Researchers from Boston University School of Medicine (BUSM) and Veterans Affairs (VA) Boston Healthcare System have demonstrated that the effects on white matter brain volume from long-term alcohol abuse are different for men and women. The study also suggests that with abstinence, women recover their white matter brain volume more quickly than men.
The study was led by Susan Mosher Ruiz, PhD, postdoctoral research scientist in the Laboratory for Neuropsychology at BUSM and research scientist at the VA Boston Healthcare System, and Marlene Oscar Berman, PhD, professor of psychiatry, neurology and anatomy and neurobiology at BUSM and research career scientist at the VA Boston Healthcare System.
In previous research, alcoholism has been associated with white matter pathology. White matter forms the connections between neurons, allowing communication between different areas of the brain. While previous neuroimaging studies have shown an association between alcoholism and white matter reduction, this study furthered the understanding of this effect by examining gender differences and utilising a novel region-of-interest approach.
The research team employed structural magnetic resonance imaging (MRI) to determine the effects of drinking history and gender on white matter volume. They examined brain images from 42 abstinent alcoholic men and women who drank heavily for more than five years and 42 non-alcoholic control men and women. Looking at the correlation between years of alcohol abuse and white matter volume, the researchers found that a greater number of years of alcohol abuse was associated with smaller white matter volumes in the abstinent alcoholic men and women. In the men, the decrease was observed in the corpus callosum while in women, this effect was observed in cortical white matter regions.
‘We believe that many of the cognitive and emotional deficits observed in people with chronic alcoholism, including memory problems and flat affect, are related to disconnections that result from a loss of white matter,’ said Mosher Ruiz.
The researchers also examined if the average number of drinks consumed per day was associated with reduced white matter volume. They found that the number of daily drinks did have a strong impact on alcoholic women, and the volume loss was one and a half to two percent for each additional daily drink. Additionally, there was an eight to 10 percent increase in the size of the brain ventricles, which are areas filled with cerebrospinal fluid (CSF) that play a protective role in the brain. When white matter dies, CSF produced in the ventricles fills the ventricular space.
Recovery of white matter brain volume also was examined. They found that, in men, the corpus callosum recovered at a rate of one percent per year for each additional year of abstinence. For people who abstained less than a year, the researchers found evidence of increased white matter volume and decreased ventricular volume in women, but not at all in men. However, for people in recovery for more than a year, those signs of recovery disappeared in women and became apparent in men.
‘These findings preliminarily suggest that restoration and recovery of the brain’s white matter among alcoholics occurs later in abstinence for men than for women,’ said Mosher Ruiz. ‘We hope that additional research in this area can help lead to improved treatment methods that include educating both alcoholic men and women about the harmful effects of excessive drinking and the potential for recovery with sustained abstinence.’
Boston University Medical Center
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Researchers for the first time have shown that members of a family of enzymes known as cathepsins – which are implicated in many disease processes – may attack one another instead of the bodily proteins they normally degrade. Dubbed ‘cathepsin cannibalism,’ the phenomenon may help explain problems with drugs that have been developed to inhibit the effects of these powerful proteases.
Cathepsins are involved in disease processes as varied as cancer metastasis, atherosclerosis, cardiovascular disease, osteoporosis and arthritis. Because cathepsins have harmful effects on critical proteins such as collagen and elastin, pharmaceutical companies have been developing drugs to inhibit activity of the enzymes, but so far these compounds have had too many side effects to be useful and have failed clinical trials.
Using a combination of modelling and experiments, researchers from the Georgia Institute of Technology and Emory University have shown that one type of cathepsin preferentially attacks another, reducing the enzyme’s degradation of collagen. The work could affect not only the development of drugs to inhibit cathepsin activity, but could also lead to a better understanding of how the enzymes work together.
‘These findings provide a new way of thinking about how these proteases are working with and against each other to remodel tissue – or fight against each other,’ said Manu Platt, an assistant professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University. ‘There has been an assumption that these cathepsins have been inert in relationship to one another, when in actuality they have been attacking one another. We think this may have broader implications for other classes of proteases.’
Platt and student Zachary Barry made their discovery accidentally while investigating the effects of cathepsin K and cathepsin S – two of the 11-member cathepsin family. Cathepsin K degrades both collagen and elastin, and is one of the most powerful proteases. Cathepsin S degrades elastin, and does not strongly attack collagen.
When the researchers combined the two cathepsins and allowed them to attack samples of elastin, they expected to see increased degradation of the protein. What they saw, however, was not much more damage than cathepsin K did by itself.
Platt at first believed the experiment was flawed, and asked Barry – an undergraduate student in his lab who specialises in modelling – to examine what possible conditions could account for the experimental result. Barry’s modelling suggested that effects observed could occur if cathepsin S were degrading cathepsin K instead of attacking the elastin – a protein essential in arteries and the cardiovascular system.
That theoretical result led to additional experiments in which the researchers measured a direct correlation between an increase in the amount of cathepsin S added to the experiment and a reduction in the degradation of collagen. By increasing the amount of cathepsin S ten-fold over the amount used in the original experiment, Platt and Barry were able to completely block the activity of cathepsin K, preventing damage to the collagen sample.
‘We saw that the cathepsin K was going away much faster when there was cathepsin S present than when it was by itself,’ said Platt, who is also a Georgia Cancer Coalition Distinguished Scholar and a Fellow of the Keystone Symposia on Molecular and Cellular Biology. ‘We kept increasing the amount of cathepsin S until the collagen was not affected at all because all of the cathepsin K was eaten by the cathepsin S.’
The researchers used a variety of tests to determine the amount of each enzyme, including fluorogenic substrate analysis, Western blotting and multiplex cathepsin zymography – a sensitive technique developed in the Platt laboratory.
Beyond demonstrating for the first time that cathepsins can attack one another, the research also shows the complexity of the body’s enzyme system – and may suggest why drugs designed to inhibit cathepsins haven’t worked as intended.
‘The effect of the cathepsins on one another complicates the system,’ said Platt. ‘If you are targeting this system pharmaceutically, you may not have the types or quantities of cathepsins that you expect, which could cause off-
Georgia Institute of Technology Research News
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Genetics researchers have identified a key gene that, when mutated, causes the rare multisystem disorder Cornelia deLange syndrome (CdLS). By revealing how mutations in the HDAC8 gene disrupt the biology of proteins that control both gene expression and cell division, the research sheds light on this disease, which causes intellectual disability, limb deformations and other disabilities resulting from impairments in early development.
