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Painkillers Increase Risk of Erectile Dysfunction

2013-05-15T18:56:00.001-07:00

Painkillers Increase Risk of Erectile Dysfunction

Regularly taking prescription painkillers, commonly called opioids, is linked to a greater risk of erectile dysfunction (ED) in men, according to a new study published in Spine.

Over 11,000 men suffering from back pain were involved in the research. The health records of the participants were analyzed to determine whether males taking prescription opioids were more likely to also receive prescriptions for testosterone replacement or ED medications.

The investigators found that over 19% of males who took high-dose opioids for 4 months or more were also given ED prescriptions, while fewer than 7% of males who did not take painkillers received prescriptions for ED.

Over 12% of men who took low-dose opioids for four months or more also received ED prescriptions or testosterone replacement.

Age was the factor most notably linked to receiving ED prescriptions. The men in the study over the age of 60 had a much higher probability of receiving ED prescriptions.

"Men 60 to 69 (years old) were 14 times more likely to receive prescriptions for ED medication than men 18 to 29," the researchers said.

Depression, other health problems (other than back pain), and use of sedative hypnotics, such as benzodiazepines, also raised the probability that men would receive prescriptions for ED.

However, the authors explained, even after adjusting for those factors, men with high-dose opioid use and males with long-term opioid use still had a 50% increased likelihood of recieving ED prescriptions than those who did not take opioids.

Leading author Richard A. Deyo, MD, MPH, investigator with the Kaiser Permanente Center for Health Research and Professor of Evidence-based Family Medicine at Oregon Health & Science University, said:

"Men who take opioid pain medications for an extended period of time have the highest risk of ED. This doesn't mean that these medications cause ED, but the association is something patients and clinicians should be aware of when deciding if opioids should be used to treat back pain."

According to the CDC (Centers for Disease Control and Prevention), the use of prescription painkillers is on the rise in the U.S. The Mortality and Morbidity Report by the CDC revealed that prescription opioid sales experienced a fourfold increase between 1999 and 2010.

A different report, published in the journal Pain, indicated that about 4.3 million Americans use opioid drugs on a regular basis.

The most commonly used prescription opioids include:

oxycodone
morphine
hydrocodone

Deyo said:

"There is no question that for some patients opioid use is appropriate, but there is also increasing evidence that long-term use can lead to addiction, fatal overdoses, sleep apnea, falls in the elderly, reduced hormone production, and now erectile dysfunction."

A CDC report from 2011 found that more Americans die each year from prescription painkiller overdoses than the combined total for cocaine and heroin.

Deyo and his team studied 11,327 men in Oregon and Washington registered for the Kaiser Permanente health plan who saw a doctor for back pain during 2004.

The subjects' pharmacy records for 6 months before and after their doctor's visit for back pain were analyzed to determine whether they had received prescriptions for opioids and for ED or testosterone replacement.

Prescription painkiller use was categorized as:

none - men who did not receive an opioid prescription
acute - men who took opioids for 3 months or less
episodic - men who took opioids for longer than 3 months, but less than 4 months and with fewer than 10 refills
long-term - men who took opioids for at least four months, or more than 3 months with 10 or more refills

High-dose use was considered anything over 120 mg of morphine equivalent, and low-dose use was considered under 120 mg.

A 2011 study published in the British Journal of Urology International showed that erectile dysfunction is linked to how many different medications are taken.

Hysterectomy Does Not Raise Heart Risk

2013-05-15T18:54:00.002-07:00

Hysterectomy Does Not Raise Heart Risk

Contrary to some previous research, a new study from the US finds women's risk of cardiovascular disease does not go up after having a hysterectomy in mid-life, with or without ovary removal. The risk is no higher than that faced by women who reach the menopause naturally, says the new study.

Lead author Karen A. Matthews of the University of Pittsburgh, and colleagues, write about their findings in a report due to be published online this week in the Journal of the American College of Cardiology.

Matthews, who is a distinguished professor of psychiatry and professor of epidemiology and psychology at Pittsburgh, declares in a press statement that the results should be encouraging to middle-aged women considering a hysterectomy:

"... our results suggest that increased levels of cardiovascular risk factors are not any more likely after hysterectomy relative to after natural menopause," says Matthews.

Hysterectomy and Risk of Cardiovascular Disease

Hysterectomy is a common surgical procedure that removes a woman's uterus. Sometimes she also has her ovaries removed, usually to reduce risk of ovarian cancer.

However, while the need for such a procedure may be obvious, for instance because of cancer, prolapsed uterus, fibroids, or because of very heavy and painful periods, as with all surgery, the benefits have to be weighed against the risks.

Because of changes to hormones, one of the effects of having a hysterectomy before the menopause is that it usually brings on the menopause earlier.

Some previous studies have suggested hysterectomy raises long term risk of cardiovascular disease, which is the number one killer of women. And they have inferred that the risk is even higher if ovaries are also removed.

But there are objections to this view, mainly because those studies tended to evaluate cardiovascular disease risk factors years after hysterectomy and/or ovary removal without taking into account what they might have been before surgery.

What the Researchers Did

For this new study, Matthews and colleagues followed 3,302 premenopausal women in the US for 11 years. The women were taking part in the Study of Women's Health across the Nation (SWAN).

At the start of the study period, when the women enrolled on SWAN, they were between 42 and 52 years of age, had an intact uterus, at least one ovary, and were not taking hormone therapy.

They underwent assessments every year over the follow up, during which time the majority reached the menopause naturally, some had hysterectomy with ovary removal, and some had hysterectomy without ovary removal.

The main reasons for hysterectomy were fibroids, heavy periods, and chronic pelvic pain.

The researchers assessed cardiovascular disease risk factors in the participants before and after hysterectomy, and compared this to the risk factors before and after the final menstrual period in those who went through the menopause naturally.

Matthews and colleagues say their study is the first multiethnic study to track prospective annual changes in cardiovascular disease risk factors relative to hysterectomy or natural menopause.

What They Found

The analysis showed that while some of the before and after individual cardiovascular risk factors changes were different for hysterectomy compared to natural menopause, overall, the pattern of changes did not suggest an increase in cardiovascular risk following hysterectomy say the researchers. And this was the same in all ethnic groups.

Plus, this was the case even after adjusting for possible influencers like Body Mass Index (BMI), which did go up after hysterectomy with ovary removal.

What the Reasons Might Be

Mathews says they are not sure why their findings disagree with earlier studies that suggest hysterectomy raises cardiovascular disease risk.

One reason could be because they did not include younger women, and hysterectomy that occurs earlier in life may result in higher cardiovascular disease risk.

Another reason, says Matthews, could be that this study excluded women who had hysterectomies because of cancer.

SWAN is co-sponsored by the National Institute on Aging, the National Institute of Nursing Research, the National Institutes of Health, Office of Research on Women's Health, and the National Center for Complementary and Alternative Medicine.

In 2011, writing in the journal Archives of Internal Medicine, researchers from the University of California at San Francisco reported finding women who underwent hysterectomy with ovary removal had a reduced risk of developing ovarian cancer, and no higher risk of developing other types of cancer, heart disease or hip fractures.

Researchers Develop An Algorithm To Predict How And When Proteins Misfold

2012-02-25T04:25:00.001-08:00

Several neurodegenerative diseases - including Alzheimer's and ALS (Lou Gehrig's disease) - are caused when the body's own proteins fold incorrectly, recruit and convert healthy proteins to the misfolded form, and aggregate in large clumps that gum up the works of the nervous system. "For Star Trek fans, this is like the Borg, [a fictional race of cyborgs that abduct and assimilate humans and other species]," says Steven Plotkin, a biophysicist at the University of British Columbia in Vancouver who studies the process of protein misfolding.

Plotkin's team has developed an algorithm that can predict which regions of a protein are prone to exposure upon misfolding, and how mutations in the protein and changes in the cellular environment might affect the stability of these vulnerable regions. These predictions help scientists gain a better understanding of protein dynamics, and may one day help in developing treatments to effectively combat currently incurable neurodegenerative diseases. The team will present its findings at the 56th Annual Meeting of the Biophysical Society (BPS), held Feb. 25-29 in San Diego, Calif.

The algorithm developed by Plotkin's group uses the energy equations of thermodynamics to calculate the likelihood that certain stretches of protein will be displayed when the protein misfolds. Since the exposed regions are specific to the misfolded version of the protein, researchers can use these regions as targets for diagnostic and therapeutic treatments. The algorithm can be adapted for different proteins and predicts several potential target regions for each protein. The group has used it to study neurodegenerative disease-causing proteins as well as misfolded proteins that have been implicated in some cancers.

More recently, the research group used computer simulations to manipulate proteins in a virtual environment, testing out how easy it is for mutated proteins to misfold and propagate. Using this tool has helped the team predict the progression of hereditary ALS disease.

"The fact that we can predict the lifetime of an individual diagnosed with hereditary ALS from simulations of a protein's mechanical properties is something that is both satisfying and that gives one pause," says Plotkin. "We hope that such information might give some clues as to how to develop effective therapies for this disease."

Stem Cell Development Triggers Memory

2012-02-25T04:24:00.007-08:00

Researchers at the RIKEN-MIT Center for Neural Circuit Genetics have discovered an answer to the long-standing mystery of how brain cells can both remember new memories while also maintaining older ones.

They found that specific neurons in a brain region called the dentate gyrus serve distinct roles in memory formation depending on whether the neural stem cells that produced them were of old versus young age.

The study will appear in the March 30 issue of Cell and links the cellular basis of memory formation to the birth of new neurons - a finding that could unlock a new class of drug targets to treat memory disorders.

The findings also suggest that an imbalance between young and old neurons in the brain could disrupt normal memory formation during post-traumatic stress disorder (PTSD) and aging. "In animals, traumatic experiences and aging often lead to decline of the birth of new neurons in the dentate gyrus. In humans, recent studies found dentate gyrus dysfunction and related memory impairments during normal aging," said the study's senior author Susumu Tonegawa, 1987 Nobel Laureate and Director of the RIKEN-MIT Center.

