Favourable results have led to crizotinib gaining approval for the treatment of advanced stage ALK-positive non-small cell lung cancer (NSCLC) in Japan, the United States, Canada, and several other countries in Europe and Asia. Now, the identification of an effective therapy for ALK-positive NSCLC places great emphasis on rapid, accurate, and cost-effective way to find patients with this subtype of lung cancer. A recent study concludes immunohistochemistry (IHC) is a reliable screening tool for identification of ALK rearrangement.
Fluorescence in situ hybridisation (FISH) is the current standard method to detect ALK rearrangement. However, FISH is not readily available as a routine method of pathology practice in most laboratories because it is time consuming and requires advanced technical and professional expertise. In contrast, IHC is relatively inexpensive, faster, and is perfectly adapted for routine practice by academics and most community hospitals.
Researchers screened 377 stage I or II NSCLC cases, diagnosed between 1978 and 2002. Tissue microarray results were available on 377 cases by IHC and 273 cases by FISH. Eleven cases were positive or possibly positive by either IHC or FISH, and three cases were positive or possibly positive by both methods.
They found, ‘that all cases exhibiting ALK rearrangement demonstrated adenocarcinoma histology.’ Their results report a sensitivity of 100 percent and high specificity with the IHC with no false-negative results. While researchers acknowledge that further study involving a larger cohort is recommended, IHC is a valid screening test.
The International Association for the Study of Lung Cancer
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Testing asthmatic children for a specific gene could prevent their condition worsening, according to new research by scientists in Brighton and Dundee.
The arginine-16 genotype of the beta-2 receptor is carried by one in seven sufferers and the research found their condition could be aggravated by the use of the long-term controller medicine, Salmeterol, a long acting beta-receptor stimulant, which is administered through an inhaler.
Testing children for the genotype would identify those who might react poorly to Salmeterol and means their asthma control may improve with the use of alternative medicines.
The research was carried out by – Professor Somnath Mukhopadhyay from the Brighton and Sussex Medical School (BSMS) which is run jointly by Brighton and Sussex universities, and Professor Brian Lipworth and genetics expert Professor Colin Palmer, both from the University of Dundee.
They carried out the first genotyped study comparing additional treatments given to asthmatic children who continue to experience symptoms despite use of their prescribed inhaled steroid preventer.
More than a million UK children have asthma and over 150,000 are affected by this genetic change, making them less likely to respond to Salmeterol. The researchers tested 62 children with the susceptible arginine-16 genotype. They had all missed school or had treatment at hospital or out-of-hours GP surgeries as a result of their asthma, despite being treated with regular inhaled steroids.
While continuing with their usual preventer, the children were randomly assigned to two treatment groups for the period of a year – Montelukast or Salmeterol.
The research found they responded better to an alternative anti-inflammatory medicine, Montelukast. They experienced an improved quality of life, wheezed and coughed much less, and were less likely to experience worsening of their symptoms and needing more ‘reliever’ treatment, compared to the Salmeterol users.
At the start of the research, 36 per cent of these children tested needed to use their relievers every day. But by the end of the year-long study, the number of children needing daily reliever use had halved in the group using Montelukast. In contrast, there was no improvement for the children in the Salmeterol group. This is despite the fact that Salmeterol is currently the preferred drug for children with asthma who are not controlled with inhaled steroids.
The researchers have warned that many children with serious asthma respond poorly to Salmeterol and may be suffering needlessly from asthma, regularly missing out on sports and recording low school attendances during long-term treatment with this medicine. They said their treatment may be made more effective with the help of a simple relatively inexpensive gene test.
Brighton and Sussex Medical School
For many women pregnancy is a happy and exciting time. However, for those who have had triple test results that indicate a high risk of Downs syndrome, things can become very stressful, not least because of the risks of miscarriage that are associated with chorionic villus sampling and amniocentesis that are required for a definitive answer. Now, however, a non-invasive molecular genetic blood test, the PrenaTest from Lifecodexx, for the detection of fetal trisomy 21 is available at over 150 qualified prenatal practices and clinics in Germany, Austria, Liechtenstein and Switzerland. Close to 1,000 women whose babies were classed at high risk of trisomy 21 have opted for the test, and evaluation of the PrenaTest analyses shows that the vast majority (97 % of the women tested) could be relieved with regard to the presence of trisomy 21 in their unborn child. Only 1.5 % of the analysed blood samples carried fetal trisomy 21, and as far as known, these positive results have been confirmed by amniocentesis. Another 1.5 % of the blood samples could initially not be reported primarily due to a low amount of cell-free fetal DNA. This is a major step forward in achieving fast, accurate, point-of-care testing at what is undoubtedly a worrying time.
http://tinyurl.com/bm4vmjg
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New research reveals a shared genetic susceptibility to epilepsy and migraine. Findings indicate that having a strong family history of seizure disorders increases the chance of having migraine with aura (MA).
Medical evidence has established that migraine and epilepsy often co-occur in patients; this co-occurrence is called ‘comorbidity.’ Previous studies have found that people with epilepsy are substantially more likely than the general population to have migraine headache. However, it is not clear whether that comorbidity results from a shared genetic cause.