‘As we better understand how CdLS operates at the level of cell biology, we will be better able to define strategies for devising treatments for CdLS, and possibly for related disorders,’ said study leader Matthew A. Deardorff, M.D., Ph.D., a pediatric genetics clinician and scientist at The Children’s Hospital of Philadelphia. Deardorff also is in the Perelman School of Medicine at the University of Pennsylvania.
The current findings add to previous discoveries by researchers at The Children’s Hospital of Philadelphia. A group led by Ian Krantz, M.D., and Laird Jackson, M.D., announced in 2004 that mutations in the NIPBL gene are the primary cause of CdLS, accounting for roughly 60 percent of the ‘classical’ cases of the disease. In 2007, Deardorff joined them to describe mutations in two additional genes, SMC1A and SMC3. First described in 1933, CdLS affects an estimated 1 in 10,000 children.
The CdLS research team at Children’s Hospital has focused on the cohesin complex, a group of proteins that form a bracelet-like structure that encircles pairs of chromosomes, called sister chromatids. ‘Cohesin has two roles,’ said Deardorff. ‘It keeps sister chromatids together during cell division, and it allows normal transcription—the transmission of information from DNA to RNA.’
Deardorff added that mutations that perturb normal cohesin function can interfere with normal human development. Such is the case in CdLS, which exemplifies a newly recognised class of diseases called cohesinopathies.
In the current study, the scientists investigated both acetylation—how an acetyl molecule is attached to part of the cohesin complex—and deactylation, the removal of that molecule. Normally, deactylation helps recycle cohesin to make it available during successive rounds of cell division. The study team found that mutations in the HDAC8 gene threw off normal cellular recycling of cohesin.
Mutations in the gene cause loss of HDAC8 protein activity, and consequently decrease the amount of ‘recharged’ cohesin available to properly regulate gene transcription. This, in turn, the researchers suggest, impairs normal embryonic development and gives rise to CdLS.
The researchers showed in cell cultures that mutations in HDAC8 lead to a decrease in cohesin binding to genes, similar to that seen for cells deficient in the NIPBL gene. They also identified HDAC8 mutations in approximately 5 percent of patients with CdLS.
Because mothers of children with CdLS may carry mutations in the HDAC8 gene, identifying these mutations will be very useful in accurately counseling families of their recurrence risk—the likelihood of having a subsequent child with CdLS.
Furthermore, added Deardorff, by providing biological details of the underlying defect in CdLS, the current research suggests future approaches to treating the genetic disease. ‘By concentrating downstream on the biological pathway in the cohesin cycle rather than focusing on the defective gene, we may be able to eventually screen for small-molecule drugs that could be used to intervene in CdLS.’
Children’s Hospital of Philadelphia
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Researchers have identified 38 new genetic regions that are associated with glucose and insulin levels in the blood. This brings the total number of genetic regions associated with glucose and insulin levels to 53, over half of which are associated with type 2 diabetes.
The researchers used a technology that is 100 times more powerful than previous techniques used to follow-up on genome-wide association results. This technology, Metabochip, was designed as a cost-effective way to find and map genomic regions for a range of cardiovascular and metabolic characteristics on a large scale. Previous approaches were not cost effective and tested only 30-40 DNA sequence variations, but this chip allowed researchers to look at up to 200,000 DNA sequence variations for many different traits at one time. The team hoped to find new variants influencing blood glucose and insulin traits and to identify pathways involved in the regulation of insulin and glucose levels.
‘We wanted to use this improved Metabochip technology to see whether we could find additional genomic associations that may have been previously missed,’ says Dr Claudia Langenberg, co-lead author from the Medical Research Council Epidemiology Unit, Cambridge. ‘Our earlier work identified 23 genetic regions associated with blood glucose levels, highlighting important biological pathways involved in the regulation of glucose. At that stage, and before the design of the Metabochip, we were still limited by our capacity to quickly follow-up and afford parallel genotyping of promising, but unconfirmed genetic regions associated with glucose levels in many different studies across the world.’
The team combined data from new samples typed on the Metabochip with data from a previous study to discover genetic regions associated with blood glucose and insulin levels. They identified 38 previously unknown regions for three different quantitative traits associated with blood glucose levels; fasting glucose concentrations, fasting insulin concentrations and post-challenge glucose concentrations.
.’ Further analysis such as genetic mapping or ‘fine-mapping’ and functional analysis will expand and improve our understanding of the control of glucose and insulin levels in healthy persons and what goes wrong in type 2 diabetes patients. ‘
…’Our research is beginning to allow us to look at the overlap between genomic regions that influence insulin levels and other metabolic traits,’ says Dr Inga Prokopenko, co-lead author from the University of Oxford. ‘We observed some overlap between the regions we identified and genetic regions associated with abdominal obesity and various lipid levels, which are a hallmark of insulin resistance. We hope that these studies will help to find gene networks with potential key modifiers for important metabolic processes and related diseases, such as type 2 diabetes.’
The team also found many more, less significant, genetic regions that may be associated with blood glucose and insulin levels but currently don’t have the available data to definitively establish them as genome-wide significant. This supports previous evidence that there is a long tail of many other genetic regions that add up to quite small genetic effects but may increase the risk of such diseases as diabetes. Collectively, these less significant associations may represent important blood glucose and insulin level associations.
‘In addition to these top signals there is statistical evidence that many other regions that appear to be biologically plausible also influence these traits, but what’s limiting is that we don’t have large enough sample sizes to have the power to validate them,’ explains Dr Inês Barroso, co-lead author from the Wellcome Trust Sanger Institute. ‘Nevertheless, studying these functionally would be extremely beneficial if we want to fully understand the biology of blood glucose levels and the origin of diabetes.’
‘What we’ve found in this study is a number of genomic regions that influence blood glucose and insulin traits. Further analysis such as genetic mapping or ‘fine-mapping’ and functional analysis will expand and improve our understanding of the control of glucose and insulin levels in healthy persons and what goes wrong in type 2 diabetes patients.’
Wellcome Trust Sanger Institute
For the millions of people world-wide with type 1 diabetes who cannot produce sufficient insulin, the potential to transplant insulin-producing cells could offer hope for a long-term cure. The discovery of a marker to help identify and isolate stem cells that can develop into insulin-producing cells in the pancreas would be a critical step forward.