Other authors include Toshiaki Nakashiba and researchers from the RIKEN-MIT Center and Picower Institute at MIT; the laboratory of Michael S. Fanselow at the University of California at Los Angeles; and the laboratory of Chris J. McBain at the National Institute of Child Health and Human Development.

In the study, the authors tested mice in two types of memory processes. Pattern separation is the process by which the brain distinguishes differences between similar events, like remembering two Madeleine cookies with different tastes. In contrast, pattern completion is used to recall detailed content of memories based on limited clues, like recalling who one was with when remembering the taste of the Madeleine cookies.

Pattern separation forms distinct new memories based on differences between experiences; pattern completion retrieves memories by detecting similarities. Individuals with brain injury or trauma may be unable to recall people they see every day. Others with PTSD are unable to forget terrible events. "Impaired pattern separation due to the loss of young neurons may shift the balance in favor of pattern completion, which may underlie recurrent traumatic memory recall observed in PTSD patients," Tonegawa said.

Neuroscientists have long thought these two opposing and potentially competing processes occur in different neural circuits. The dentate gyrus, a structure with remarkable plasticity within the nervous system and its role in conditions from depression to epilepsy to traumatic brain injury - was thought to be engaged in pattern separation and the CA3 region in pattern completion. Instead, the MIT researchers found that dentate gyrus neurons may perform pattern separation or completion depending on the age of their cells.

The MIT researchers assessed pattern separation in mice who learned to distinguish between two similar but distinct chambers: one safe and the other associated with an unpleasant foot shock. To test their pattern completion abilities, the mice were given limited cues to escape a maze they had previously learned to negotiate. Normal mice were compared with mice lacking either young neurons or old neurons. The mice exhibited defects in pattern completion or separation depending on which set of neurons was removed.

"By studying mice genetically modified to block neuronal communication from old neurons -- or by wiping out their adult-born young neurons - we found that old neurons were dispensable for pattern separation, whereas young neurons were required for it," co-author Toshiaki Nakashiba said. "Our data also demonstrated that mice devoid of old neurons were defective in pattern completion, suggesting that the balance between pattern separation and completion may be altered as a result of loss of old neurons."

The Number Of GP Visits Before Cancer Patients Are Referred To Specialists Examined By Study

2012-02-25T04:24:00.005-08:00

More than three quarters (77%) of cancerpatients who first present to their family doctors (GPs) with suspicious symptoms are referred to hospital after only one or two consultations, a new study has found. However, the new research also shows a wide variation in the number of times a cancer patient sees their general practitioner before they are referred to a specialist, with the most pre-referral consultations occurring when the cancer was one of the less common types, or when the patient was either female, young, or an older person from an ethnic minority. The research was published 24 February, in the journalThe Lancet Oncology.

The study, led by researchers at the University of Cambridge, found that patients with breast,melanoma, testicular and endometrial cancers are more likely to be referred to a specialist after just one or two consultations. However, patients with some less common cancers such asmultiple myeloma, pancreatic, stomach and ovarian cancer, as well as patients with lung andcolon cancers and lymphomas are more likely to require three or more visits to their family doctor before they are referred to a hospital specialist. Patients with multiple myeloma, a blood cancer that is notoriously difficult to diagnose since it mimics many other conditions, are 18 times more likely to require three or more pre-referral consultations compared with patients withbreast cancer.

"These findings highlight limitations in current scientific knowledge about these cancers," said lead investigator Dr Georgios Lyratzopoulos, Clinical Senior Research Associate at the University of Cambridge. "Medical research in recent decades has prioritised improving cancer treatments, but knowledge about the 'symptom signature' of common cancers and practical solutions on how best to diagnose them is still emerging. Hopefully, our study will stimulate investment into research, focusing on patients with cancers and characteristics where the potential to improve the experience of diagnosis of cancer is greatest."

The researchers have also found that the diagnosis of cancer is more challenging among young patients, women, and older ethnic minority patients - all of these three groups are known to have a lower risk of developing cancer compared with older, male and white patients in the United Kingdom.

These findings amplify similar patterns first reported by co-author Dr Richard Neal, Senior Lecturer in General Practice at Bangor University, among cancer patients who took part in a similar survey that was carried out in 2000. Dr Neal said: "The fact that the diagnosis of cancer may be more challenging in some patient groups and for some cancers can help us to tailor diagnostic efforts. The findings will also inform the forthcoming update of the NICE Guidelines for Referral of Suspected Cancer, which will have an important impact on policy and practice."

The researchers proposed some explanations as to why some of the patient groups were less likely to receive a prompt referral:

As differences in ethnic minorities were only apparent for older patients, they indicate that communication difficulties may be responsible.
For bladder cancer, women were more than twice as likely as men to have required three or more consultations with their doctor before a decision to refer to hospital was made. In women, there may be difficulties in discriminating symptoms and signs of bladder cancer from those of benign gynaecological conditions or bladder infection.
As young people have a lower rate of cancer, the researchers believe GPs are less likely to consider cancer as a possibility.

The research used data from more than 41,000 patients with 24 different cancers who took part in the English National Cancer Patient Experience Survey 2010. (The UK government has indicated that patient experience is a critical aspect of measuring care quality.) The researchers examined variation in the number of general practitioner consultations with cancer symptoms before hospital referral to diagnose cancer.

"Whilst doctors may have concerns about the accuracy of patient-reported data, we have good reasons to believe the validity of our findings", said co-author Greg Rubin, Professor of General Practice and Primary Care at Durham University. "This is because they correlate well with data collected by general practitioners who took part in the independent National Audit of Diagnosis of Cancer in Primary Care. We hope further strides towards diagnosing cancer earlier will be made through the use of both patient experience and clinical audit data."

In order to improve the promptness of referrals, the study makes recommendations for both clinicians and policy makers. For clinicians, they highlight the need to be more aware of some of the patient groups and cancers which tended to be diagnosed less promptly and the need to participate in data collection to benchmark their practice. They also suggest that policy makers 'should explore and evaluate physician-level educational interventions, further development of point-of-care decisions aids, risk calculators and diagnostic tests, and system re-design to enable greater appropriate and timely use of specialist diagnostic tests (such as imaging or endoscopy)'.

Although the researchers are based in the UK, they believe their findings have implications for other countries as well, as they reflect the difficulties of diagnosis cancers with non-specific symptoms and signs more generally. Most patients subsequently diagnosed with cancer first see a doctor in the community regardless of where they live.

Exploiting A Weakness In Cancer's Defense System

2012-02-25T04:24:00.003-08:00

Researchers at the EPFL have identified an important mechanism that could lead to the design of more effective cancer vaccines. Their discovery of a new-found role of the lymphatic system in tumour growth shows how tumours evade detection by using a patient's own immune system.

Tumour cells present antigens or protein markers on their surfaces which make them identifiable to the host immune system. In the last decade, cancer vaccines have been designed that work by exposing the patient's immune cells to tumour-associated antigens and so priming them to kill cells that present those antigens. These have caused much excitement, not least because by acting so specifically on cancer cells, they could potentially eliminate the unpleasant side effects of chemo- and radiotherapy.

Like soldiers protecting a fort

However, clinical trials of such vaccines have had a very low success rate to date, mainly because tumours have various mechanisms for evading detection by immune cells, even when those immune cells - called T cells - have been primed to seek them out. Those mechanisms are, in general, poorly understood. But in a paper to be published this week in Cell Reports, the laboratories of Melody Swartz at EPFL and Stéphanie Hugues at UNIGE provide a key insight into one of them. They describe for the first time how, like soldiers protecting a fort, lymph vessels surrounding a tumour ward off T cell attack.

Plenty of research has shown that tumours can induce the growth of lymph vessels in their vicinity, and that this growth is correlated with metastasis and poor prognosis. It was assumed that these lymph vessels simply provided an escape route for cancer cells, transporting them to distant sites. In the new study, led by postdoc Amanda Lund, the researchers show that lymph vessels actually suppress the immune response, deleting the attacking T cells or leaving them "functionally exhausted" by the time they reach the tumour.

They studied a type of tumour that expresses large amounts of VEGF-C, a molecule that is naturally expressed in humans and that stimulates lymphatic growth. Having engineered the tumour cells to express a foreign antigen, they compared the efficacy of a vaccine designed to prime T cells to kill cells carrying that antigen, either when VEGF-C was present or when its activity was blocked . With VEGF-C suppressed, the vaccine's efficacy increased and tumour growth slowed fourfold.

A weakness in cancer's defense system exploited

The researchers went on to show that the endothelial cells which line lymph vessels "scavenge" tumour-specific antigens and present them to the tumour-specific T cells in a suppressive manner. This, in turn, promotes the local deletion of those T cells. According to Prof Swartz, that means that first targeting the lymph vessels associated with a tumour could, in theory, significantly increase the efficacy of existing cancer vaccines. "It would be like removing the soldiers from around the fort before sending in your opposing army," she says. "If you disable the lymph vessels' suppressive functions, our data suggest that tumour-killing T cells would do their job a lot more effectively." Future clinical trials are needed to put that theory to the test.

Discovery Of Genetic Risk For Elevated Arsenic Toxicity

2012-02-25T04:24:00.001-08:00

One of the first large-scale genomic studies conducted in a developing country has discovered genetic variants that elevate the risk for skin lesions in people chronically exposed to arsenic. Genetic changes found near the enzyme for metabolizing the chemical into a less toxic form can significantly increase an individual's risk for developing arsenic-related disease.

The discovery could point the way to new screening and intervention options for people who are exposed to groundwater with high levels of arsenic, said scientists at the University of Chicago Medicine, Columbia University, and in Bangladesh in a study published in PLoS Genetics.

"These results add clarity to the genetic architecture that is playing a role in arsenic toxicity and its underlying biology," said senior author Habibul Ahsan, MD, MMedSc, Louis Block Professor of health studies, medicine and human genetics at the University of Chicago Medicine. "It's a rare type of study for a major problem affecting millions of people around the world, and it opens up opportunities for genetic studies of other major public health problems in developing countries."

The group's genome-wide association study, or GWAS, was conducted in nearly 3,000 individuals exposed to arsenic for decades in Bangladesh. Since the widespread installation of hand-pumped wells to tap groundwater sources in the 1970s, as many as 77 million people - about half the population of Bangladesh - have been accidentally exposed to dangerous levels of arsenic. The World Health Organization calls the exposure "the largest mass poisoning of a population in history."