‘Epilepsy and migraine are each individually influenced by genetic factors,’ explains lead author Dr. Melodie Winawer from Columbia University Medical Center in New York. ‘Our study is the first to confirm a shared genetic susceptibility to epilepsy and migraine in a large population of patients with common forms of epilepsy.’
For the present study, Dr. Winawer and colleagues analysed data collected from participants in the Epilepsy Phenome/Genome Project (EPGP)—a genetic study of epilepsy patients and families from 27 clinical centres in the U.S., Canada, Argentina, Australia, and New Zealand. The study examined one aspect of EPGP: sibling and parent-child pairs with focal epilepsy or generalised epilepsy of unknown cause. Most people with epilepsy have no family members affected with epilepsy. EPGP was designed to look at those rare families with more than one individual with epilepsy, in order to increase the chance of finding genetic causes of epilepsy.
Analysis of 730 participants with epilepsy from 501 families demonstrated that the prevalence of MA—when additional symptoms, such as blind spots or flashing lights, occur prior to the headache pain— was substantially increased when there were several individuals in the family with seizure disorders. EPGP study participants with epilepsy who had three or more additional close relatives with a seizure disorder were more than twice as likely to experience MA than patients from families with fewer individuals with seizures. In other words, the stronger the genetic effect on epilepsy in the family, the higher the rates of MA. This result provides evidence that a gene or genes exist that cause both epilepsy and migraine.
Identification of genetic contributions to the comorbidity of epilepsy with other disorders, like migraine, has implications for epilepsy patients. Prior research has shown that coexisting conditions impact the quality of life, treatment success, and mortality of epilepsy patients, with some experts suggesting that these comorbidities may have a greater impact on patients than the seizures themselves. In fact, comorbid conditions are emphasised in the National Institutes of Health Epilepsy Research Benchmarks and in a recent report on epilepsy from the Institute of Medicine.
‘Our study demonstrates a strong genetic basis for migraine and epilepsy, because the rate of migraine is increased only in people who have close (rather than distant) relatives with epilepsy and only when three or more family members are affected,’ concludes Dr. Winawer. ‘Further investigation of the genetics of groups of comorbid disorders and epilepsy will help to improve the diagnosis and treatment of these comorbidities, and enhance the quality of life for those with epilepsy.’
Columbia University Medical Center
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Researchers have found new evidence that metabolic stress can increase the onset of atrial arrhythmias, such as atrial fibrillation (AF), a common heart condition that causes an irregular and often abnormally fast heart rate. The findings may pave the way for the development of new therapies for the condition which can be expected to affect almost one in four of the UK population at some point in their lifetime.
The British Heart Foundation (BHF) study, led by University of Bristol scientists found that metabolic stress — a condition induced by insufficient oxygen supply to the heart (e.g. following blockage of a coronary artery) — caused marked changes in the electrical activity of the heart’s atria (the upper chambers of the heart).
While it has been recognised for many years that metabolic stress causes ventricular arrhythmias — abnormal heart rhythms that originate in the two lower chambers of the heart (the ventricles) and which form the basis to heart attacks — it is the first time it has been demonstrated for arrhythmias in the atria.
The research team led by Dr Andrew James from the University’s School of Physiology and Pharmacology together with Professor Saadeh Suleiman in the School of Clinical Sciences, examined the contribution of a particular kind of protein underlying the electrical activity of the atria during metabolic stress.
These proteins, known as KATP channels enable cells to respond to changes in metabolism. ATP (adenosine triphosphate) is a small molecule that represents the ‘energy currency’ for cell metabolism and when ATP levels inside cells fall, KATP channels are activated. For example, KATP channels in the pancreas are involved in the regulation of insulin secretion and drugs targeting these channels are used to treat type 2 diabetes mellitus.
Dr Andrew James, the study’s lead author, said: ‘It is well-established that KATP channels in the ventricles of the heart can become activated following metabolic stress caused by blockage of a coronary artery. In principle, their activation could protect the heart muscle cells against metabolic stress-induced damage. On the other hand, the activation of ventricular KATP channels can contribute to disturbances in the electrical activity of the heart known as arrhythmias.
‘Arrhythmias in the ventricles can be very dangerous, leading to ventricular fibrillation and death. Atrial arrhythmias, such as atrial fibrillation (AF), are not usually immediately fatal but they are very common and a major cause of stroke. Notably, KATP channels are also found in the atria but, in contrast to the ventricles, their role in atrial arrhythmias remains unknown.’
The findings show that metabolic stress caused marked changes in the electrical activity of the atrium consistent with the activation of KATP channels. Electrical stimulation was applied to try to evoke atrial arrhythmia. It was possible to induce atrial arrhythmia during, but not before, metabolic stress.
Importantly, blockade of KATP channels with drugs used to treat patients with type 2 diabetes (glibenclamide and tolbutamide), completely reversed the effects of metabolic stress on the electrical activity of the atrium and prevented the induction of atrial arrhythmia. The anti-diabetic drugs were without effect in the absence of metabolic stress.