Pancreatic stem cells, the precursors of insulin-producing cells, have not yet been identified in humans or animals, and there is much debate about where they may reside. Ivka Afrikanova, Ayse Kayali, Ana Lopez, and Alberto Hayek, University of California, San Diego, CA, have identified a biochemical marker—stage-specific embryonic antigen 4 (SSEA4)—that they propose can be used to identify and purify human pancreatic stem cells. The article ‘Is Stage-Specific Embryonic Antigen 4 a Marker for Human Ductal Stem/Progenitor Cells’ reports that when grown in culture with high levels of glucose and B27, these SSEA4+ stem cells can differentiate into insulin-producing pancreatic cells.
EurekAlert
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A research team from King’s College London and the University of Exeter Medical School has identified how a genetic mutation acts during the development of nerves responsible for controlling eye muscles, resulting in movement disorders such as Duane Syndrome, a form of squint.
The findings could provide the key to reversing the condition and unlocking the causes of movement disorders in other parts of the body.
As nerves develop in the womb they respond to signals that tell them in which direction to grow. Some signals encourage them to grow to a particular part of the body, while other signals tell them to avoid certain areas.
When the system works as it should, the right type of nerve grows to the appropriate part of the body.
The surface of growing nerves includes identification receptors that respond to signals from secreted proteins. The protein mutated in Duane Syndrome acts as a switch that weighs up incoming signals from the receptors – in this way the nerve knows whether it must grow towards a part of the body or be repulsed away.
In conditions such as Duane Syndrome, the signalling breaks down and the nerve cells are unable to distinguish between a signal of attraction or repulsion. As a result, the nerves that control eye movements grow to the wrong muscles causing limited or complete loss of eye movement. If not corrected surgically, this can lead to partial blindness in later life.
This recent research has provided new insights into how this ‘switch signal’ system works and how it has failed in cases of Duane Syndrome, causing the ‘wiring up’ of the wrong muscle or ‘overshooting’ of nerve development past the correct muscle.
The findings are likely to lead to further study which will identify how the ‘switch signal’ mechanism could be harnessed to selectively change nerve cell development behaviour, how the protein could be targeted to encourage damaged cells to re-grow, and how the ‘switch’ could be manipulated to reverse damage.
EurekAlert
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In a comparison of novel cardiovascular risk markers, coronary artery calcium, ankle-brachial index, high-sensitivity C-reactive protein, and family history were independent predictors of coronary heart disease/cardiovascular disease in intermediate-risk individuals beyond traditional risk factors, with coronary artery calcium providing superior discrimination and risk reclassification compared with other risk markers, according to a study.
‘Current trends in primary prevention of cardiovascular disease (CVD) emphasise the need to treat individuals based on their global cardiovascular risk. Accordingly, practice guidelines recommend approaches to classify individuals as high, intermediate, or low risk using the Framingham Risk Score (FRS) or other similar CVD risk prediction models. However, there is increasing recognition of the imprecision of these classifications such that the intermediate-risk group actually represents a composite of higher-risk individuals for whom more aggressive (i.e., drug) therapy might be indicated. The intermediate-risk group also contains lower-risk individuals in whom CVD might be managed with lifestyle measures alone. This recognition has motivated researchers to identify markers that could offer greater discrimination of higher- and lower-risk patients within the intermediate-risk group,’ according to background information in the article.
‘Risk markers including coronary artery calcium (CAC), carotid intima-media thickness (CIMT), ankle-brachial index (ABI), brachial flow-mediated dilation (FMD), high-sensitivity C-reactive protein (CRP), and family history of coronary heart disease (CHD) have been reported to improve on the Framingham Risk Score for prediction of CHD, but there are no direct comparisons of these markers for risk prediction in a single cohort,’ the authors write.
Joseph Yeboah, M.D., M.S., of the Wake Forest University School of Medicine, Winston-Salem, N.C., and colleagues assessed the improvements in CHD/CVD prediction accuracy and reclassification to high- and low-risk categories using CIMT, CAC, FMD, ABI, high-sensitivity CRP, and family history of CHD in asymptomatic adults classified as intermediate risk who participated in the Multi-Ethnic Study of Atherosclerosis (MESA). Of 6,814 MESA participants from 6 U.S. field centres, 1,330 were intermediate risk, without diabetes mellitus, and had complete data on all 6 markers. Recruitment spanned July 2000 to September 2002, with follow-up through May 2011. Analysis was conducted to compare incremental contributions of each marker when added to the FRS, plus race/ethnicity. Incident CHD was defined as heart attack, angina followed by revascularisation, resuscitated cardiac arrest, or CHD death. Incident CVD additionally included stroke or CVD death.
After a median (midpoint) follow-up of 7.6 years, 94 participants (7.1 percent) experienced a CHD event and 123 (9.2 percent) experienced a CVD event. After analyses, the researchers found that each of the novel risk markers was associated with incident CHD; however, after adjusting for confounders, the associations with CIMT and FMD were no longer significant. Among all of the risk markers, CAC had the strongest association. Similarly, for incident CVD, each of the markers was associated with events except high-sensitivity CRP. However, after adjusting for confounders, the associations between CIMT and FMD were no longer significant. CAC also had the strongest association in the multivariable models for CVD.
‘The current study shows that among 6 of the most promising novel risk markers, CAC provides the highest improvement in discrimination over the FRS and Reynolds score (RS) in individuals classified as intermediate risk. The present study provides additional support for the use of CAC as a tool for refining cardiovascular risk prediction in individuals classified as intermediate risk by the FRS or the RS,’ the authors write. ‘Additional research is warranted to explore further both the costs and benefits of CAC screening in intermediate-risk individuals.’
Catalan researchers identify a key component of cell division
EurekAlert
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A new ‘traffic light’ test devised by Dr Nick Sheron and colleagues at University of Southampton and Southampton General Hospital could be used in primary care to diagnose liver fibrosis and cirrhosis in high risk populations more easily than at present.
Liver disease develops silently without symptoms, and many people have no idea they have liver failure until it is too late – one-third of people admitted to hospital with end-stage liver disease die within the first few months. A simple test available in primary care could diagnose disease much earlier, enabling those at risk to change their behaviour and save lives.