For more than a decade, Ahsan and colleagues have studied the epidemiology of arsenic-related disease, such as skin lesions, diabetes, and respiratory illnesses, in this population, as well as the effectiveness of interventions to prevent toxicity. In the new study, funded by the National Institute of Environmental Health Sciences and the National Cancer Institute, the researchers sought genetic answers for why some individuals appear to be at higher risk for developing disease after arsenic exposure.

"Whatever the source of exposure, different individuals vary with respect to their susceptibility to the toxicity of arsenic," Ahsan said. "Even if they consume or are exposed to arsenic at the same dose and duration, some individuals will manifest toxicity phenotypes and others won't."

Researchers genotyped thousands of arsenic-exposed individuals from the group's main studies for single nucleotide polymorphisms (SNPs) throughout the genome, and looked for associations with arsenic metabolite levels and risk of skin lesions.

After ingestion, the body metabolizes inorganic arsenic into first monomethylarsonic acid (MMA) and then dimethylarsinic acid (DMA). MMA is considered to be more toxic, while DMA is water-soluble and more easily excreted. Higher levels of DMA or lower levels of MMA measured from an individual's urine are associated with lower toxicity.

A research team led by Ahsan and Brandon Pierce, PhD, an assistant professor of epidemiology at the University of Chicago Medicine, then used GWAS to search for SNPs associated with DMA and MMA levels. They found several significant genetic variants in the region of a likely candidate gene: arsenite methyltransferase (As3MT), an enzyme critical for arsenic metabolism. A second GWAS looking for SNPs associated with the development of skin lesions after arsenic exposure, pointed to many of the same variants. In a further study of gene expression levels, those same SNPs were associated with reduced expression of the arsenic metabolizing enzyme.

"This makes perfect sense," Ahsan said. "It gives us a very coherent story that we can now investigate in relation to other arsenic pathologies and in relation to a wide range of arsenic doses in this population."

"Now that we understand the molecular basis of some of this disease risk, it is conceivable to now think of incorporating this information into testing, evaluating, or potentially coming up with successful biomedical interventions," Ahsan continued. "By exploiting these metabolic pathways for a subgroup of individuals who will really be at higher risk for getting those diseases, we may be able to reduce fatal outcomes in this population."

The genetic findings provide strong evidence that efficient metabolism of arsenic through methylation protects against the toxin. Compounds that boost methylation, such as folic acid, could reduce arsenic toxicity - a strategy currently being tested by co-author Mary Gamble, PhD, associate professor of Environmental Health Sciences at Columbia University.

"If we could somehow find a way to do that in Bangladesh, it would make individuals much better methylators of arsenic, and as this current study shows if you're a better methylator you're at a lower risk for disease," said co-author Joseph Graziano, PhD, Professor of Environmental Health Sciences and Director of Superfund Research Program at the Mailman School of Public Health of Columbia University.

Risk variants may also help assess the potential toxicity of cancer chemotherapies which use arsenic or related compounds. SNPs associated with elevated sensitivity to arsenic toxicity could steer oncologists toward lower doses or alternative treatments in certain cancer patients, Ahsan said.

Beyond the clinical applications, the current study demonstrates that large-scale genomic studies are possible in a largely rural population of a developing country. The study offers a rare example of a GWAS result with clear, immediate potential for translational impact.

"Many genomic signals that we see are not robust enough or do not pertain to a large population," Ahsan said. "But in this study, that is not the case. The finding is robust, and the impact is massive."

Confirming The Efficacy Of CT Colonography As A Front Line Colorectal Cancer Screening Tool For Seniors

2012-02-25T04:23:00.004-08:00

Computerized tomographic (CT) colonography (CTC), also known as virtual colonoscopy, is comparable to standard colonoscopy in its ability to accurately detectcancer and precancerous polyps in people ages 65 and older, according to a paper published online in Radiology. This is consistent with results of the ACRIN National CT colonography Trial, published in the New England Journal of Medicine in 2008, which demonstrated CT colonography can serve as a primary colorectal cancer screening option for adults ages 50 and older, but did not specifically break out data for participants ages 65 and older included in the overall analysis. The Centers for Medicare and Medicaid Services has deferred coverage for CT colonography primarily citing a lack of data on the exam's performance in Medicare-eligible recipients ages 65 and older.

"Our goal in carrying out this secondary analysis was to determine if the accuracy of CT colonography to detect polyps of clinical concern in patients 65 and older is comparable to the test's accuracy for the 50 and over population studied in the 2008 ACRIN trial. We found no significant difference in the screening exam's performance between the two age groups," said C. Daniel Johnson, MD, of the Mayo Clinic in Scottsdale, AZ and principal investigator of the National CT Colonography Trial and the paper's primary author. "CT colonography is a perfectly viable colorectal cancer screening tool for the traditional Medicare age population. Wider availability made possible by Medicare coverage of CT colonography would attract more seniors to be screened for colorectal cancer - which is so successfully treated when detected early. Making CT colonography more available to seniors ultimately could save lives," summarizes Johnson.

The National CT Colonography Trial recruited 2,600 study participants ages 50 and over from 15 US medical centers to compare the accuracy of state-of-the-art CT colonography to the gold standard of conventional colonoscopy. Ninety percent of the polyps 1 centimeter or larger - the polyps most likely to become cancerous - were detected by CT colonography. Polyps as small as one-half centimeter were also detected by CT colonography with a high degree of accuracy.

In the secondary analysis of the 65 and over cohort, data were available for 477 study participants. The percentage of participants with large polyps was significantly greater among the older participant group (3.7% for aged < 65 vs. 6.9% for > 65); however, even if intermediate-sized polyps of 6mm or larger were targeted for removal with standard colonoscopy, the colonoscopy referral rate would not exceed 12.6 percent.

ACRIN Chair Mitchell J. Schnall, MD, PhD, Matthew J. Wilson Professor of Research Radiology at the University of Pennsylvania, comments, "These results demonstrate the wealth of data that are collected in ACRIN clinical trials that can be used to explore important cancer screening and other research questions. For example, ACRIN has undertaken another study leveraging the National CT Colonography Trial data investigating the prevalence and type of incidental findings reported as part of a CT colonography examination to better understand their impact and to develop guidelines for the reporting and management incidental findings."

CT colonography employs virtual reality technology to produce a three-dimensional visualization that permits a thorough and minimally invasive evaluation of the entire colon and rectum. The ACRIN trial is the largest multi-center study to compare the accuracy of state-of-the-art CT colonography to the gold standard of conventional colonoscopy in patients 50 and older. Colorectal cancer is the third most frequently diagnosed cancer and second leading cause of cancer death in men and women in the United States. Yet, despite the known benefits of screening, studies indicate that millions of Americans age 50 and older are not being screened for the disease.

Disarming The Botulinum Neurotoxin

2012-02-25T04:23:00.001-08:00

Sanford-Burnham researchers determine the first 3-D structure of the botulinum neurotoxin, together with the protein bodyguard that guides it through the body -- revealing weak spots that could be exploited to develop new counterterrorism measures.

Researchers at Sanford-Burnham Medical Research Institute (Sanford-Burnham) and the Medical School of Hannover in Germany recently discovered how the botulinum neurotoxin, a potential bioterrorism agent, survives the hostile environment in the stomach on its journey through the human body. Their study, published February 24 in Science, reveals the first 3D structure of a neurotoxin together with its bodyguard, a protein made simultaneously in the same bacterium. The bodyguard keeps the toxin safe through the gut, then lets go as the toxin enters the bloodstream. This new information also reveals the toxin's weak spot - a point in the process that can be targeted with new therapeutics.

"Now that we better understand the structure of the bacterial machinery that was designed for highly efficient toxin protection and delivery, we can see more clearly how to break it," said Rongsheng Jin, Ph.D., assistant professor in Sanford-Burnham's Del E. Webb Neuroscience, Aging and Stem Cell Research Center and senior author of the study.

The Janus-faced toxin

The botulinum neurotoxin is two-faced. On one side, it's the most poisonous substance known to man, causing botulism. Accidental botulinum neurotoxin poisoning is usually food-borne, but it's also considered a potential bioterrorism agent. On the other side, botulinum neurotoxin is also used an effective therapy and popular cosmetic, such as in BOTOX.

The neurotoxin accomplishes both the good and the bad using the same trick - paralyzing muscle cells by disrupting their connections with the nerves that tell them how and when to move. But before the neurotoxin can gain access to muscles and the neurons that control them, it must make a remarkable journey through the body - surviving the digestive enzymes and extreme acidic environment in the stomach, penetrating the small intestine, and entering the bloodstream.

Sneaking a peek at the neurotoxin and its bodyguard

This latest study on the botulinum neurotoxin was the result of a close collaboration between the Jin group and a research group at the Institute of Toxicology at the Medical School of Hannover, led by Andreas Rummel, Ph.D., an expert on clostridial neurotoxins. They used a technique called X-ray crystallography, which uses powerful X-ray beams to produce 3D images of proteins at the atomic level, to study a genetically inactivated, nontoxic version of the botulinum neurotoxin.

These experiments helped the team visualize the atomic structure of all three parts of the toxin: 1) the region that recognizes neurons, 2) the enzyme that acts like a pair of scissors to cut human neural proteins and cause paralysis, and 3) the needle that punches holes to help deliver the enzyme to the nerve terminal. What's more, the researchers also captured the toxin's interaction with a second bacterial protein, called nontoxic nonhemagglutinin (NTNHA).

"We were surprised to see that NTNHA, which is not toxic, turned out to be remarkably similar to botulinum neurotoxin. It's composed of three parts, just like a copy of the toxin itself. These two proteins hug each other and interlock with what looks like a handshake," said Jin.

As the toxin moves through the body, NTNHA acts as its bodyguard, keeping it from being degraded when times are tough in the acidic stomach. However, as this study revealed, the toxin has a weak spot: when the toxin/NTNHA complex punches its way out of the small intestine, it's the change in pH that triggers a conformational change, breaks up the duo, and releases only the unprotected toxin into the bloodstream.