The findings represent a ‘proof-of-principle’ (the stage at which any new drug must undergo before full-scale clinical trials can begin) that atrial KATP channels can be activated by metabolic stress and facilitate atrial arrhythmias. Thus, atrial KATP channels may represent a target for drugs for the treatment of atrial arrhythmias, such as atrial fibrillation.
However, Dr James added: ‘Further studies are required and a key point to address will be whether differences exist between the properties of atrial, ventricular and pancreatic KATP channels that might be exploited to produce an atrial-selective drug. Perhaps these channels might be useful as targets to treat atrial arrhythmias.’
Professor Jeremy Pearson, Associate Medical Director at the BHF, commented: ‘Atrial fibrillation is a very common irregular heart rhythm which greatly increases the risk of stroke. This study brings us closer to understanding how it develops, in particular in people whose hearts are under greater pressure due to the effects of a previous history of heart disease. It’s vital that we continue to improve our understanding of this condition so we can find new treatments for patients in the future.’
University of Bristol
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Researchers from Inserm and the Université Lille/Université Lille Nord de France have recently used a neurodegeneration model of Alzheimer’s disease to provide experimental evidence of the relationship between obesity and disorders linked to the tau protein. This research was conducted on mice and it corroborates the theory that metabolic anomalies contribute massively to the development of dementia.
In France, more than 860,000 people suffer from Alzheimer’s disease and related disorders, making them the largest cause of age-related loss of intellectual function. Cognitive impairments observed in Alzheimer’s disease result from the accumulation of abnormal tau proteins in nerve cells undergoing degeneration. We know that obesity, a major risk factor in the development of insulin resistance and type 2 diabetes, increases the risk of dementia during the ageing process. However, the effects of obesity on ‘Taupathies’ (i.e. tau protein-related disorders), including Alzheimer’s disease, were not clearly understood. In particular, researchers assumed that insulin resistance played a major role in terms of the effects of obesity.
The ‘Alzheimer & Tauopathies’ team from mixed research unit 837 (Inserm/Université Lille 2/Université Lille Nord de France) directed by Dr. Luc Buée, in collaboration with mixed research unit 1011 ‘Nuclear receptors, cardiovascular diseases and diabetes’, have just demonstrated, in mice, that obese subjects develop aggravated disorders. To achieve this result, young transgenic mice, who develop tau-related neurodegeneration progressively with age, were put on a high-fat diet for five months, leading to progressive obesity.
‘At the end of this diet, the obese mice had developed an aggravated disorder both from the point of view of memory and modifications to the Tau protein’ explains David Blum, in charge of research at Inserm.
This study uses a neurodenegeneration model of Alzheimer’s disease to provide experimental evidence of the relationship between obesity and disorders linked to the tau protein. Furthermore, it indicates that insulin resistance is not the aggravating factor, as was suggested in previous studies.
‘Our research supports the theory that environmental factors contribute massively to the development of this neurodegenerative disorder’ underlines the researcher. ‘Our work is now focussing on identifying the factors responsible for this aggravation’ he adds.
Inserm
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Scientists have wrestled to understand why Huntington’s disease, which is caused by a single gene mutation, can produce such variable symptoms. An authoritative review by a group of leading experts summarises the progress relating cell loss in the striatum and cerebral cortex to symptom profile in Huntington’s disease, suggesting a possible direction for developing targeted therapies
Huntington’s disease (HD) is an inherited progressive neurological disorder for which there is presently no cure. It is caused by a dominant mutation in the HD gene leading to expression of mutant huntingtin (HTT) protein. Expression of mutant HTT causes subtle changes in cellular functions, which ultimately results in jerking, uncontrollable movements, progressive psychiatric difficulties, and loss of mental abilities.
Although it is caused by a single gene, there are major variations in the symptoms of HD. The pattern of symptoms shown by each individual during the course of the disease can differ considerably and present as varying degrees of movement disturbances, cognitive decline, and mood and behavioural changes. Disease duration is typically between ten and twenty years.
Recent investigations have focused on what the presence of the defective gene does to various structures in the brain and understanding the relationship between changes in the brain and the variability in symptom profiles in Huntington’s disease.
Analyses of post-mortem human HD tissue suggest that the variation in clinical symptoms in HD is strongly associated with the variable pattern of neurodegeneration in two major regions of the brain, the striatum and the cerebral cortex. The neurodegeneration of the striatum generally follows an ordered and topographical distribution, but comparison of post-mortem human HD tissue and in vivo neuro-imaging techniques reveal that the disease produces a striking bilateral atrophy of the striatum, which in these recent studies has been found to be highly variable.
‘What is especially interesting is that recent findings suggest that the pattern of striatal cell death shows regional differences between cases in the functionally and neurochemically distinct striosomal and matrix compartments of the striatum which correspond with symptom variation,’ says author Richard L.M. Faull, MB, ChB, PhD, DSc, Director of the Centre for Brain Research, University of Auckland, New Zealand.