The Southampton Traffic Light (STL) test combines several different tests and clinical markers which are given a score that indicates the patient’s likelihood of developing liver fibrosis and liver cirrhosis.
The result comes in three colours: red means that the patient has liver scarring (fibrosis) and may even have cirrhosis, green means that there is no cirrhosis and the patient is highly unlikely to die from liver disease over the next five years. Amber means there is at least a 50:50 chance of scarring with a significant possibility of death within five years, and patients are advised to stop drinking to avoid further disease and death.
The test was given to over 1,000 patients, and their progress was carefully followed and monitored afterwards, in some cases over several years, to assess the accuracy of the test in predicting whether they developed liver fibrosis or cirrhosis.
The test proved to be accurate in severe liver disease, and while not a substitute for clinical judgement or other liver function tests, can provide GPs with an objective means to accurately assess the potential severity of liver fibrosis in high-risk patients – for example, heavy drinkers, those with type II diabetes, or obese people.
Dr Nick Sheron, lead author and Head of Clinical Hepatology at the University of Southampton, and consultant hepatologist at Southampton General Hospital, said: ‘We are reliant on general practitioners detecting liver disease in the community so they can intervene to prevent serious liver problems developing, but so far we haven’t been able to give them the tools they need to do this. We hope that this type of test for liver scarring may start to change this because the earlier we can detect liver disease, the more liver deaths we should be able to prevent.’
University of Southampton
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People with Parkinson’s disease performed markedly better on a test of working memory after a night’s sleep, and sleep disorders can interfere with that benefit, researchers have shown.
While the classic symptoms of Parkinson’s disease include tremors and slow movements, Parkinson’s can also affect someone’s memory, including ‘working memory.’ Working memory is defined as the ability to temporarily store and manipulate information, rather than simply repeat it. The use of working memory is important in planning, problem solving and independent living.
The findings underline the importance of addressing sleep disorders in the care of patients with Parkinson’s, and indicate that working memory capacity in patients with Parkinson’s potentially can be improved with training. The results also have implications for the biology of sleep and memory.
‘It was known already that sleep is beneficial for memory, but here, we’ve been able to analyse what aspects of sleep are required for the improvements in working memory performance,’ says postdoctoral fellow Michael Scullin, who is the first author of the paper. The senior author is Donald Bliwise, professor of neurology at Emory University School of Medicine.
The performance boost from sleep was linked with the amount of slow wave sleep, or the deepest stage of sleep. Several research groups have reported that slow wave sleep is important for synaptic plasticity, the ability of brain cells to reorganise and make new connections.
Sleep apnea, the disruption of sleep caused by obstruction of the airway, interfered with sleep’s effects on memory. Study participants who showed signs of sleep apnea, if it was severe enough to lower their blood oxygen levels for more than five minutes, did not see a working memory test boost.
In this study, participants took a ‘digit span test,’ in which they had to repeat a list of numbers forward and backward. The test was conducted in an escalating fashion: the list grows incrementally until someone makes a mistake. Participants took the digit span test eight times during a 48-hour period, four during the first day and four during the second. In between, they slept.
Repeating numbers in the original order is a test of short-term memory, while repeating the numbers in reverse order is a test of working memory.
‘Repeating the list in reverse order requires some effort to manipulate the numbers, not just spit them back out again,’ Scullin says. ‘It’s also a purely verbal test, which is important when working with a population that may have motor impairments.’
54 study participants had Parkinson’s disease, and 10 had dementia with Lewy bodies: a more advanced condition, where patients may have hallucinations or fluctuating cognition as well as motor symptoms. Those who had dementia with Lewy bodies saw no working memory boost from the night’s rest. As expected, their baseline level of performance was lower than the Parkinson’s group.
Participants with Parkinson’s who were taking dopamine-enhancing medications saw their performance on the digit span test jump up between the fourth and fifth test. On average, they could remember one more number backwards. The ability to repeat numbers backward improved, even though the ability to repeat numbers forward did not.
Patients needed to be taking dopamine-enhancing medications to see the most performance benefit from sleep. Patients not taking dopamine medications, even though they had generally had Parkinson’s for less time, did not experience as much of a performance benefit. This may reflect a role for dopamine, an important neurotransmitter, in memory.
Emory University
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A simple blood test for Creutzfeldt-Jakob Disease and Mad Cow disease is a step closer, following a breakthrough by medical researchers at the University of Melbourne.
Using newly available genetic sequencing scientists discovered cells infected with prions (the infectious agent responsible for these diseases) release particles which contain easily recognised ‘signature genes’.
Associate Professor Andrew Hill — from the Department of Biochemistry and Molecular Biology at the Bio21 Institute — said these particles travel in the blood stream, making a diagnostic blood test a possibility.
‘This might provide a way to screen people who have spent time in the UK, who currently face restrictions on their ability to donate blood,’ he said.
‘With a simple blood test nurses could deem a prospective donor’s blood as healthy, with the potential to significantly boost critical blood stocks.’
Mad Cow disease was linked to the deaths of nearly 200 people in Great Britain who consumed meat from infected animals in the late 1980s.
Since 2000, the Australia Red Cross Blood Service has not accepted blood from anybody who lived in the UK for more than six months between 1980 and 1996, or who received a blood transfusion in the UK after 1980.
Lead author Dr Shayne Bellingham said the breakthrough might also help detect other human neurodegenerative diseases, such as Alzheimer’s and Parkinson’s.
‘This is an exciting new field where we can test for conditions in the brain and throughout the body, without being invasive,’ he said.
The researchers’ genetic testing focused on a form of cell discharge called exosomes.
If exosomes were infected with prions (the pathogen that causes Creutzfeldt-Jakob Disease and Bovine Spongiform Encephalopathy, commonly known as Mad Cow Disease) they were found to also carry a specific signature of small genes called microRNA’s.
University of Melbourne
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Researchers uncover gender differences in the effects of long-term alcoholism
, /in E-News /by 3wmediaResearchers from Boston University School of Medicine (BUSM) and Veterans Affairs (VA) Boston Healthcare System have demonstrated that the effects on white matter brain volume from long-term alcohol abuse are different for men and women. The study also suggests that with abstinence, women recover their white matter brain volume more quickly than men.