Towards prevention and therapy

According to Jin, this new knowledge about how the botulinum neurotoxin and NTNHA balance the need for strong binding and a timely release could be exploited to outsmart them.

"We now hope we might be able to fool the toxin and its bodyguard using a small molecule that sends the wrong signal - mimicking pH change, prematurely breaking up their protective embrace, and leaving the stomach's digestive enzymes and acid to do their job," he said. "We envision this type of therapy - either alone or in combination with other therapies currently in development - could be given preventively at a time when botulinum neurotoxin contamination becomes a public health concern."

Moreover, this type of therapy could be designed for oral delivery, rather than injection, making it easier to treat large numbers of people during an outbreak. A similar strategy could be used to deliver other protein-based drugs that usually need to be injected. "Here, protein drugs could be linked to a botulinum neurotoxin fragment and protected with NTNHA. Then we could possibly take them by mouth," Jin said.

Nighttime Or Daily Dialysis May Improve Patients' Health And Survival

2012-02-25T04:22:00.007-08:00

Frequent and longer dialysis treatments may provide more benefits for patients than conventional dialysis treatments, according to several studies appearing in upcoming issues of the Journal of the American Society Nephrology (JASN). The findings suggest that daily or nightly dialysis sessions at home or in the clinic are viable - and perhaps superior - alternatives for some patients with kidney failure.

Most kidney failure patients who undergo dialysis receive treatments at outpatient facilities three times per week, for three to four hours per visit. Researchers suspect that more frequent and longer treatments might be more effective, but these would be inconvenient for most patients and would take up too much of their time. Therefore, nighttime dialysis while patients sleep (at home or in a clinic) or daily treatments at home might be good options.

Several groups of researchers set out to test these alternatives. Their findings are summarized below.

Eric Weinhandl (Minneapolis Medical Research Foundation) and his co-investigators compared survival of 1,873 daily home dialysis patients using the NxStage System One - a portable hemodialysis machine for use in the home - between 2005 and 2008 with 9,365 thrice-weekly in-center hemodialysis patients. Over an average period of 1.7 to 1.8 years, daily home dialysis patients were 13% less likely to die than thrice-weekly clinic patients, and the survival benefit of daily home dialysis appeared to apply to all types of patients (different sexes, races, weights, etc.). "Whether these results apply to all hemodialysis patients needs further study because patients in our analysis were generally younger and less sick," said Weinhandl.
Gihad Nesrallah, MD, Rita Suri, MD (University of Western Ontario, in London, Canada), and their team compared 338 patients who received intensive home hemodialysis (during the day or night) for an average of 4.8 sessions per week and an average treatment time of 7.4 hours per session with 1,388 patients who received conventional hemodialysis. After following patients for an average of 1.8 years, the researchers found that patients receiving intensive dialysis were 45% less likely to die than patients receiving conventional dialysis. "Whether this improvement in survival is due to increased intensity of dialysis itself or due to the fact that the intensive dialysis patients performed their own dialysis treatments at home is not yet clear," said Dr. Suri.
Eduardo Lacson, Jr., MD (Fresenius Medical Care North America) and his colleagues studied the health of 746 patients who received hemodialysis treatments at a clinic for three nights per week and for an average of eight hours per night, compared with 2,062 similar patients who received conventional hemodialysis treatments. During a two-year follow-up period, patients who received nighttime dialysis had a 25% reduced risk of dying compared with conventional dialysis. Nighttime dialysis patients also experienced improvements in certain measures such as lower weight, blood pressure, and blood phosphorous levels. "This comparison primarily evaluated the impact of the length of treatment time on hemodialysis because patients were all dialyzed in the center and at the same frequency of three times per week," said Dr. Lacson. "Longer treatment time allows for removal of fluid and waste products at a slower pace, but with the added benefit of potentially removing larger quantities from the body."
Finally, John Daugirdas, MD (University of Illinois at Chicago) and his team analyzed data from two studies, the Frequent Hemodialysis Network Daily and Nocturnal Trials, which compared frequent (six times per week) treatments received during the day or at night, with conventional dialysis. Daugirdas and his colleagues looked to see if more frequent dialysis treatments could help lower patients' blood phosphorus levels. (Traditionally, dialysis patients often have high levels, which puts them at risk of developing various complications such as heart disease.) Compared with conventional dialysis treatments, daily or nightly dialysis treatments for 12 months lowered patients' phosphorus levels and reduced their need for phosphorus-lowering medications.

The studies' findings indicate that additional research is warranted to determine if extended or more frequent dialysis treatments provide benefits for all dialysis patients and to determine the optimal treatment frequency and session length.

Only 9 Percent Of Israeli Firefighters Do Not Exhibit Symptoms Of PTSD

2012-02-25T04:22:00.004-08:00

A new study on the prevalence of Post Traumatic Stress Disorder (PTSD) among firefighters in Israel indicates that approximately 90 percent show some form of full or partial symptoms.

According to the study by Ben-Gurion University of the Negev's Dr. Marc Lougassi, a firefighter himself, 24 percent of active firefighters in Israel suffer from full PTSD, 67 percent display partial PTSD while only nine percent showed no symptoms.

PTSD can occur after exposure to serious injury to oneself or another, or another's death and then result in recurring stress symptoms such as nightmares, trouble sleeping and other difficulties for over a month.

According to Dr. Lougassi, "Professional firefighters are frequently exposed to extreme stress during their work in emergency situations. In addition to the physical challenges of firefighting, they must evacuate burned and injured victims or bodies. Their involvement in traumatic events exposes them not only to the pressures stemming from the traumatic event itself, but also to post-traumatic emotional expressions that result in secondary traumatization."

"As far as Israeli firefighters are concerned, there has been no documented evidence of PTSD prevalence, despite the fact that they are exposed to additional traumas such as war and terror strikes," says Lougassi about the first of its kind study.

Approximately 342 active firefighters were recruited for this study, from all age groups, marital statuses (single, married, divorced), educational backgrounds, seniority levels (over two years), roles (firefighter, crew leader, officer, service commander, etc.). Firefighters with a psychiatric background, head injuries (loss of consciousness and neurological disturbances), in psychiatric and/or psychological treatment, with chronic diseases and those taking medications on a regular basis were excluded from the sample.

An additional 42 firefighters from flight firefighting services at Ben-Gurion Airport constituted the control group, since firefighters are not exposed to similar events. Only five percent of the control group showed signs of PTSD.

"These results support the hypothesis that increased exposure to recurring traumatizing events is a significant factor contributing to PTSD development," according to Lougassi.

"The findings of this study can help researchers and the Israeli Firefighting Service improve the firefighters' abilities to cope with extended exposure to traumatizing events through professional intervention programs," he suggests.

"Moreover, these results can help the Israeli Firefighting Services develop appropriate screening tools to be used during the recruiting process of new firefighters, in order to assure their future psychological safety."

Physical Activity Keeps Workers Mentally Fit

2012-02-25T04:22:00.001-08:00

Obesity can be a dangerous risk to our physical health, but according to a Tel Aviv University researcher, avoiding the gym can also take a toll on our mental health, leading to depression and greater burnout rates at work.

Dr. Sharon Toker of TAU's Recanati Faculty of Management, working with Dr. Michal Biron from the University of Haifa, discovered that employees who found the time to engage in physical activity were less likely to experience a deterioration of their mental health, including symptoms of burnout and depression. The best benefits were achieved among those exercising for four hours per week - they were approximately half as likely to experience deterioration in their mental state as those who did no physical activity.

Drs. Toker and Biron say that employers will benefit from encouraging the physical fitness of their employees. If the fight against obesity isn't enough of an incentive, inspiring workers to be physically active lessens high heath costs, reduces absenteeism, and increases productivity in the workplace. Their research was recently published in the Journal of Applied Psychology.

Preventing a downward spiral

Though depression and burnout are connected, they are not the same entity, says Dr. Toker. Depression is a clinical mood disorder, and burnout is defined by physical, cognitive, and emotional exhaustion. But both contribute towards a "spiral of loss" where the loss of one resource, such as a job, could have a domino effect and lead to the loss of other resources such as one's home, marriage, or sense of self-worth.

Originally designed to examine the relationship between depression and burnout, the study assessed the personal, occupational, and psychological states of 1,632 healthy Israeli workers in both the private and public sectors. Participants completed questionnaires when they came to medical clinics for routine check-ups and had three follow-up appointments over a period of nine years.

Findings indicate that an increase in depression predicts an increase in job burnout over time, and vice versa. But for the first time, the researchers also considered the participants' levels of physical activity, defined as any activity that increases the heart rate and brings on a sweat. The participants were divided into four groups: one that did not engage in physical activity; a second that did 75 to 150 minutes of physical activity a week; a third that did 150 to 240 minutes a week; and a fourth that did more than 240 minutes a week.

Depression and burnout rates were clearly the highest among the group that did not participate in physical activity. The more physical activity that participants engaged in, the less likely they were to experience elevated depression and burnout levels during the next three years. The optimal amount of physical activity was a minimum of 150 minutes per week, where its benefits really started to take effect.

In those who engaged in 240 minutes of physical activity or more, the impact of burnout and depression was almost nonexistent. But even 150 minutes a week will have a highly positive impact, says Dr. Toker, helping people to deal with their workday, improving self-efficacy and self-esteem, and staving off the spiral of loss.

Fighting stress at work

If they're feeling stressed at work, employees can always ask the boss to effect changes, such as providing more opportunities for emotional support in the workplace. But if the organization is unwilling to change, workers can turn to physical activities in their leisure time as an effectivestress management tool.

Far-sighted employers can benefit by building a gym on company grounds or subsidizing memberships to gyms in the community, and by allowing for flexible work hours to encourage employees to make physical activity an integral part of their day, suggests Dr. Toker. Such a strategy pays business dividends in the long run.