‘Our own recent detailed quantitative study using stereological cell counting in the post-mortem human HD cortex has complemented and expanded the neuroimaging studies by providing a cortical cellular basis of symptom heterogeneity in HD,’ continues Dr Faull. ‘In particular, HD cases which were dominated by motor dysfunction showed a major total cell loss (28% loss) in the primary motor cortex but no cell loss in the limbic cingulate cortex, whereas cases where mood symptoms predominated showed a total of 54% neuronal loss in the limbic cingulate cortex but no cell loss in the motor cortex. This suggests that the variable neuronal loss and alterations in the circuitry of the primary motor cortex and anterior cingulate cortex associated with the variable compartmental pattern of cell degeneration in the striatum contribute to the differential impairments of motor and mood functions in HD.’
The authors note that there are still questions to be answered in the field of HD pathology, such as, how and when pathological neuronal loss occurs; whether the progressive loss of neurons in the striatum is the primary process or is consequential to cortical cell dysfunction; and how these changes relate to symptom profiles.
‘What is clear however is that the diverse symptoms of HD patients appear to relate to the heterogeneity of cell loss in both the striatum and cerebral cortex,’ the authors conclude. ‘While there is currently no cure, this contemporary evidence suggests that possible genetic therapies aimed at HD gene silencing should be directed towards intervention at both the cerebral cortex and the striatum in the human brain. This poses challenging problems requiring the application of gene silencing therapies to quite widespread regions of the forebrain which may be assisted via CSF delivery systems using gene suppression agents that cross the CSF/brain barrier.’
EurekAlert
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Effective diagnosis and treatment of tuberculosis (TB) is notoriously difficult and the incidence of drug-resistant strains is increasing. However, using T-cell based diagnostic test systems, Lophius Biosciences has achieved its first successfully concluded clinical Proof of Principle study with respect to detection of active TB using its novel T-Track TB test, which is based on the company’s proprietary Reverse T Cell Technology (RT Technology). The clinical Proof of Principle was concluded in India with a cohort of 44 patients. Results demonstrated that the new TB test was able to detect active TB in in 10 of 12 non-treated patients. Besides its high sensitivity and specificity the test also demonstrated a remarkably short turnaround time of 2 days, which compares favourably to currently used detection methods. These results suggest that the T-Track TB test could represent an innovative and fast detection approach for this area of strong medical need.
http://tinyurl.com/cm6r8e4
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A fast, accurate diagnosis is essential for efficient treatment, especially in patients with complications. The Rapid Influenza Diagnostic Tests (RIDTs) for influenza detection have been developed to subtype the influenza virus, but rapid testing is no good unless it is accompanied by high levels of selectivity, specificity and accuracy. Over the course of a year, this study obtained over 1,000 nasal aspirate samples from patients with symptoms of influenza-like illness and evaluated by 2 types of RIDTs, Standard Diagnosis (SD) and QuickVue (QV) Rapid tests followed by real-time RT-PCR. The results showed that the SD rapid test appeared to be more sensitive than the QV test during high season activity, whereas the QV test was more sensitive during the period of low influenza virus activity. The conclusion was that due to persistent genetic drift of the influenza virus, the available RIDTs should be re-evaluated each year.
Makkoch J. et al. Clin. Lab. 2012; 58(9-10): 905-910. DOI: 10.7754/Clin.Lab.2011.111003
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Following a six-month pilot phase, the Asha Jyoti mobile outreach programme is now becoming fully operational in both semi-urban and rural areas of northern India. With a commitment from the Postgraduate Institute of Medical Education and Research (PGIMER) in Chandigarh, India, RAD-AID International and Philips are to provide education and screening to poor women in India. The Women’s Healthcare Outreach Mobile programme is a population-based screening programme of women aged between 40 and 60 years, which aims to ensure early detection of breast cancer, cervical cancer and osteoporosis, even before the individual has any signs or symptoms. It was established as a model for preventive healthcare for semi-urban and rural areas in northern India and involved the creation of a special mobile outreach van with imaging technology and clinical referral services to efficiently and effectively address multiple care needs. All women who visited the van received results from their tests within 7 to 10 days. Seven women with suspicious mammography findings and 41 women with suspicious colposcopy findings received follow-up testing and treatment, if needed, at PGIMER hospital. The aim now is to screen 2,000–3,000 women every year for at least the next 4–5 years and provide a clear plan for follow-up and further routine screening. The mobile diagnostic imaging technology is a key factor in making primary healthcare available to poor rural communities.
RAD-AID conference on International Radiology for Developing Countries at the Johns Hopkins Hospital in Baltimore, Maryland , USA.
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Study shows immunohistochemistry is reliable screening tool for ALK rearrangement
, /in E-News /by 3wmediaFavourable results have led to crizotinib gaining approval for the treatment of advanced stage ALK-positive non-small cell lung cancer (NSCLC) in Japan, the United States, Canada, and several other countries in Europe and Asia. Now, the identification of an effective therapy for ALK-positive NSCLC places great emphasis on rapid, accurate, and cost-effective way to find patients with this subtype of lung cancer. A recent study concludes immunohistochemistry (IHC) is a reliable screening tool for identification of ALK rearrangement.