The study was led by Susan Mosher Ruiz, PhD, postdoctoral research scientist in the Laboratory for Neuropsychology at BUSM and research scientist at the VA Boston Healthcare System, and Marlene Oscar Berman, PhD, professor of psychiatry, neurology and anatomy and neurobiology at BUSM and research career scientist at the VA Boston Healthcare System.
In previous research, alcoholism has been associated with white matter pathology. White matter forms the connections between neurons, allowing communication between different areas of the brain. While previous neuroimaging studies have shown an association between alcoholism and white matter reduction, this study furthered the understanding of this effect by examining gender differences and utilising a novel region-of-interest approach.
The research team employed structural magnetic resonance imaging (MRI) to determine the effects of drinking history and gender on white matter volume. They examined brain images from 42 abstinent alcoholic men and women who drank heavily for more than five years and 42 non-alcoholic control men and women. Looking at the correlation between years of alcohol abuse and white matter volume, the researchers found that a greater number of years of alcohol abuse was associated with smaller white matter volumes in the abstinent alcoholic men and women. In the men, the decrease was observed in the corpus callosum while in women, this effect was observed in cortical white matter regions.
‘We believe that many of the cognitive and emotional deficits observed in people with chronic alcoholism, including memory problems and flat affect, are related to disconnections that result from a loss of white matter,’ said Mosher Ruiz.
The researchers also examined if the average number of drinks consumed per day was associated with reduced white matter volume. They found that the number of daily drinks did have a strong impact on alcoholic women, and the volume loss was one and a half to two percent for each additional daily drink. Additionally, there was an eight to 10 percent increase in the size of the brain ventricles, which are areas filled with cerebrospinal fluid (CSF) that play a protective role in the brain. When white matter dies, CSF produced in the ventricles fills the ventricular space.
Recovery of white matter brain volume also was examined. They found that, in men, the corpus callosum recovered at a rate of one percent per year for each additional year of abstinence. For people who abstained less than a year, the researchers found evidence of increased white matter volume and decreased ventricular volume in women, but not at all in men. However, for people in recovery for more than a year, those signs of recovery disappeared in women and became apparent in men.
‘These findings preliminarily suggest that restoration and recovery of the brain’s white matter among alcoholics occurs later in abstinence for men than for women,’ said Mosher Ruiz. ‘We hope that additional research in this area can help lead to improved treatment methods that include educating both alcoholic men and women about the harmful effects of excessive drinking and the potential for recovery with sustained abstinence.’ Boston University Medical Center
Enzymes implicated in disease processes attack one another instead of harming body proteins
, /in E-News /by 3wmediaResearchers for the first time have shown that members of a family of enzymes known as cathepsins – which are implicated in many disease processes – may attack one another instead of the bodily proteins they normally degrade. Dubbed ‘cathepsin cannibalism,’ the phenomenon may help explain problems with drugs that have been developed to inhibit the effects of these powerful proteases.
Cathepsins are involved in disease processes as varied as cancer metastasis, atherosclerosis, cardiovascular disease, osteoporosis and arthritis. Because cathepsins have harmful effects on critical proteins such as collagen and elastin, pharmaceutical companies have been developing drugs to inhibit activity of the enzymes, but so far these compounds have had too many side effects to be useful and have failed clinical trials.
Using a combination of modelling and experiments, researchers from the Georgia Institute of Technology and Emory University have shown that one type of cathepsin preferentially attacks another, reducing the enzyme’s degradation of collagen. The work could affect not only the development of drugs to inhibit cathepsin activity, but could also lead to a better understanding of how the enzymes work together.
‘These findings provide a new way of thinking about how these proteases are working with and against each other to remodel tissue – or fight against each other,’ said Manu Platt, an assistant professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University. ‘There has been an assumption that these cathepsins have been inert in relationship to one another, when in actuality they have been attacking one another. We think this may have broader implications for other classes of proteases.’
Platt and student Zachary Barry made their discovery accidentally while investigating the effects of cathepsin K and cathepsin S – two of the 11-member cathepsin family. Cathepsin K degrades both collagen and elastin, and is one of the most powerful proteases. Cathepsin S degrades elastin, and does not strongly attack collagen.
When the researchers combined the two cathepsins and allowed them to attack samples of elastin, they expected to see increased degradation of the protein. What they saw, however, was not much more damage than cathepsin K did by itself.
Platt at first believed the experiment was flawed, and asked Barry – an undergraduate student in his lab who specialises in modelling – to examine what possible conditions could account for the experimental result. Barry’s modelling suggested that effects observed could occur if cathepsin S were degrading cathepsin K instead of attacking the elastin – a protein essential in arteries and the cardiovascular system.
That theoretical result led to additional experiments in which the researchers measured a direct correlation between an increase in the amount of cathepsin S added to the experiment and a reduction in the degradation of collagen. By increasing the amount of cathepsin S ten-fold over the amount used in the original experiment, Platt and Barry were able to completely block the activity of cathepsin K, preventing damage to the collagen sample.
‘We saw that the cathepsin K was going away much faster when there was cathepsin S present than when it was by itself,’ said Platt, who is also a Georgia Cancer Coalition Distinguished Scholar and a Fellow of the Keystone Symposia on Molecular and Cellular Biology. ‘We kept increasing the amount of cathepsin S until the collagen was not affected at all because all of the cathepsin K was eaten by the cathepsin S.’
The researchers used a variety of tests to determine the amount of each enzyme, including fluorogenic substrate analysis, Western blotting and multiplex cathepsin zymography – a sensitive technique developed in the Platt laboratory.
Beyond demonstrating for the first time that cathepsins can attack one another, the research also shows the complexity of the body’s enzyme system – and may suggest why drugs designed to inhibit cathepsins haven’t worked as intended.
‘The effect of the cathepsins on one another complicates the system,’ said Platt. ‘If you are targeting this system pharmaceutically, you may not have the types or quantities of cathepsins that you expect, which could cause off- Georgia Institute of Technology Research News
Researchers at The Children’s Hospital of Philadelphia identify new gene in Cornelia deLange syndrome
, /in E-News /by 3wmediaGenetics researchers have identified a key gene that, when mutated, causes the rare multisystem disorder Cornelia deLange syndrome (CdLS). By revealing how mutations in the HDAC8 gene disrupt the biology of proteins that control both gene expression and cell division, the research sheds light on this disease, which causes intellectual disability, limb deformations and other disabilities resulting from impairments in early development.
