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The scientists from the Montreal Neurological Institute and Hospital at McGill University, led by Peter McPherson, along with collaborators in Saudi Arabia, Jordan, Germany, and at SickKids Hospital and the University of Toronto, have discovered that a severe form of epileptic encephalopathy is caused by recessive loss-of-function mutations in the gene DENND5A.
Epileptic encephalopathy is a rare but devastating sub-form of epilepsy that results in severe mental and physical disabilities in children from birth. It is often caused by improper development of the brain. Individuals with epileptic encephalopathy caused by mutations in DENND5A present with serious anomalies in brain structure along with calcifications in the brain and altered facial features.
Researchers performed whole exome sequencing on three children with epileptic encephalopathy from two families, one from Saudi Arabia and another from Jordan. Both families were consanguineous, meaning the parents were related to each other. This greatly increases the chance that rare mutations that are recessive and that cause no harm to the parents are expressed in the children. The whole exome sequencing, along with extensive and complex genetic analysis, revealed that recessive mutations in DENND5A were responsible for the disease, with the Saudi family and the Jordanian family having different mutations but in the same DENND5A gene. They found that mutations in DENND5A lead to a lack of the DENND5A protein, resulting in underdevelopment of the central nervous system. The protein expressed from the DENND5A gene is present at highest levels in the nervous system especially while the brain is developing, corroborating the evidence that mutations in the gene cause epileptic encephalopathy.
The researchers discovered that the DENND5A protein controls the movement of receptors for key developmental factors called neurotrophins. Disruption of DENND5A function leads to altered levels of these receptors, which could explain why loss of DENND5A leads to the severe neurological developmental defects in the patients.
Epilepsy affects approximately three per cent of the world population, and epileptic encephalopathy is a rare sub-form of the disease. It is difficult to say how many children with epileptic encephalopathy have the DENND5A mutations, but now that the gene has been identified as a cause, researchers around the world can begin to test patients for mutations in this gene.
This finding also improves our understanding of neuronal development. The observation that loss-of-function mutations in DENND5A causes epileptic encephalopathy suggests that DENND5A protein controls membrane trafficking pathways critical for normal neuronal development and strengthens the argument that protein trafficking processes in cells are critical for normal neuronal development and function.
“Our study demonstrates the importance of membrane trafficking in neuronal development and it provides a new pathophysiological mechanism for this disease type. This will allow physicians around the world to test if mutations in DENND5A are causing the disease in their patients, and also to provide genetic counselling for affected families,” says Dr. Chanshuai Han, the lead author on the study.
The Montreal Neurological Institute and Hospital http://tinyurl.com/jfb7aho
In overweight and obese children and adolescents, vitamin D deficiency is associated with early markers of cardiovascular disease, a new study reports.
"Paediatric obesity affects 17 percent of infants, children, and adolescents ages 2 to 19 in the United States, and obesity is a risk factor for vitamin D deficiency. These findings suggest that vitamin D deficiency may have negative effects on specific lipid markers with an increase in cardiovascular risk among children and adolescents," said lead author Marisa Censani, M.D., pediatric endocrinologist and director of the Pediatric Obesity Program in the Division of Pediatric Endocrinology at New York Presbyterian Hospital/Weill Cornell Medicine in New York, N.Y.
"This research is newsworthy because this is one of the first studies to assess the relationship of vitamin D deficiency to both lipoprotein ratios and non-high density lipoprotein (non-HDL) cholesterol, specific lipid markers impacting cardiovascular risk during childhood, in children and adolescents with obesity/overweight," Censani noted.
Censani and her colleagues reviewed the medical records, including vitamin D levels, of children and adolescents between 6 and 17 years of age who were evaluated at the paediatric endocrinology outpatient clinics at Weill Cornell Medicine over a two-year period.
Overall, 178 of 332 patients met criteria for overweight and obesity: Body Mass Index (BMI) above the 85th percentile; and 60 patients with BMI above the 85th percentile had fasting lipid test results available.
Total cholesterol, triglycerides, HDL, low-density lipoprotein (LDL), and non-HDL cholesterol were collected; and total cholesterol/HDL and triglyceride/HDL ratios were calculated. Vitamin D deficiency was considered to be 25 hydroxyvitamin D (25OHD) below 20 ng/ml.
Vitamin D deficiency was found to be significantly associated with an increase in atherogenic lipids and markers of early cardiovascular disease. Total cholesterol, triglycerides, LDL, non-HDL cholesterol, as well as total cholesterol/HDL and triglyceride/HDL ratios, were all higher in vitamin D-deficient patients compared to patients without vitamin D deficiency.
"These results support screening children and adolescents with overweight and obesity for vitamin D deficiency and the potential benefits of improving vitamin D status to reduce cardiometabolic risk," Censani said.