A New Design Strategy For The Development Of Vaccines For HIV

2012-02-25T04:21:00.003-08:00

HIV has eluded vaccine-makers for thirty years, in part due to the virus' extreme ability to mutate. Physical scientists and clinical virologists from the Massachusetts Institute of Technology (MIT) and the Ragon Institute in Cambridge, Mass., have identified a promising strategy for vaccine design using a mathematical technique that has also been used in problems related to quantum physics, as well as in analyses of stock market price fluctuations and studies of enzyme sequences. The team, led by Arup Chakraborty of MIT and Bruce Walker of the Ragon Institute, will give an update on its work at the Biophysical Society 56th Annual Meeting, held Feb. 25-29 in San Diego, Calif.

Vaccines prime the immune system to target molecular signatures associated with a particular pathogen. But HIV's ability to mutate has made it difficult to identify reliable vaccine targets. In their search for a new type of target, the team from the Ragon Institute did not focus on individual amino acids. Instead, the researchers sought to identify independently evolving groups of amino acids where, within each group, amino acids mutate in tandem (meaning that they rely on one another to maintain the viability of the virus). In particular, they looked for groups of amino acids within which combinations of mutations would have a greater chance of making the virus unviable. By staging a multi-pronged attack against these regions of HIV, the researchers reasoned, they might be able to trap the virus between two bad choices: be destroyed by the immune system, or mutate and destroy itself.

With a mathematical tool called random matrix theory, the team searched for high-order evolutionary constraints in the so-called Gag region of HIV. The researchers were looking for collectively co-evolving groups of amino acids with a high number of negative correlations (meaning multiple mutations would destroy the virus) and a low number of positive correlations (meaning the virus could survive multiple mutations). They found this combination in a region, which they call Gag sector 3, that is involved in stabilizing the protein shell of the virus: too many mutations here, and the virus' structure would collapse.

Interestingly, when the team studied HIV-infected individuals whose bodies are naturally able to fend off the virus' attacks - so-called "elite controllers" - they found that these individuals' immune systems preferentially targeted Gag sector 3 over other proteins.

At the moment, the study authors are working to extend their methods to HIV proteins beyond Gag. The team is also developing elements of the active components of a vaccine that would prime the immune system to selectively target Gag sector 3 proteins. They expect to begin testing in animal models soon.

Some Antipsychotics May Raise Risk Of Death In Dementia Patients

2012-02-25T04:21:00.001-08:00

Some antipsychotic drugs may raise risk of death in elderly dementia patients, according to a new large study from Harvard Medical School published in BMJ on Thursday that looked at over 75,000 residents over the age of 65 living in US nursing homes.

Although the study does not prove that specific antipsychotics cause the increased risk, and the researchers say they can't rule out all other possible factors, they conclude their findings suggest that risk of death with antipsychotics is "generally increased with higher doses and seems to be highest for haloperidol and least for quetiapine".

The senior author of the study is Dr Sebastian Schneeweiss, associate professor of medicine in the Division of Pharmacoepidemiology and Pharmacoeconomics of Brigham and Women's Hospital and Harvard Medical School, in Boston in the US.

For their study, the largest of its kind ever undertaken in the US, Schneeweiss and colleagues looked at data on 75,445 older residents aged 65 and over living in nursing homes in 45 US states between 2001 and 2005.

Over a six-month period, during which 6,598 of the patients died from non-cancer related causes, the researchers assessed risks of death associated with individual antipsychotic drugs such as aripiprazole, haloperidol, olanzapine, quetiapine, risperidone and ziprasidone.

49% of deaths were reported as due to circulatory disorders, 10% to brain disorders and 15% to respiratory disorders.

The analysis shows that patients treated with haloperidol had double the risk of death compared to those taking risperidone, while patients taking quetiapine had a reduced risk.

The researchers also found that the link with haloperidol was strongest during the first 40 days of treatment which did not change after a dose adjustment.

They took into account a wide range of possible influencers, including gender, age, ethnicity, education, geographic location, as well as size, occupancy, staffing levels, ownership, resident characteristics and quality indicators of the nursing home, and whether it had special care units. They also corrected for the presence of any physical illnesses that might raise mortality risk.

While the study does not claim to deal with the trade off between effectiveness and safety that clinicians caring for dementia patients have to consider every day, in their conclusions, it suggests clinicians take into account the following points when they make their decisions:

"If the clinician faces a situation in which use of these drugs seems inevitable, our findings underscore the importance of always prescribing the lowest possible dose and of closely monitoring patients, especially shortly after the start of treatment," write the authors.

"The evidence accumulated so far implies that use of haloperidol in this vulnerable population cannot be justified because of the excess harm. Quetiapine might be somewhat safer than other atypical drugs, but these findings will require replication in other studies," they add.

In 2005, the US Food and Drug Administration (FDA) issued a public health advisory about "off-label" use of antipsychotic drugs approved for the treatment of schizophrenia and mania to treat other disorders. They had determined that "treatment of behavioral disorders in elderly patients with dementia with atypical (second generation) antipsychotic medications is associated with increased mortality". In 2008, the agency extended the warning to include conventional antipsychotics.

Schneeweiss and his fellow authors write that despite these warnings, doctors are likely to continue prescribing these drugs because there is a need for some type of intervention and the dementia population continues to grow.

Among their conclusions, they note:

"The evidence provided in our study reinforces the important risks associated with the use of these drugs and underscores the need to try alternative means of dealing with behavioural problems in older patients with dementia."

In an accompanying editorial, Dr McCleery of the Oxford NHS Foundation Trust, calls for future studies to focus more on how non-drug interventions might be made more effective and implemented more simply and efficiently.

Genes That Enable Diagnosis Of Age-Related Macular Degeneration

2012-02-25T04:19:00.003-08:00

Age-related macular degeneration (AMD) is one of the leading causes of blindness worldwide, especially in developed countries, and there is currently no known treatment or cure or for the vast majority of AMD patients. New research published in BioMed Central's open access journal Genome Medicine has identified genes whose expression levels can identify people with AMD, as well as tell apart AMD subtypes.

It is estimated that 6.5% of people over age 40 in the US currently have AMD. There is an inheritable genetic risk factor but risk is also increased for smokers and with exposure to UV light. Genome-wide studies have indicated that genes involved in the innate immune system and fat metabolism are involved in this disease. However none of these prior studies examined gene expression differences between AMD and normal eyes.

In order to address this question, researchers at the University of California Santa Barbara, the University of Utah John Moran Eye Center, and the University of Iowa combined forces and used a human donor eye repository to identify genes up-regulated in AMD. The ability of these genes to recognize AMD was tested on a separate set of samples.

The team discovered over 50 genes that have higher than normal levels in AMD, the top 20 of which were able to 'predict' a clinical AMD diagnosis. Genes over-expressed in the RPE-choroid (a tissue complex located beneath the retina) included components of inflammatory responses, while in the retina, the researchers found genes involved in wound healing and the complement cascade, a part of the innate immune system. They found retinal genes with expression levels that matched the disease severity for advanced stages of AMD.

Dr. Monte Radeke, one of the project leaders, explained, "Not only are these genes able to identify people with clinically recognized AMD and distinguish between different advanced types - some of these genes appear to be associated with pre-clinical stages of AMD. This suggests that they may be involved in key processes that drive the disease. Now that we know the identity and function of many of the genes involved in the disease, we can start to look among them to develop new diagnostic methods, and for new targets for the development of treatments for all forms of AMD."

Citrus Fruits May Help Women Reduce Risk Of Stroke

2012-02-25T04:19:00.001-08:00

Eating citrus fruits, especially oranges and grapefruit, because of the flavonone they contain, may lower women's risk of developing clot-associated or ischemicstroke, according to a new study led by Norwich Medical School of the University of East Anglia in the UK that was published online in Stroke: Journal of the American Heart Association on Thursday.

The researchers wanted to examine more closely how consumption of foods containing different classes of flavonoids affected the risk of stroke.

Flavonoids are a group of compounds found in fruits, vegetables, dark chocolate and red wine.

Study lead author and professor of nutrition at Norwich Medical School, Dr Aedín Cassidy, told the press:

"Studies have shown higher fruit, vegetable and specifically vitamin C intake is associated with reduced stroke risk."

A stroke is where part of the brain shuts down because of loss of blood supply, caused either by a blockage or embolism that stops the blood flow (ischemia), or due to leakage caused by a hemorrhage.

Cassidy said flavonoids are thought to provide some protection against stroke by improving blood vessel function and reducing inflammation, among other things.

For their study, Cassidy and colleagues examined data from the Nurse's Health Study. Based in the US, this is one of the largest and longest running investigations of factors that influence women's health. It started in 1976 and expanded in 1989.

The researchers looked at 14 years of follow-up data completed by 69,622 female participants who every four years had reported their dietary intake, including details of the fruits and vegetables they consumed.

They looked for links between the six major subclasses of flavonoids commonly present in the American diet and risk of ischemic, hemorrhagic and total stroke.

The six major subclasses they examined were: flavonones, anthocyanins, flavon-3-ols, flavonoid polymers, flavonols and flavones.

Since we already know that each subclass has a different biological effect, the researchers did not expect to find any strong beneficial links between total flavonoid consumption and stroke risk.

But they did find a strong link between high consumption of flavonones in citrus fruits and reduced stroke risk: women who consumed the most showed a 19% lower risk of ischemic stroke compared to women who ate the least amounts of flavonones in citrus fruits.

In this study, oranges and orange juice (82%) and grapefruit and grapefruit juice (14%) had the highest amounts of flavonones. But the researchers said if you are looking to increase your intake, then go for the fruit rather than the juice, because the latter tends to be accompanied by high amounts of sugar.

While previous studies have shown links between various foods and protection against both kinds of stroke, and this study further informs the field, the researchers said we still need to get a better understanding about why the link occurs, and that has to come from further research.

Funds from the National Institutes of Health helped pay for the research.

Detecting Down Syndrome Risk - Noninvasive Method Efficient and Accurate

2012-02-25T04:18:00.003-08:00

Two studies published online, ahead of the April issue of the American Journal of Obstetrics & Gynecology (AJOG), show that the risk of a fetus having chromosomal abnormalities that cause Down syndrome, and a genetic disorder known as Edwards syndrome, can now be almost precisely be identified by using a noninvasive test on maternal blood that involves a novel biochemical assay and a new algorithm for analysis.