‘As we better understand how CdLS operates at the level of cell biology, we will be better able to define strategies for devising treatments for CdLS, and possibly for related disorders,’ said study leader Matthew A. Deardorff, M.D., Ph.D., a pediatric genetics clinician and scientist at The Children’s Hospital of Philadelphia. Deardorff also is in the Perelman School of Medicine at the University of Pennsylvania.
The current findings add to previous discoveries by researchers at The Children’s Hospital of Philadelphia. A group led by Ian Krantz, M.D., and Laird Jackson, M.D., announced in 2004 that mutations in the NIPBL gene are the primary cause of CdLS, accounting for roughly 60 percent of the ‘classical’ cases of the disease. In 2007, Deardorff joined them to describe mutations in two additional genes, SMC1A and SMC3. First described in 1933, CdLS affects an estimated 1 in 10,000 children.
The CdLS research team at Children’s Hospital has focused on the cohesin complex, a group of proteins that form a bracelet-like structure that encircles pairs of chromosomes, called sister chromatids. ‘Cohesin has two roles,’ said Deardorff. ‘It keeps sister chromatids together during cell division, and it allows normal transcription—the transmission of information from DNA to RNA.’
Deardorff added that mutations that perturb normal cohesin function can interfere with normal human development. Such is the case in CdLS, which exemplifies a newly recognised class of diseases called cohesinopathies.
In the current study, the scientists investigated both acetylation—how an acetyl molecule is attached to part of the cohesin complex—and deactylation, the removal of that molecule. Normally, deactylation helps recycle cohesin to make it available during successive rounds of cell division. The study team found that mutations in the HDAC8 gene threw off normal cellular recycling of cohesin.
Mutations in the gene cause loss of HDAC8 protein activity, and consequently decrease the amount of ‘recharged’ cohesin available to properly regulate gene transcription. This, in turn, the researchers suggest, impairs normal embryonic development and gives rise to CdLS.
The researchers showed in cell cultures that mutations in HDAC8 lead to a decrease in cohesin binding to genes, similar to that seen for cells deficient in the NIPBL gene. They also identified HDAC8 mutations in approximately 5 percent of patients with CdLS.
Because mothers of children with CdLS may carry mutations in the HDAC8 gene, identifying these mutations will be very useful in accurately counseling families of their recurrence risk—the likelihood of having a subsequent child with CdLS.
Furthermore, added Deardorff, by providing biological details of the underlying defect in CdLS, the current research suggests future approaches to treating the genetic disease. ‘By concentrating downstream on the biological pathway in the cohesin cycle rather than focusing on the defective gene, we may be able to eventually screen for small-molecule drugs that could be used to intervene in CdLS.’ Children’s Hospital of Philadelphia
Metabolic MAGIC
, /in E-News /by 3wmediaResearchers have identified 38 new genetic regions that are associated with glucose and insulin levels in the blood. This brings the total number of genetic regions associated with glucose and insulin levels to 53, over half of which are associated with type 2 diabetes.
The researchers used a technology that is 100 times more powerful than previous techniques used to follow-up on genome-wide association results. This technology, Metabochip, was designed as a cost-effective way to find and map genomic regions for a range of cardiovascular and metabolic characteristics on a large scale. Previous approaches were not cost effective and tested only 30-40 DNA sequence variations, but this chip allowed researchers to look at up to 200,000 DNA sequence variations for many different traits at one time. The team hoped to find new variants influencing blood glucose and insulin traits and to identify pathways involved in the regulation of insulin and glucose levels.
‘We wanted to use this improved Metabochip technology to see whether we could find additional genomic associations that may have been previously missed,’ says Dr Claudia Langenberg, co-lead author from the Medical Research Council Epidemiology Unit, Cambridge. ‘Our earlier work identified 23 genetic regions associated with blood glucose levels, highlighting important biological pathways involved in the regulation of glucose. At that stage, and before the design of the Metabochip, we were still limited by our capacity to quickly follow-up and afford parallel genotyping of promising, but unconfirmed genetic regions associated with glucose levels in many different studies across the world.’
The team combined data from new samples typed on the Metabochip with data from a previous study to discover genetic regions associated with blood glucose and insulin levels. They identified 38 previously unknown regions for three different quantitative traits associated with blood glucose levels; fasting glucose concentrations, fasting insulin concentrations and post-challenge glucose concentrations.
.’ Further analysis such as genetic mapping or ‘fine-mapping’ and functional analysis will expand and improve our understanding of the control of glucose and insulin levels in healthy persons and what goes wrong in type 2 diabetes patients. ‘
…’Our research is beginning to allow us to look at the overlap between genomic regions that influence insulin levels and other metabolic traits,’ says Dr Inga Prokopenko, co-lead author from the University of Oxford. ‘We observed some overlap between the regions we identified and genetic regions associated with abdominal obesity and various lipid levels, which are a hallmark of insulin resistance. We hope that these studies will help to find gene networks with potential key modifiers for important metabolic processes and related diseases, such as type 2 diabetes.’
The team also found many more, less significant, genetic regions that may be associated with blood glucose and insulin levels but currently don’t have the available data to definitively establish them as genome-wide significant. This supports previous evidence that there is a long tail of many other genetic regions that add up to quite small genetic effects but may increase the risk of such diseases as diabetes. Collectively, these less significant associations may represent important blood glucose and insulin level associations.
‘In addition to these top signals there is statistical evidence that many other regions that appear to be biologically plausible also influence these traits, but what’s limiting is that we don’t have large enough sample sizes to have the power to validate them,’ explains Dr Inês Barroso, co-lead author from the Wellcome Trust Sanger Institute. ‘Nevertheless, studying these functionally would be extremely beneficial if we want to fully understand the biology of blood glucose levels and the origin of diabetes.’
‘What we’ve found in this study is a number of genomic regions that influence blood glucose and insulin traits. Further analysis such as genetic mapping or ‘fine-mapping’ and functional analysis will expand and improve our understanding of the control of glucose and insulin levels in healthy persons and what goes wrong in type 2 diabetes patients.’ Wellcome Trust Sanger Institute
New marker for identifying precursors to insulin-producing cells in pancreas
, /in E-News /by 3wmediaFor the millions of people world-wide with type 1 diabetes who cannot produce sufficient insulin, the potential to transplant insulin-producing cells could offer hope for a long-term cure. The discovery of a marker to help identify and isolate stem cells that can develop into insulin-producing cells in the pancreas would be a critical step forward.