Fluorescence in situ hybridisation (FISH) is the current standard method to detect ALK rearrangement. However, FISH is not readily available as a routine method of pathology practice in most laboratories because it is time consuming and requires advanced technical and professional expertise. In contrast, IHC is relatively inexpensive, faster, and is perfectly adapted for routine practice by academics and most community hospitals.
Researchers screened 377 stage I or II NSCLC cases, diagnosed between 1978 and 2002. Tissue microarray results were available on 377 cases by IHC and 273 cases by FISH. Eleven cases were positive or possibly positive by either IHC or FISH, and three cases were positive or possibly positive by both methods.
They found, ‘that all cases exhibiting ALK rearrangement demonstrated adenocarcinoma histology.’ Their results report a sensitivity of 100 percent and high specificity with the IHC with no false-negative results. While researchers acknowledge that further study involving a larger cohort is recommended, IHC is a valid screening test. The International Association for the Study of Lung Cancer
www.bsms.ac.uk/about/news/gene-testing-asthmatic-children-could-lead-to-better-treatment/
, /in E-News /by 3wmediaTesting asthmatic children for a specific gene could prevent their condition worsening, according to new research by scientists in Brighton and Dundee.
The arginine-16 genotype of the beta-2 receptor is carried by one in seven sufferers and the research found their condition could be aggravated by the use of the long-term controller medicine, Salmeterol, a long acting beta-receptor stimulant, which is administered through an inhaler.
Testing children for the genotype would identify those who might react poorly to Salmeterol and means their asthma control may improve with the use of alternative medicines.
The research was carried out by – Professor Somnath Mukhopadhyay from the Brighton and Sussex Medical School (BSMS) which is run jointly by Brighton and Sussex universities, and Professor Brian Lipworth and genetics expert Professor Colin Palmer, both from the University of Dundee.
They carried out the first genotyped study comparing additional treatments given to asthmatic children who continue to experience symptoms despite use of their prescribed inhaled steroid preventer.
More than a million UK children have asthma and over 150,000 are affected by this genetic change, making them less likely to respond to Salmeterol. The researchers tested 62 children with the susceptible arginine-16 genotype. They had all missed school or had treatment at hospital or out-of-hours GP surgeries as a result of their asthma, despite being treated with regular inhaled steroids.
While continuing with their usual preventer, the children were randomly assigned to two treatment groups for the period of a year – Montelukast or Salmeterol.
The research found they responded better to an alternative anti-inflammatory medicine, Montelukast. They experienced an improved quality of life, wheezed and coughed much less, and were less likely to experience worsening of their symptoms and needing more ‘reliever’ treatment, compared to the Salmeterol users.
At the start of the research, 36 per cent of these children tested needed to use their relievers every day. But by the end of the year-long study, the number of children needing daily reliever use had halved in the group using Montelukast. In contrast, there was no improvement for the children in the Salmeterol group. This is despite the fact that Salmeterol is currently the preferred drug for children with asthma who are not controlled with inhaled steroids.
The researchers have warned that many children with serious asthma respond poorly to Salmeterol and may be suffering needlessly from asthma, regularly missing out on sports and recording low school attendances during long-term treatment with this medicine. They said their treatment may be made more effective with the help of a simple relatively inexpensive gene test. Brighton and Sussex Medical School
Women choose blood test for the detection of fetal trisomy 2
, /in E-News /by 3wmediaFor many women pregnancy is a happy and exciting time. However, for those who have had triple test results that indicate a high risk of Downs syndrome, things can become very stressful, not least because of the risks of miscarriage that are associated with chorionic villus sampling and amniocentesis that are required for a definitive answer. Now, however, a non-invasive molecular genetic blood test, the PrenaTest from Lifecodexx, for the detection of fetal trisomy 21 is available at over 150 qualified prenatal practices and clinics in Germany, Austria, Liechtenstein and Switzerland. Close to 1,000 women whose babies were classed at high risk of trisomy 21 have opted for the test, and evaluation of the PrenaTest analyses shows that the vast majority (97 % of the women tested) could be relieved with regard to the presence of trisomy 21 in their unborn child. Only 1.5 % of the analysed blood samples carried fetal trisomy 21, and as far as known, these positive results have been confirmed by amniocentesis. Another 1.5 % of the blood samples could initially not be reported primarily due to a low amount of cell-free fetal DNA. This is a major step forward in achieving fast, accurate, point-of-care testing at what is undoubtedly a worrying time.
http://tinyurl.com/bm4vmjg
All in the family: A genetic link between epilepsy and migraine
, /in E-News /by 3wmediaNew research reveals a shared genetic susceptibility to epilepsy and migraine. Findings indicate that having a strong family history of seizure disorders increases the chance of having migraine with aura (MA).
Medical evidence has established that migraine and epilepsy often co-occur in patients; this co-occurrence is called ‘comorbidity.’ Previous studies have found that people with epilepsy are substantially more likely than the general population to have migraine headache. However, it is not clear whether that comorbidity results from a shared genetic cause.