Apart from being more scalable, compared with other recently developed genetic screening tests, this test is also able to potentially reduce unnecessary amniocentesis or CVS.

Diagnosing fetal chromosomal abnormalities, or aneuploidies, requires invasive tests that consist of chorionic villous sampling or amniocentesis in pregnancies that are known to be of high-risk, and even though these tests are accurate, they are costly and carry a risk of miscarriage.

Massively parallel shotgun sequencing (MPSS), a technique that examines cell-free DNA (cfDNA) from the mother's plasma for fetal conditions has been used to identify trisomy 21 (T21) pregnancies, i.e. pregnancies with an extra copy of chromosome 21, which leads to Down syndrome, and trisomy 18 (T18), the chromosomal defect underlying Edwards syndrome. Although MPSS can accurately detect these conditions by analyzing the entire genome, it requires DNA sequencing large amounts and therefore its clinical usefulness is limited.

A novel assay, called Digital Analysis of Selected Regions (DANSR™), has recently been developed by scientists at Aria Diagnostics in San Jose, CA, which sequences loci from only those chromosomes under investigation, which requires 10 times less DNA sequencing as compared with MPSS.

The current study describes a novel statistical algorithm, the Fetal-fraction Optimized Risk of Trisomy Evaluation (FORTE™), which takes age-related risks and the percentage of fetal DNA in the sample into account, in order to provide an individualized risk score for trisomy. Lead researcher Dr. Ken Song, MD, explains:

"The higher the fraction of fetal cfDNA, the greater the difference in the number of cfDNA fragments originating from trisomic versus disomic [normal] chromosomes and hence the easier it is to detect trisomy. The FORTE algorithm explicitly accounts for fetal fraction in calculating trisomy risk."

Dr. Song and his team set out to assess 123 normal pregnancies, 36 T21, and 8 T18 pregnancies to assess the performance of the DANSR/FORTE assay. They referenced all samples for FORTE odd scores of chromosome 18 and chromosome 21 and discovered in a blinded analysis that the combination of DANSR and FORTE managed to correctly identify all 36 cases of T21 and 8 cases of T18 as having a risk of more than 99% for each trisomy. The separations in risk score between trisomic and disomic samples were at least a 1,000-fold magnitude.

In an associated study, researchers from the Harris Birthright Research Centre for Fetal Medicine at Kings College Hospital in London and the University College London Hospital provided 400 maternal plasma samples to Aria for a DANSR analysis with the FORTE algorithm. All subjects were at risk for aneuploidies and had been tested by chorionic villous sampling.

According to the analysis results, all cases of T21 and 98% of T18 cases from euploid pregnancies were identified, showing that all cases of T21 had an estimated risk for this aneuploidy of ≥ 99%, whilst all normal pregnancies and those with T18 had a risk score for T21 of ≤ 0.01%.

Dr. Song explains:

"Combining the DANSR assay with the FORTE algorithm provides a robust and accurate assessment of fetal trisomy risk. Because DANSR allows analysis of specific genomic regions, it could be potentially used to evaluate genetic conditions other than trisomy. The incorporation of additional risk information, such as from ultrasonography, into the FORTE algorithm warrants investigation."

Lead researcher Kypros H. Nicolaides, MD, of the University of London study believes that fetal trisomy evaluation with cfDNA testing will be introduced into clinical practice sooner or later, saying:

"It would be useful as a secondary test contingent upon the results of a more universally applicable primary method of screening. The extent to which it could be applied as a universal screening tool depends on whether the cost becomes comparable to that of current methods of sonographic and biochemical testing."

Dr. Nicolaides highlights that the plasma samples were taken from high-risk pregnancies that showed some evidence of impaired placental function, and adds that it would require further tests to confirm that the observed accuracy with cfDNA testing from the investigation of pregnancies at high-risk for aneuploidies also applies to the general population, in which prevalence of fetal trisomy 21 is significantly lower.

He concludes:

"This may well prove to be the case because the ability to detect aneuploidy with cfDNA is dependent upon assay precision and fetal DNA percentage in the sample rather than the prevalence of the disease in the study population."

Survival Circuits In Animal Brains: What Can They Tell Us About Human Emotion?

2012-02-25T04:18:00.001-08:00

New York University neuroscientist Joseph LeDoux, author of "The Emotional Brain", has come up with a new theory called "the survival circuit concept" that he outlines in Wednesday's issue of the journal Neuron. He suggests that instead of asking whether the feelings and emotions we humans experience are also present in other animals, we should ask to what extent the survival circuits present in other animals are also present in humans, and then consider how they contribute to emotions.

The basis for his reasoning, drawn from twenty years researching emotion and memory in the brain, is the neurological common ground that exists between humans and other animals: we both have brain functions used for survival, these include "circuits" responsible for defense, managing energy and nutrition, fluid balance, regulating heat, and reproduction.

LeDoux, a professor in New York University's Center for Neuroscience and Department of Psychology, says in a press statement released earlier this week that while the functions of these "survival circuits" are not causally related to emotional feelings, they will contribute to them indirectly.

"The survival circuit concept integrates ideas about emotion, motivation, reinforcement, and arousal in the effort to understand how organisms survive and thrive by detecting and responding to challenges and opportunities in daily life," he explains.

LeDoux, who is also director of the Emotional Brain Institute, part of the Nathan S. Kline Institute for Psychiatric Research, is fully aware of the difficulty of researching feelings and emotions. It is not easy, he says, because you can't measure them directly, you have to rely on "outward expression of emotional responses, or on verbal declarations by the person experiencing the feeling, as ways of assessing what that person is feeling".

"This is true both when scientists do research on emotions and when people judge emotions in their social interactions with one another," he adds.

As if that is not complicated enough, we are even more limited when we try to interpret the emotions and feelings of animals.

LeDoux says we tend to ascribe human subjective feelings to explain what we see when animals behave in ways we can relate to:

"When a deer freezes to the sound of a shotgun we say it is afraid, and when a kitten purrs or a dog wags its tail, we say it is happy."

Although LeDoux accepts that we may probably never know what animals truly "feel", he thinks we could improve the way we try to understand and interpret their emotions. One way to do this is to look at the brain, and he suggests:

"If we can find neural correlates of conscious feelings in humans -- and distinguish them from correlates of unconscious emotional computations in survival circuits -- and show that similar correlates exists in homologous brain regions in animals, then some basis for speculating about animal feelings and their nature would exist."

LeDoux has done a lot of work on fear, and his research shows we can respond to danger before we even "know" consciously what we are responding to. He has also discovered a lot about how we form and store emotional memories in the brain.

His research has helped us to map the brain's neural circuits for fear and fear memory, to the point of identifying cells, synapses and molecules that make emotional learning and memory possible.

New Approach To Fighting Cancer - New Combo Of Chemo And Malaria Drug Delivers Double Punch To Tumors

2012-02-23T08:06:00.006-08:00

Blocking autophagy - the process of "self-eating" within cells -- is turning out to be a viable way to enhance the effectiveness of a wide variety of cancer treatments.

Specifically, blocking the action of an acidic inner cell part, which acts like a stomach and chews up proteins for recycling, is the main attack strategy, says Ravi K. Amaravadi, MD, an assistant professor of Medicine at the Perelman School of Medicine and Abramson Cancer Center at the University of Pennsylvania. Amaravadi gave a presentation on the role of autophagy in fighting cancer at the annual American Association for Advancement of Science meeting in Vancouver, British Columbia.

His lab and others have demonstrated that adding hydroxychloroquine (HCQ) - an FDA-approved drug used commonly for malaria and rheumatoid arthritis - to many cancer therapies, including chemotherapy, targeted therapy, radiation, and immunotherapy, can enhance the antitumor activity of these drugs in laboratory models of treatment-resistant cancers, and ongoing clinical trials.

Autophagy is increased in cancer cells. Normally, it is a survival pathway allowing a cell to recycle damaged proteins when it's under stress and reuse the damaged parts to fuel further growth.

Cancer cells might be addicted to autophagy, since this innate response may be a critical means by which the cells survive nutrient limitation and lack of oxygen commonly found within tumors. And, it is likely to explain how some cancer cells evade chemotherapies by using, essentially, a work around.

Nearly 30 phase I and Phase II clinical trials involving HCQ have been launched or are in planning stages in many different malignancies, including melanoma, multiple myeloma, renal cell carcinoma, colon cancer, prostate cancer, breast cancer, and others.

Preliminary results for most of the trials are encouraging. "Our assays performed on human blood and tissue samples indicate that high doses of HCQ are required to block autophagy in patients, and in some cases, such as in a brain tumor trial, these high doses, in combination with specific anticancer agents, can lead to toxicity for the tumor," says Amaravadi. "As the first phase I trials of HCQ are being completed, it is clear that in most cases the high-dose HCQ, in combination with existing cancer therapy, is well tolerated."

Randomized controlled trials using HCQ combinations to truly determine the effectiveness of the approach are planned. While these are being considered, the team will conduct additional laboratory experiments to identify more potent and specific inhibitors of autophagy and to identify biomarkers that can predict which patients are most likely to respond to this approach. To that end, the Amaravadi lab has identified a compound called Lys05, which is 10-fold more potent than HCQ at blocking the cell from giving the cancer cell a source of raw energy.

"While our knowledge of the role of autophagy in cancer is still in its infancy, the opportunity to learn about autophagy, both at the bench and the bedside, could accelerate the translation of basic advances in this field into clinical benefit for patients with cancer," says Amaravadi.

Earlier Detection Of Breast Cancer By Mammography Leads To Better Prognosis In 40-49 Year-Olds

2012-02-23T08:06:00.003-08:00

Based on a study of nearly 2,000 breast cancer patients, researchers at the Swedish Cancer Institute in Seattle say that, in women between the ages of 40 and 49, breast cancers detected by mammography have a better prognosis. The study appears in the March issue of Radiology.

"In our study, women aged 40 to 49 whose breast cancer was detected by mammography were easier to treat and had less recurring disease and mortality, because their cancer was found at an earlier stage," said Judith A. Malmgren, Ph.D., president of HealthStat Consulting, Inc.