Pancreatic stem cells, the precursors of insulin-producing cells, have not yet been identified in humans or animals, and there is much debate about where they may reside. Ivka Afrikanova, Ayse Kayali, Ana Lopez, and Alberto Hayek, University of California, San Diego, CA, have identified a biochemical marker—stage-specific embryonic antigen 4 (SSEA4)—that they propose can be used to identify and purify human pancreatic stem cells. The article ‘Is Stage-Specific Embryonic Antigen 4 a Marker for Human Ductal Stem/Progenitor Cells’ reports that when grown in culture with high levels of glucose and B27, these SSEA4+ stem cells can differentiate into insulin-producing pancreatic cells. EurekAlert
Research identifies mechanism responsible for eye movement disorder
, /in E-News /by 3wmediaA research team from King’s College London and the University of Exeter Medical School has identified how a genetic mutation acts during the development of nerves responsible for controlling eye muscles, resulting in movement disorders such as Duane Syndrome, a form of squint.
The findings could provide the key to reversing the condition and unlocking the causes of movement disorders in other parts of the body.
As nerves develop in the womb they respond to signals that tell them in which direction to grow. Some signals encourage them to grow to a particular part of the body, while other signals tell them to avoid certain areas.
When the system works as it should, the right type of nerve grows to the appropriate part of the body.
The surface of growing nerves includes identification receptors that respond to signals from secreted proteins. The protein mutated in Duane Syndrome acts as a switch that weighs up incoming signals from the receptors – in this way the nerve knows whether it must grow towards a part of the body or be repulsed away.
In conditions such as Duane Syndrome, the signalling breaks down and the nerve cells are unable to distinguish between a signal of attraction or repulsion. As a result, the nerves that control eye movements grow to the wrong muscles causing limited or complete loss of eye movement. If not corrected surgically, this can lead to partial blindness in later life.
This recent research has provided new insights into how this ‘switch signal’ system works and how it has failed in cases of Duane Syndrome, causing the ‘wiring up’ of the wrong muscle or ‘overshooting’ of nerve development past the correct muscle.
The findings are likely to lead to further study which will identify how the ‘switch signal’ mechanism could be harnessed to selectively change nerve cell development behaviour, how the protein could be targeted to encourage damaged cells to re-grow, and how the ‘switch’ could be manipulated to reverse damage. EurekAlert
Measure of coronary artery calcium linked with improved prediction of cardiovascular disease risk
, /in E-News /by 3wmediaIn a comparison of novel cardiovascular risk markers, coronary artery calcium, ankle-brachial index, high-sensitivity C-reactive protein, and family history were independent predictors of coronary heart disease/cardiovascular disease in intermediate-risk individuals beyond traditional risk factors, with coronary artery calcium providing superior discrimination and risk reclassification compared with other risk markers, according to a study.
‘Current trends in primary prevention of cardiovascular disease (CVD) emphasise the need to treat individuals based on their global cardiovascular risk. Accordingly, practice guidelines recommend approaches to classify individuals as high, intermediate, or low risk using the Framingham Risk Score (FRS) or other similar CVD risk prediction models. However, there is increasing recognition of the imprecision of these classifications such that the intermediate-risk group actually represents a composite of higher-risk individuals for whom more aggressive (i.e., drug) therapy might be indicated. The intermediate-risk group also contains lower-risk individuals in whom CVD might be managed with lifestyle measures alone. This recognition has motivated researchers to identify markers that could offer greater discrimination of higher- and lower-risk patients within the intermediate-risk group,’ according to background information in the article.
‘Risk markers including coronary artery calcium (CAC), carotid intima-media thickness (CIMT), ankle-brachial index (ABI), brachial flow-mediated dilation (FMD), high-sensitivity C-reactive protein (CRP), and family history of coronary heart disease (CHD) have been reported to improve on the Framingham Risk Score for prediction of CHD, but there are no direct comparisons of these markers for risk prediction in a single cohort,’ the authors write.
Joseph Yeboah, M.D., M.S., of the Wake Forest University School of Medicine, Winston-Salem, N.C., and colleagues assessed the improvements in CHD/CVD prediction accuracy and reclassification to high- and low-risk categories using CIMT, CAC, FMD, ABI, high-sensitivity CRP, and family history of CHD in asymptomatic adults classified as intermediate risk who participated in the Multi-Ethnic Study of Atherosclerosis (MESA). Of 6,814 MESA participants from 6 U.S. field centres, 1,330 were intermediate risk, without diabetes mellitus, and had complete data on all 6 markers. Recruitment spanned July 2000 to September 2002, with follow-up through May 2011. Analysis was conducted to compare incremental contributions of each marker when added to the FRS, plus race/ethnicity. Incident CHD was defined as heart attack, angina followed by revascularisation, resuscitated cardiac arrest, or CHD death. Incident CVD additionally included stroke or CVD death.
After a median (midpoint) follow-up of 7.6 years, 94 participants (7.1 percent) experienced a CHD event and 123 (9.2 percent) experienced a CVD event. After analyses, the researchers found that each of the novel risk markers was associated with incident CHD; however, after adjusting for confounders, the associations with CIMT and FMD were no longer significant. Among all of the risk markers, CAC had the strongest association. Similarly, for incident CVD, each of the markers was associated with events except high-sensitivity CRP. However, after adjusting for confounders, the associations between CIMT and FMD were no longer significant. CAC also had the strongest association in the multivariable models for CVD.
‘The current study shows that among 6 of the most promising novel risk markers, CAC provides the highest improvement in discrimination over the FRS and Reynolds score (RS) in individuals classified as intermediate risk. The present study provides additional support for the use of CAC as a tool for refining cardiovascular risk prediction in individuals classified as intermediate risk by the FRS or the RS,’ the authors write. ‘Additional research is warranted to explore further both the costs and benefits of CAC screening in intermediate-risk individuals.’
Catalan researchers identify a key component of cell division EurekAlert
New ‘traffic light’ test could save lives with earlier diagnosis of liver disease
, /in E-News /by 3wmediaA new ‘traffic light’ test devised by Dr Nick Sheron and colleagues at University of Southampton and Southampton General Hospital could be used in primary care to diagnose liver fibrosis and cirrhosis in high risk populations more easily than at present.