‘Epilepsy and migraine are each individually influenced by genetic factors,’ explains lead author Dr. Melodie Winawer from Columbia University Medical Center in New York. ‘Our study is the first to confirm a shared genetic susceptibility to epilepsy and migraine in a large population of patients with common forms of epilepsy.’
For the present study, Dr. Winawer and colleagues analysed data collected from participants in the Epilepsy Phenome/Genome Project (EPGP)—a genetic study of epilepsy patients and families from 27 clinical centres in the U.S., Canada, Argentina, Australia, and New Zealand. The study examined one aspect of EPGP: sibling and parent-child pairs with focal epilepsy or generalised epilepsy of unknown cause. Most people with epilepsy have no family members affected with epilepsy. EPGP was designed to look at those rare families with more than one individual with epilepsy, in order to increase the chance of finding genetic causes of epilepsy.
Analysis of 730 participants with epilepsy from 501 families demonstrated that the prevalence of MA—when additional symptoms, such as blind spots or flashing lights, occur prior to the headache pain— was substantially increased when there were several individuals in the family with seizure disorders. EPGP study participants with epilepsy who had three or more additional close relatives with a seizure disorder were more than twice as likely to experience MA than patients from families with fewer individuals with seizures. In other words, the stronger the genetic effect on epilepsy in the family, the higher the rates of MA. This result provides evidence that a gene or genes exist that cause both epilepsy and migraine.
Identification of genetic contributions to the comorbidity of epilepsy with other disorders, like migraine, has implications for epilepsy patients. Prior research has shown that coexisting conditions impact the quality of life, treatment success, and mortality of epilepsy patients, with some experts suggesting that these comorbidities may have a greater impact on patients than the seizures themselves. In fact, comorbid conditions are emphasised in the National Institutes of Health Epilepsy Research Benchmarks and in a recent report on epilepsy from the Institute of Medicine.
‘Our study demonstrates a strong genetic basis for migraine and epilepsy, because the rate of migraine is increased only in people who have close (rather than distant) relatives with epilepsy and only when three or more family members are affected,’ concludes Dr. Winawer. ‘Further investigation of the genetics of groups of comorbid disorders and epilepsy will help to improve the diagnosis and treatment of these comorbidities, and enhance the quality of life for those with epilepsy.’ Columbia University Medical Center
Researchers identify new target for common heart condition
, /in E-News /by 3wmediaResearchers have found new evidence that metabolic stress can increase the onset of atrial arrhythmias, such as atrial fibrillation (AF), a common heart condition that causes an irregular and often abnormally fast heart rate. The findings may pave the way for the development of new therapies for the condition which can be expected to affect almost one in four of the UK population at some point in their lifetime.
The British Heart Foundation (BHF) study, led by University of Bristol scientists found that metabolic stress — a condition induced by insufficient oxygen supply to the heart (e.g. following blockage of a coronary artery) — caused marked changes in the electrical activity of the heart’s atria (the upper chambers of the heart).
While it has been recognised for many years that metabolic stress causes ventricular arrhythmias — abnormal heart rhythms that originate in the two lower chambers of the heart (the ventricles) and which form the basis to heart attacks — it is the first time it has been demonstrated for arrhythmias in the atria.
The research team led by Dr Andrew James from the University’s School of Physiology and Pharmacology together with Professor Saadeh Suleiman in the School of Clinical Sciences, examined the contribution of a particular kind of protein underlying the electrical activity of the atria during metabolic stress.
These proteins, known as KATP channels enable cells to respond to changes in metabolism. ATP (adenosine triphosphate) is a small molecule that represents the ‘energy currency’ for cell metabolism and when ATP levels inside cells fall, KATP channels are activated. For example, KATP channels in the pancreas are involved in the regulation of insulin secretion and drugs targeting these channels are used to treat type 2 diabetes mellitus.
Dr Andrew James, the study’s lead author, said: ‘It is well-established that KATP channels in the ventricles of the heart can become activated following metabolic stress caused by blockage of a coronary artery. In principle, their activation could protect the heart muscle cells against metabolic stress-induced damage. On the other hand, the activation of ventricular KATP channels can contribute to disturbances in the electrical activity of the heart known as arrhythmias.
‘Arrhythmias in the ventricles can be very dangerous, leading to ventricular fibrillation and death. Atrial arrhythmias, such as atrial fibrillation (AF), are not usually immediately fatal but they are very common and a major cause of stroke. Notably, KATP channels are also found in the atria but, in contrast to the ventricles, their role in atrial arrhythmias remains unknown.’
The findings show that metabolic stress caused marked changes in the electrical activity of the atrium consistent with the activation of KATP channels. Electrical stimulation was applied to try to evoke atrial arrhythmia. It was possible to induce atrial arrhythmia during, but not before, metabolic stress.
Importantly, blockade of KATP channels with drugs used to treat patients with type 2 diabetes (glibenclamide and tolbutamide), completely reversed the effects of metabolic stress on the electrical activity of the atrium and prevented the induction of atrial arrhythmia. The anti-diabetic drugs were without effect in the absence of metabolic stress.
