people who were in the womb during the flu pandemic, at any trimester of pregnancy.

According to the researchers, the original Finnish study that focused on the 1957 pandemic used an “inappropriate statistical method” to arrive at its conclusions. Their re-analysis of that data, they add, uncovered no increased risk of schizophrenia.

“We conclude that the evidence to support the maternal influenza hypothesis is insufficient,” the researchers write.

SOURCE: Schizophrenia Bulletin

Paramedics often work quickly to stabilize the spines of trauma patients, to avoid a broken neck or other problems, but new research suggests that practice could double the likelihood that gunshot and stabbing victims will die if they aren’t taken immediately to a trauma center instead.

The researchers, who report their findings in the January issue of the Journal of Trauma, noted that spine immobilization is encouraged in some states for victims of gunshot and stabbing wounds. Paramedics place the patients in cervical collars and secure them on boards.

“If you’re twice as likely to die, that seems like a bad thing to do,” study leader Dr. Elliott R. Haut, an assistant professor of surgery at the Johns Hopkins University School of Medicine, said in a news release from the school. “We like to use interventions that preserve life.”

Although it may seem counterintuitive, the study authors reported that those who are least injured by gunshot and stabbing are most likely to die if paramedics spend time immobilizing their spines.

“The patients who are very, very severely injured from their penetrating trauma are going to die no matter what you do,” Haut said. “But if someone is stabbed in the lung or shot in the liver, what we do for them and how fast we do it makes a huge difference. That time difference in getting them to the hospital for treatment may make the difference between life and death.”

The researchers came up with their conclusions after reviewing data about more than 45,000 trauma patients who were injured from 2001 to 2004.

SOURCE: Johns Hopkins Medicine, news release

Study examines potential for injury when doctors decide benefits of imaging outweigh the risks

MRI scans can pose a serious risk to people with heart pacemakers, researchers warn.

U.S. Food and Drug Administration researchers exposed pacemakers to a simulated MRI magnetic field and then measured the electrical voltage produced at the tip of the pacemaker lead, where it would touch the interior of the patient’s heart.

The exposure to MRI magnetic pulses caused certain pacemakers to deliver a drastically altered pulse and stimulate the heart inappropriately, which could have serious consequences for a patient, the study authors reported in the Dec. 14 edition of BioMedical Engineering OnLine.

“MRI systems emit several types of extremely intense magnetic fields and have caused injury to patients due to interactions with pacemakers,” study author Howard Bassen said in a news release from the journal’s publisher. “Cardiologists who choose to scan patients with cardiac pacemakers must assess the risks versus the benefits of the scan. This paper identifies one more risk.”

About 40 million MRI scans are performed annually in the United States, where 10 million people have pacemakers.

Study examines potential for injury when doctors decide benefits of imaging outweigh the risks
Pacemaker and MRI manufacturers instruct physicians not to expose patients with pacemakers to MRI scans, which can disrupt a pacemaker’s electronic system and burn heart tissue at the tip of the pacemaker lead.

But, despite these instructions, some cardiologists have developed special protocols that describe how to perform MRI scans on patients with pacemakers. Their belief is that the diagnostic benefits of MRI outweigh the pacemaker malfunction risks.