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."
Saturday, February 25, 2012
Stem Cell Development Triggers Memory
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."
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
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:
"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.
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.
"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
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.
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
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."
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
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.
"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
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.
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
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.
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.
Only 9 Percent Of Israeli Firefighters Do Not Exhibit Symptoms Of PTSD
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."
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
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.
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
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.
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