The findings represent a ‘proof-of-principle’ (the stage at which any new drug must undergo before full-scale clinical trials can begin) that atrial KATP channels can be activated by metabolic stress and facilitate atrial arrhythmias. Thus, atrial KATP channels may represent a target for drugs for the treatment of atrial arrhythmias, such as atrial fibrillation.
However, Dr James added: ‘Further studies are required and a key point to address will be whether differences exist between the properties of atrial, ventricular and pancreatic KATP channels that might be exploited to produce an atrial-selective drug. Perhaps these channels might be useful as targets to treat atrial arrhythmias.’
Professor Jeremy Pearson, Associate Medical Director at the BHF, commented: ‘Atrial fibrillation is a very common irregular heart rhythm which greatly increases the risk of stroke. This study brings us closer to understanding how it develops, in particular in people whose hearts are under greater pressure due to the effects of a previous history of heart disease. It’s vital that we continue to improve our understanding of this condition so we can find new treatments for patients in the future.’ University of Bristol
Detrimental effect of obesity on lesions associated with Alzheimer’s disease
, /in E-News /by 3wmediaResearchers from Inserm and the Université Lille/Université Lille Nord de France have recently used a neurodegeneration model of Alzheimer’s disease to provide experimental evidence of the relationship between obesity and disorders linked to the tau protein. This research was conducted on mice and it corroborates the theory that metabolic anomalies contribute massively to the development of dementia.
In France, more than 860,000 people suffer from Alzheimer’s disease and related disorders, making them the largest cause of age-related loss of intellectual function. Cognitive impairments observed in Alzheimer’s disease result from the accumulation of abnormal tau proteins in nerve cells undergoing degeneration. We know that obesity, a major risk factor in the development of insulin resistance and type 2 diabetes, increases the risk of dementia during the ageing process. However, the effects of obesity on ‘Taupathies’ (i.e. tau protein-related disorders), including Alzheimer’s disease, were not clearly understood. In particular, researchers assumed that insulin resistance played a major role in terms of the effects of obesity.
The ‘Alzheimer & Tauopathies’ team from mixed research unit 837 (Inserm/Université Lille 2/Université Lille Nord de France) directed by Dr. Luc Buée, in collaboration with mixed research unit 1011 ‘Nuclear receptors, cardiovascular diseases and diabetes’, have just demonstrated, in mice, that obese subjects develop aggravated disorders. To achieve this result, young transgenic mice, who develop tau-related neurodegeneration progressively with age, were put on a high-fat diet for five months, leading to progressive obesity.
‘At the end of this diet, the obese mice had developed an aggravated disorder both from the point of view of memory and modifications to the Tau protein’ explains David Blum, in charge of research at Inserm.
This study uses a neurodenegeneration model of Alzheimer’s disease to provide experimental evidence of the relationship between obesity and disorders linked to the tau protein. Furthermore, it indicates that insulin resistance is not the aggravating factor, as was suggested in previous studies.
‘Our research supports the theory that environmental factors contribute massively to the development of this neurodegenerative disorder’ underlines the researcher. ‘Our work is now focussing on identifying the factors responsible for this aggravation’ he adds. Inserm
Cell loss in the brain relates to variations in individual symptoms in Huntington’s disease
, /in E-News /by 3wmediaScientists have wrestled to understand why Huntington’s disease, which is caused by a single gene mutation, can produce such variable symptoms. An authoritative review by a group of leading experts summarises the progress relating cell loss in the striatum and cerebral cortex to symptom profile in Huntington’s disease, suggesting a possible direction for developing targeted therapies
Huntington’s disease (HD) is an inherited progressive neurological disorder for which there is presently no cure. It is caused by a dominant mutation in the HD gene leading to expression of mutant huntingtin (HTT) protein. Expression of mutant HTT causes subtle changes in cellular functions, which ultimately results in jerking, uncontrollable movements, progressive psychiatric difficulties, and loss of mental abilities.
Although it is caused by a single gene, there are major variations in the symptoms of HD. The pattern of symptoms shown by each individual during the course of the disease can differ considerably and present as varying degrees of movement disturbances, cognitive decline, and mood and behavioural changes. Disease duration is typically between ten and twenty years.
Recent investigations have focused on what the presence of the defective gene does to various structures in the brain and understanding the relationship between changes in the brain and the variability in symptom profiles in Huntington’s disease.
Analyses of post-mortem human HD tissue suggest that the variation in clinical symptoms in HD is strongly associated with the variable pattern of neurodegeneration in two major regions of the brain, the striatum and the cerebral cortex. The neurodegeneration of the striatum generally follows an ordered and topographical distribution, but comparison of post-mortem human HD tissue and in vivo neuro-imaging techniques reveal that the disease produces a striking bilateral atrophy of the striatum, which in these recent studies has been found to be highly variable.
‘What is especially interesting is that recent findings suggest that the pattern of striatal cell death shows regional differences between cases in the functionally and neurochemically distinct striosomal and matrix compartments of the striatum which correspond with symptom variation,’ says author Richard L.M. Faull, MB, ChB, PhD, DSc, Director of the Centre for Brain Research, University of Auckland, New Zealand.