Dr. Malmgren and a team of researchers reviewed breast cancer patient data from a dedicated registry at the Swedish Cancer Institute's community cancer center. The researchers analyzed data on 1,977 breast cancer patients between the ages of 40 and 49 who were treated between 1990 and 2008. The researchers looked at method of diagnosis (detected by mammography, patient or physician), stage at diagnosis (0-IV, confirmed by biopsy), treatment, and annual follow-up information, including recurrence of disease.

"Our goal was to assess the differences between mammography and non-mammography detected breast cancer, to determine whether earlier detection confers a treatment and morbidity advantage because the disease is found at an earlier stage," Dr. Malmgren said.

The data analysis revealed a significant increase in the percentage of mammography-detected breast cancer over the 18-year period: from 28 percent in 1990 to 58 percent in 2008. Over the same period, patient- and physician-detected breast cancer declined from 73 percent of all cases in 1990 to 42 percent in 2008.

"The shift toward more mammography-detected breast cancer cases was accompanied by a shift toward diagnosis at an earlier stage of disease that required less treatment," Dr. Malmgren said.

Over the 18-year period, the number of breast cancers diagnosed at Stage 0 increased by 66 percent, while the number of Stage III breast cancers decreased by 66 percent. The majority of Stage 0 cancer cases were ductal carcinoma in situ (DCIS), a non-invasive cancer that is confined to a milk duct. The treatment of DCIS remains controversial, because not all experts agree that it is potentially life threatening.

Dr. Malmgren said another key finding of the study was the extent of treatment patients received. Compared with women whose cancer was self-detected or discovered by a physician, patients whose cancer was detected using mammography were more likely to have breast-conserving treatment and less likely to have chemotherapy. Specifically, they were more likely to undergo lumpectomy (67 percent versus 48 percent), less likely to undergo modified radical mastectomy (25 percent versus 47 percent), and less likely to die of breast cancer (4 percent versus 11 percent).

"The benefits of breast cancer treatment are accompanied by significant harms," Dr. Malmgren said. "Chemotherapy may have long-lasting toxic effects on a woman's body, and mastectomy and reconstructive surgery are difficult and expensive operations that can have a significant effect on body image."

The American Cancer Society and other medical organizations recommend that women should begin receiving annual mammograms to screen for breast cancer beginning at age 40. In 2009, the U.S. Preventive Services Task Force issued controversial new guidelines that eliminated the longstanding recommendation for routine mammography screening for women between the ages of 40 and 49, stating that the benefits of screening were potentially outweighed by the harms of screening, such as false-positive results.

"The objective of screening is to detect disease at an earlier, more treatable stage, which - based on our review - mammography accomplishes," Dr. Malmgren said.

What Is Breast Cancer?

2012-02-23T08:06:00.001-08:00

Breast cancer is a tumor that has become malignant - it has developed from the breast cells. A 'malignant' tumor can spread to other parts of the body - it may also invade surrounding tissue. When it spreads around the body, we call it 'metastasis'.

A woman's breast consists of lobules. Lobules are milk-producing glands. The breast is also full of ducts - milk passages that connect the lobules to the nipple. There is also fatty and connective tissue surrounding the ducts and lobules - this is called stroma.

The most common breast cancers start in the cells around the ducts. Others can start in the cells that line the lobules. A smaller number of breast cancers can start in other parts of the breast.

The human body has two ways of moving fluid about. One is through the blood stream, which carries plasma, red and white blood cells and platelets. Lymphatic vessels carry tissue fluid, waste products and infection fighting cells (immune system cells). Immune system cells are located in the lymph nodes - the nodes are shaped like a bean.

It is common for cancer cells to grow in the lymph nodes. They get there via the lymphatic vessels.

The lymphatic system of the breasts connect to the lymph nodes in three areas: Under the arm (axillary lymph node), in the chest (internal mammary node) and by the collarbone (supra or infraclavicular node).

Doctors guess that if cancer cells are in the lymphatic system, they are most likely to be in the bloodstream and will spread to other organs in the body. It is very hard to test for breast cancer cells in the bloodstream.

If breast cancer cells have got to the nodes under the arm (axillary), it will most likely swell. Whether or not it has swollen there, will decide what type of treatment a patient should have. If cancer cells are found in more lymph nodes, then the likelihood of it turning up in different parts of the body is greater. However, there is no hard and fast rule here. Women have had swellings in many nodes and did not develop metastases, while some women with no swellings in their nodes did.

Most breast lumps are benign (harmless)

Although most breast lumps do not develop into anything dangerous (benign) some will need to be biopsied (doctor takes a piece out and tests it). Most lumps are harmless cysts - sacs filled with fluid.

A benign tumor cannot spread to other parts of the body - it stays inside the breast. They pose no threat to the patient's life. They are not cancer. Some of them, however, can increase the woman's chance of developing breast cancer later on. Tumors such as papillomas and atypical hyperplasia are examples of this.

How common is breast cancer?

Breast cancer is the most common cancer for women. About one in every nine women will develop breast cancer in her lifetime. 99% of all breast cancers are diagnosed in women, 1% affect men.

In the USA there were 100,000 new cases in 1985. In 1994 the number rose to 180,000. The main reason for the increase is better awareness leading to more diagnostic tests.

Why do some women get breast cancer?

We don't know the answer to that yet. We know that heredity plays a part. The more close relatives a woman has who had breast cancer, the higher is her risk of developing it.

Links for further reading:
American Cancer Society, Inc. Breast Cancer
Lawrence Berkeley National Laboratory. Breast Cancer Screening

"DNA Origami" Robots Target Cancer Cells

2012-02-23T08:03:00.001-08:00

Using a technique called "DNA origami", US scientists have made programmable molecule-transporting nanorobots that can seek out particular cell targets and deliver specific instructions for them to follow. One example of such use could be to tell cancercells to destroy themselves. The researchers write about their findings in Friday's online issue of Science.

The programmable nanorobots carry cargoes of molecules that are released when aptamers (peptide molecules that bind to a specific target) in their structure bind to specific proteins on the surface of targeted cells.

Researchers at the Wyss Institute for Biologically Inspired Engineering at Harvard University modeled the technology on the immune system's white blood cells that patrol the bloodstream, looking for signs of trouble. They hope one day it will be used to program immune responses to treat diseases.

The DNA origami method is one that folds strands of DNA into complex three-dimensional shapes.

This latest study is considered a breakthrough because it brings together recent advances in DNA origami that have been pioneered in research centres around the world, not just at the Wyss Institute, to try and meet the challenge of how to kill cancer cells in a highly selective way.

First author Dr Shawn Douglas, a Wyss Technology Development Fellow when he worked on the study, and colleagues, devised their nanosized robot in the shape of an open barrel made of two halves joined by a hinge. (Douglas is now an Assistant Professor in the Faculty of Life Sciences and the Nano-Center at Bar-Ilan University in Israel).

The two halves are held shut by special DNA latches that respond to particular targets by allowing the two halves to swing open and expose their payload.

The targets the latches respond to are particular combinations of cell-surface proteins: for example these could be disease markers.

The DNA barrel can contain various payloads. Examples include molecules with specific instructions that receptors on cell surfaces respond to, causing them to change the signals they send to the cells.

The researchers demonstrated the technology on cells from two types of cancer: leukemia andlymphoma. The message encoded in the payload was to activate the cells' suicide switch. This triggers a standard feature of all cells, called apoptosis, which allows aging or abnormal cells to be eliminated.

Leukemia and lymphoma cells don't speak the same language, so the suicide triggering instructions had to be encoded in different antibody combinations.

Senior author Dr George Church, a Wyss core faculty member and Professor of Genetics at Harvard Medical School, told the press:

"We can finally integrate sensing and logical computing functions via complex, yet predictable, nanostructures -- some of the first hybrids of structural DNA, antibodies, aptamers and metal atomic clusters -- aimed at useful, very specific targeting of human cancers and T-cells."

The versatility of the technology emulates that of white blood cells that have the ability to sense a whole range of cell distress signals, bind to the cells, and then transmit the appropriate self-destruct instructions in the language of that cell type.

The DNA nanorobot uses modular components to achieve a similar range of versatility: different hinges, different molecular payloads. These can be switched in and out of the underlying "chassis", rather like swapping various engines and tires in and out of cars.

Such a system should have the potential to treat a variety of diseases. DNA nanotechnology is widely recognized as a potential way to deliver drugs and molecular signals: another plus is it is biodegradable.

But there are considerable challenges in how to program this tiny machine, never mind how to make the right structure, then get it to open and close, then re-open, insert, carry and deliver the payload.

The study represents a big step forward in meeting these challenges because three new elements have been combined for the first time. One of these is because the DNA barrel has no lids, the payloads can be inserted from the side in one step: there is no need to open and then close the barrel.

The second new element is that this system uses latches that respond to proteins (not DNA or RNA like other systems), which are commonly found on cell surfaces. And the third new element is that it uses antibody fragments to send the molecular signals, so by using different combinations of these, different types of immune responses can be replicated to target specific diseases.

Peptide Helps Improve Learning And Memory

2012-02-23T08:02:00.001-08:00

Although there are several drugs and experimental conditions that can block cognitive function and impair learning and memory, researchers have recently shown that some drugs can actually improvecognitive function.

The new multi-national study, published in the 21 February issue of the open-access journalPLoS Biology, reveals that these findings may implicate scientists' understanding of cognitive disorders like Alzheimer's disease.

There are trillions of neuronal connections, called synapses in the human brain that are dynamic and constantly change in strength and property. This pattern of activity, known as synaptic plasticity, controls people's cognitive functions, and scientists hypothesize this to be the cellular basis for learning and memory. They also believe that changes in synaptic plasticity mechanisms are responsible for various cognitive deficits, including autism, Alzheimer's disease and several forms of mental conditions and disorders.

Research leaders, Dr. Jose A. Esteban, Dr. Shira Knafo and Dr. Cesar Venero collaborated with researchers from The Centro de Biología Molecular Severo Ochoa and UNED in Spain, the Brain Mind Institute EPFL in Switzerland and the Department of Neuroscience and Pharmacology at the Faculty of Health Sciences in Denmark, to provide new information on the molecular mechanisms of synaptic plasticity as well as how this process may be manipulated to improve cognitive performance.