Liver disease develops silently without symptoms, and many people have no idea they have liver failure until it is too late – one-third of people admitted to hospital with end-stage liver disease die within the first few months. A simple test available in primary care could diagnose disease much earlier, enabling those at risk to change their behaviour and save lives.
The Southampton Traffic Light (STL) test combines several different tests and clinical markers which are given a score that indicates the patient’s likelihood of developing liver fibrosis and liver cirrhosis.
The result comes in three colours: red means that the patient has liver scarring (fibrosis) and may even have cirrhosis, green means that there is no cirrhosis and the patient is highly unlikely to die from liver disease over the next five years. Amber means there is at least a 50:50 chance of scarring with a significant possibility of death within five years, and patients are advised to stop drinking to avoid further disease and death.
The test was given to over 1,000 patients, and their progress was carefully followed and monitored afterwards, in some cases over several years, to assess the accuracy of the test in predicting whether they developed liver fibrosis or cirrhosis.
The test proved to be accurate in severe liver disease, and while not a substitute for clinical judgement or other liver function tests, can provide GPs with an objective means to accurately assess the potential severity of liver fibrosis in high-risk patients – for example, heavy drinkers, those with type II diabetes, or obese people.
Dr Nick Sheron, lead author and Head of Clinical Hepatology at the University of Southampton, and consultant hepatologist at Southampton General Hospital, said: ‘We are reliant on general practitioners detecting liver disease in the community so they can intervene to prevent serious liver problems developing, but so far we haven’t been able to give them the tools they need to do this. We hope that this type of test for liver scarring may start to change this because the earlier we can detect liver disease, the more liver deaths we should be able to prevent.’ University of Southampton
Sleep improves memory in people with Parkinson’s disease
, /in E-News /by 3wmediaPeople with Parkinson’s disease performed markedly better on a test of working memory after a night’s sleep, and sleep disorders can interfere with that benefit, researchers have shown.
While the classic symptoms of Parkinson’s disease include tremors and slow movements, Parkinson’s can also affect someone’s memory, including ‘working memory.’ Working memory is defined as the ability to temporarily store and manipulate information, rather than simply repeat it. The use of working memory is important in planning, problem solving and independent living.
The findings underline the importance of addressing sleep disorders in the care of patients with Parkinson’s, and indicate that working memory capacity in patients with Parkinson’s potentially can be improved with training. The results also have implications for the biology of sleep and memory.
‘It was known already that sleep is beneficial for memory, but here, we’ve been able to analyse what aspects of sleep are required for the improvements in working memory performance,’ says postdoctoral fellow Michael Scullin, who is the first author of the paper. The senior author is Donald Bliwise, professor of neurology at Emory University School of Medicine.
The performance boost from sleep was linked with the amount of slow wave sleep, or the deepest stage of sleep. Several research groups have reported that slow wave sleep is important for synaptic plasticity, the ability of brain cells to reorganise and make new connections.
Sleep apnea, the disruption of sleep caused by obstruction of the airway, interfered with sleep’s effects on memory. Study participants who showed signs of sleep apnea, if it was severe enough to lower their blood oxygen levels for more than five minutes, did not see a working memory test boost.
In this study, participants took a ‘digit span test,’ in which they had to repeat a list of numbers forward and backward. The test was conducted in an escalating fashion: the list grows incrementally until someone makes a mistake. Participants took the digit span test eight times during a 48-hour period, four during the first day and four during the second. In between, they slept.
Repeating numbers in the original order is a test of short-term memory, while repeating the numbers in reverse order is a test of working memory.
‘Repeating the list in reverse order requires some effort to manipulate the numbers, not just spit them back out again,’ Scullin says. ‘It’s also a purely verbal test, which is important when working with a population that may have motor impairments.’
54 study participants had Parkinson’s disease, and 10 had dementia with Lewy bodies: a more advanced condition, where patients may have hallucinations or fluctuating cognition as well as motor symptoms. Those who had dementia with Lewy bodies saw no working memory boost from the night’s rest. As expected, their baseline level of performance was lower than the Parkinson’s group.
Participants with Parkinson’s who were taking dopamine-enhancing medications saw their performance on the digit span test jump up between the fourth and fifth test. On average, they could remember one more number backwards. The ability to repeat numbers backward improved, even though the ability to repeat numbers forward did not.
Patients needed to be taking dopamine-enhancing medications to see the most performance benefit from sleep. Patients not taking dopamine medications, even though they had generally had Parkinson’s for less time, did not experience as much of a performance benefit. This may reflect a role for dopamine, an important neurotransmitter, in memory. Emory University
Mad Cow’ blood test now on the horizon
, /in E-News /by 3wmediaA simple blood test for Creutzfeldt-Jakob Disease and Mad Cow disease is a step closer, following a breakthrough by medical researchers at the University of Melbourne.
Using newly available genetic sequencing scientists discovered cells infected with prions (the infectious agent responsible for these diseases) release particles which contain easily recognised ‘signature genes’.
Associate Professor Andrew Hill — from the Department of Biochemistry and Molecular Biology at the Bio21 Institute — said these particles travel in the blood stream, making a diagnostic blood test a possibility.
‘This might provide a way to screen people who have spent time in the UK, who currently face restrictions on their ability to donate blood,’ he said.
‘With a simple blood test nurses could deem a prospective donor’s blood as healthy, with the potential to significantly boost critical blood stocks.’
Mad Cow disease was linked to the deaths of nearly 200 people in Great Britain who consumed meat from infected animals in the late 1980s.
Since 2000, the Australia Red Cross Blood Service has not accepted blood from anybody who lived in the UK for more than six months between 1980 and 1996, or who received a blood transfusion in the UK after 1980.
Lead author Dr Shayne Bellingham said the breakthrough might also help detect other human neurodegenerative diseases, such as Alzheimer’s and Parkinson’s.
‘This is an exciting new field where we can test for conditions in the brain and throughout the body, without being invasive,’ he said.
The researchers’ genetic testing focused on a form of cell discharge called exosomes.
If exosomes were infected with prions (the pathogen that causes Creutzfeldt-Jakob Disease and Bovine Spongiform Encephalopathy, commonly known as Mad Cow Disease) they were found to also carry a specific signature of small genes called microRNA’s. University of Melbourne