‘Our own recent detailed quantitative study using stereological cell counting in the post-mortem human HD cortex has complemented and expanded the neuroimaging studies by providing a cortical cellular basis of symptom heterogeneity in HD,’ continues Dr Faull. ‘In particular, HD cases which were dominated by motor dysfunction showed a major total cell loss (28% loss) in the primary motor cortex but no cell loss in the limbic cingulate cortex, whereas cases where mood symptoms predominated showed a total of 54% neuronal loss in the limbic cingulate cortex but no cell loss in the motor cortex. This suggests that the variable neuronal loss and alterations in the circuitry of the primary motor cortex and anterior cingulate cortex associated with the variable compartmental pattern of cell degeneration in the striatum contribute to the differential impairments of motor and mood functions in HD.’
The authors note that there are still questions to be answered in the field of HD pathology, such as, how and when pathological neuronal loss occurs; whether the progressive loss of neurons in the striatum is the primary process or is consequential to cortical cell dysfunction; and how these changes relate to symptom profiles.
‘What is clear however is that the diverse symptoms of HD patients appear to relate to the heterogeneity of cell loss in both the striatum and cerebral cortex,’ the authors conclude. ‘While there is currently no cure, this contemporary evidence suggests that possible genetic therapies aimed at HD gene silencing should be directed towards intervention at both the cerebral cortex and the striatum in the human brain. This poses challenging problems requiring the application of gene silencing therapies to quite widespread regions of the forebrain which may be assisted via CSF delivery systems using gene suppression agents that cross the CSF/brain barrier.’ EurekAlert
First clinical proof of principle for T-Track TB for detection of active tuberculosis
, /in E-News /by 3wmediaEffective diagnosis and treatment of tuberculosis (TB) is notoriously difficult and the incidence of drug-resistant strains is increasing. However, using T-cell based diagnostic test systems, Lophius Biosciences has achieved its first successfully concluded clinical Proof of Principle study with respect to detection of active TB using its novel T-Track TB test, which is based on the company’s proprietary Reverse T Cell Technology (RT Technology). The clinical Proof of Principle was concluded in India with a cohort of 44 patients. Results demonstrated that the new TB test was able to detect active TB in in 10 of 12 non-treated patients. Besides its high sensitivity and specificity the test also demonstrated a remarkably short turnaround time of 2 days, which compares favourably to currently used detection methods. These results suggest that the T-Track TB test could represent an innovative and fast detection approach for this area of strong medical need.
http://tinyurl.com/cm6r8e4
Evaluation of rapid influenza virus tests
, /in E-News /by 3wmediaA fast, accurate diagnosis is essential for efficient treatment, especially in patients with complications. The Rapid Influenza Diagnostic Tests (RIDTs) for influenza detection have been developed to subtype the influenza virus, but rapid testing is no good unless it is accompanied by high levels of selectivity, specificity and accuracy. Over the course of a year, this study obtained over 1,000 nasal aspirate samples from patients with symptoms of influenza-like illness and evaluated by 2 types of RIDTs, Standard Diagnosis (SD) and QuickVue (QV) Rapid tests followed by real-time RT-PCR. The results showed that the SD rapid test appeared to be more sensitive than the QV test during high season activity, whereas the QV test was more sensitive during the period of low influenza virus activity. The conclusion was that due to persistent genetic drift of the influenza virus, the available RIDTs should be re-evaluated each year.
Makkoch J. et al. Clin. Lab. 2012; 58(9-10): 905-910. DOI: 10.7754/Clin.Lab.2011.111003
Successful health initiative results in long-term commitment to screening India’s rural population
, /in E-News /by 3wmediaFollowing a six-month pilot phase, the Asha Jyoti mobile outreach programme is now becoming fully operational in both semi-urban and rural areas of northern India. With a commitment from the Postgraduate Institute of Medical Education and Research (PGIMER) in Chandigarh, India, RAD-AID International and Philips are to provide education and screening to poor women in India. The Women’s Healthcare Outreach Mobile programme is a population-based screening programme of women aged between 40 and 60 years, which aims to ensure early detection of breast cancer, cervical cancer and osteoporosis, even before the individual has any signs or symptoms. It was established as a model for preventive healthcare for semi-urban and rural areas in northern India and involved the creation of a special mobile outreach van with imaging technology and clinical referral services to efficiently and effectively address multiple care needs. All women who visited the van received results from their tests within 7 to 10 days. Seven women with suspicious mammography findings and 41 women with suspicious colposcopy findings received follow-up testing and treatment, if needed, at PGIMER hospital. The aim now is to screen 2,000–3,000 women every year for at least the next 4–5 years and provide a clear plan for follow-up and further routine screening. The mobile diagnostic imaging technology is a key factor in making primary healthcare available to poor rural communities.
RAD-AID conference on International Radiology for Developing Countries at the Johns Hopkins Hospital in Baltimore, Maryland , USA.