Their findings reveal that by using a small protein fragment or peptide, called FGL, derived from a neuronal protein involved in cell-to-cell communication, synapses can be made more plastic. FGL initiates multiple events inside the neuron, which leads to the synapses becoming plastic.

The researchers found that FGL in particular triggers the insertion of new neurotransmitter receptors into synapses in the brain's hippocampus, which is known to play a role in various forms of learning and memory. Significantly, when FGL was administered to rats, the animals experienced an enhanced ability to learn and retain spatial information.

Dr. Esteban states:

"We have known for three decades that synaptic connections are not fixed from birth, but they respond to neuronal activity modifying their strength. Thus, outside stimuli will lead to the potentiation of some synapses and the weakening of others. It is precisely this code of ups and downs what allows the brain to store information and form memories during learning".

The new findings reveal that within this framework, synaptic plasticity mechanisms can be pharmacologically manipulated in adult animals, with the goal of improving cognitive ability. Dr. Knafo concludes:

"These are basic studies on the molecular and cellular processes that control our cognitive function. Nevertheless, they shed light into potential therapeutic avenues for mental disorders where these mechanisms go awry".

Researchers Propose New Approach To Tackle Terrorism

2012-02-23T08:01:00.004-08:00

With a growing number of terrorist attacks being committed by 'home-grown' radicals, researchers at Queen Mary, University of London are proposing a totally new approach to preventing terrorism.

Researchers say the current approach, via the criminal justice system, has failed to prevent terrorism and may have even increased membership of terrorist groups by alienating those most vulnerable to radicalisation.

After examining the evidence the researchers propose a drastic re-think and suggest that public health measures could hold the key to preventing radicalisation.

The study suggests that current counter-terrorism initiatives by the British Government have stigmatised and alienated Muslim groups in the UK by treating them as 'under suspicion'. This has actually hampered the prevention of terrorism by distancing radicals from main stream society and pushing them towards extremist groups. The research also shows that there is very little evidence that 'profiling' works.

The research is published in BioMed Central's open access journal BMC Medicine by Kam Bhui, Professor of Cultural Psychiatry and Epidemiology at Queen Mary, and co-researchers from King's College London. It looks at all the available evidence and draws a number of surprising conclusions.

It reports that violent radicalisation is more common in people who are young, educated, and isolated or marginalised. In fact those who committed acts of terrorism tended to kill more people if they were highly educated. Therefore the researchers suggest that education in schools and universities is an excellent way to intervene.

The study also suggests that young people are particularly vulnerable to radicalisation when they are going through times of great change such migration, changing schools, going to university or just going through adolescence. At such times, extremist groups can offer a feeling of belonging.

The researchers suggest that instead, such young people could be helped to integrate and to engage positively with the political process.

Finally the research concludes that including the current surveillance system could be greatly improved simply by including data about factors which either increase the likelihood of radicalisation or offer a protective effect.

Professor Bhui explains: "These home-grown terrorists are thankfully rare so trying to identify them individually is like looking for a needle in a haystack. And in doing so, lots of innocent people have been marginalised.

"On the other hand, using a public health approach we can work with a large group of people to make radicalisation less likely while also improving inclusion and health in general."

The paper explains that a public health approach would mean looking at the whole population, trying to understand how people are radicalised, and using this information to aim prevention strategies at large groups of people.

This approach has been successfully used for improving health, for example by encouraging people to quit smoking or by preventing knife crime injuries. It is also a more holistic approach which addresses education, inequality, housing, family, community relations, etc.

"This approach doesn't condone terrorism but it does aim to understand how people become radicalised and provides new tactics for preventing terrorists attacks," explains Professor Bhui.

Professor Bhui and his colleagues are continuing with this research and are now studying how and why people develop sympathies towards extremist groups.

Anthrax Susceptibility Varies Between Individuals

2012-02-23T08:01:00.001-08:00

Susceptibility to anthrax toxin is a heritable genetic trait that may vary tremendously among individuals, according to a new study by researchers at the Stanford University School of Medicine.

Among 234 people studied, the cells of three people were virtually insensitive to the toxin, while the cells of some people were hundreds of times more sensitive than those of others. The findings may have important implications for national security, as people known to be more resistant to anthrax exposure could be effective first-line responders in times of crises.

The research also highlights the fact that many lethal pathogens, including HIV, malaria, leprosy and hepatitis, rely on interactions with host genes to infect and replicate within human cells. Inherited differences in the level of expression of these genes can lead to large variations in the relative susceptibility of different individuals to the pathogen.

The research was published online Feb. 6 in the Proceedings of the National Academy of Sciences. The senior author of the report is professor of genetics Stanley N. Cohen, MD, the Kwoh-Ting Li Professor at the School of Medicine. Postdoctoral scholar Mikhail Martchenko, PhD, is the first author. Collaborating in analysis of the data were associate professor of genetics Hua Tang, PhD, and research associate Sophie Candille, PhD. The study was funded by the Defense Threat Reduction Agency of the U.S. Department of Defense.

"Every pathogen has its own virulence strategy," said Stanford professor of microbiology and immunology and of medicine David Relman, MD, the chair of the Institute of Medicine's Forum on Microbial Threats and a member of the U.S. Department of Health and Human Service's National Science Advisory Board for Biosecurity, who was not involved in the research. "We already knew that infection by the same organisms in different people can have different outcomes. But until now it's been very difficult to determine whether this variability was due to genetic or environmental factors. This is one of the few studies that has successfully identified a host-genetics-based molecular cause of this variability."

Relman is also the chief of infectious diseases at the Veterans Affairs Palo Alto Health Care System, and the president-elect of the Infectious Diseases Society of America. In addition, he was the vice chair of the National Academy of Sciences' committee charged in 2008 with reviewing the scientific approaches used in the FBI investigation of the anthrax attacks of 2001.

"This paper is an important contribution to our understanding of the mechanisms of host susceptibility to anthrax," said Alan Rudolph, PhD, the director of the Chemical and Biological Technologies Directorate at the Defense Threat Reduction Agency. "We are committed to supporting outstanding science in this field and will seek opportunities to translate key discoveries such as this into useful applications in diagnostics and medical countermeasures for enhanced preparedness for the department of defense and global health security."

In the new study, Cohen and his colleagues found that variation in the level of expression of a gene that produces a cell-surface protein called CMG2 affects the success of the anthrax toxin in gaining entry into human cells. The research suggests that analogous effects may occur in people exposed to anthrax bacteria. The authors suggest that the investigational approach they used may be broadly applicable for learning about individual susceptibility to various pathogens in human populations.

Cohen's laboratory has been studying host gene exploitation by pathogens for several years; they've termed such genes "cellular genes exploited by pathogens," or CGEPs. They've identified and categorized CGEPs in an electronic registry. This registry makes it easier to identify correlations between variations in particular genes and a pathogen's virulence. Rather than searching blindly through the genomes of many individuals (an approach known as a genome wide association study) for associations, the researchers can instead home in on and look for variations in the much smaller number of host genes already known to play a role in infection. The registry also provides possible targets for drugs designed to prevent or treat infection by disrupting the exploitation of host genes by pathogens.

Anthrax disease is caused by infection with the anthrax bacteria. Spores of the bacteria exist naturally in the environment. When inhaled by humans or animals (commonly livestock), the spores are transported by immune cells to lymph nodes, where the bacteria begin to multiply and are secreted into the bloodstream. Once in the bloodstream, the bacteria begin to produce the anthrax toxin that infiltrates and kills host cells. Untreated, anthrax infection can cause widespread tissue damage, bleeding and death.

Previous studies had shown that CMG2 is the principal cell-surface protein bound by an anthrax toxin component called "protective antigen." This binding allows protective antigen to smuggle into the host cell two other toxin proteins that then kill the cell. Cohen and Martchenko wondered whether naturally occurring variations in either the sequence or the levels of expression of CMG2 would affect the killing ability of the toxins.

To find out, the researchers used cells obtainable through the International HapMap Project - an effort to catalog and understand genetic diversity in human populations. The researchers studied immune cells called lymphocytes collected from 234 individuals of varying ethnic and geographic backgrounds: 84 Nigerians, 63 Americans whose ancestors came from northern and western Europe, 44 Japanese and 43 Han Chinese.

They found that, of the 234 samples, lymphocytes from three individuals of European ancestry were thousands of times more resistant to killing by an engineered hybrid toxin brought into the cells by protective antigen. (The researchers couldn't use the natural anthrax toxin because it doesn't kill lymphocytes - one of the few cell types available through the HapMap project.)

The extent of variation in sensitivity was surprising to the scientists. Even excluding the virtually resistant cells, they sometimes had to apply as much as 250 times more toxin to kill a similar number of cells in one sample as in another. In addition, they observed that cells isolated from parents and their children responded similarly, indicating that toxin sensitivity is an inherited trait.

The researchers next modified mouse cells to express varying levels of human CMG2 on their surface. They found a direct correlation between the level of expression of CMG2 and the ability of toxin to kill the cells: increased expression of CMG2 resulted in increased toxin sensitivity, possibly by providing more entry points for the toxin.

Finally, the researchers also examined whether there was any correlation between a common sequence variation in the CMG2 gene and anthrax susceptibility. They found that creating a similar sequence variation altered the susceptibility of mouse cells to toxin. However, the correlation of this change with toxicity was not statistically significant in the human lymphocyte populations they studied.

"This research offers an important proof of principle," said Relman. "They've showed that genetically-determined variations in the level of expression of a human protein can influence the susceptibility of host cells to anthrax toxin. The findings also provide a possible means for predicting who is likely to become seriously ill after exposure, which could be extremely useful when faced with a large number of exposed people, such as was the case during the 2001 anthrax attacks. Finally, they could lead to the development of novel treatment strategies, perhaps by blocking the interaction between the toxin and the receptor, or by down-regulating its expression."

The authors note in the study that the research has implications beyond anthrax exposure. "Our findings, which reveal the previously unsuspected magnitude of genetically determined differences in toxin sensitivity among cells from different individuals, suggest a broadly applicable approach for investigating pathogen susceptibility in diverse human populations."