The Endocrine Society
www.endocrine.org/news-room/current-press-releases/vitamin-d-deficiency-may-indicate-cardiovascular-disease-in-overweight-and-obese-children
Massachusetts General Hospital (MGH) researchers have identified a mechanism that controls the expression of genes regulating the growth of the most aggressive form of medulloblastoma, the most common paediatric brain tumour. The team also identifies potential targets for future treatments.
“We set out to find the most important regulators of gene expression programs in medulloblastoma,” says senior author Miguel Rivera, MD, of the MGH Department of Pathology and the Center for Cancer Research. “To do that we used a powerful genomic technology called chromatin profiling to map all the genomic elements contributing to transcription regulation in Group 3 medulloblastoma – the most aggressive subtype. This goes beyond measuring gene expression because it tells you how genes are turned on and off.”
Medulloblastoma is a fast-growing tumour that arises in the developing brain and most commonly affects children under the age of 10. Four molecular variants, each with different patterns of DNA alteration and gene expression, have been identified. Subtypes WNT and SSH are the best understood; the other two – Group 3 and Group 4 – are poorly understood and account for 60 percent of tumours.
Cells regulate whether specific genes are transcribed into RNA through the action of transcription factors, proteins that bind to DNA and either stimulate or suppress the expression of their target genes. Rivera’s team used advanced genomic technologies to identify key DNA elements called enhancers that were active in primary Group 3 medulloblastoma samples and cell lines. The transcription factor OTX2, which plays a role in normal brain development and is known to be highly expressed in Group 3 medulloblastomas, was present at the majority of active enhancer sites in tumours, suggesting it may have a role in promoting the expression of tumour-associated genes.
Subsequent experiments revealed that OTX2 can function as a “pioneer factor,” opening up chromatin – which consists of DNA wound around proteins called histones – to activate enhancers and that its function is amplified by a second transcription factor called NEUROD1. The investigators then identified a set of genes the expression of which was significantly reduced when OTX2 was suppressed. Among these genes, they found that expression of the kinase NEK2 responded to OTX2 levels and that its depletion or pharmacologic inhibition strongly reduced the growth and survival of medulloblastoma cells.
“Overall, our findings show that OTX2 is a critical factor in regulating gene expression programs in Group 3 medulloblastoma and possibly in the WNT and Group 4 subtypes, where it is also expressed,” says Rivera, who is an assistant professor of Pathology at Harvard Medical School. “This work points to OTX2 itself and its target genes – including NEK2 – as potential therapeutic targets. Disruption of the relationship between OTX2 and NEUROD1 may also be a potential treatment strategy.
Massachusetts General Hospitalwww.massgeneral.org/about/pressrelease.aspx?id=2063
The health risks and mortality associated with pre-diabetes seem to increase at the lower cut-off point for blood sugar levels recommended by some guidelines, finds a large study published.
Pre-diabetes is a ‘pre-diagnosis’ of diabetes — when a person’s blood glucose level is higher than normal, but not high enough to be considered diabetes. If left untreated, pre-diabetes can develop into type 2 diabetes. An estimated 79 million people in the US and 7 million people in the UK are thought to be affected.
Doctors define pre-diabetes as impaired fasting glucose (higher than normal blood sugar levels after a period of fasting), impaired glucose tolerance (higher than normal blood sugar levels after eating), or raised haemoglobin levels.
But the cut-off points vary across different guidelines and remain controversial.
For example, the World Health Organization (WHO) defines pre-diabetes as fasting plasma glucose of 6.1-6.9 mmol/L, while the 2003 American Diabetes Association (ADA) guideline recommends a cut-off point of 5.6-6.9 mmol/L.
Results of studies on the association between pre-diabetes and risk of cardiovascular disease and all cause mortality are also inconsistent. Furthermore, whether raised haemoglobin levels for defining pre-diabetes is useful for predicting future cardiovascular disease is unclear.
So a team of researchers from the affiliated Hospital at Shunde, Southern Medical University in China analysed the results of 53 studies involving over 1.6 million individuals to shed more light on associations between different definitions of pre-diabetes and the risk of cardiovascular disease, coronary heart disease, stroke, and all cause mortality.
They found that pre-diabetes, defined as impaired fasting glucose or impaired glucose tolerance, was associated with an increased risk of cardiovascular disease and all cause mortality.
The risk increased in people with a fasting glucose concentration as low as 5.6 mmol/L – the lower cut-off point according to ADA criteria.
Raised haemoglobin levels were also associated with an increased risk of cardiovascular disease and coronary heart disease, but not with an increased risk of stroke and all cause mortality.
The authors point to some study limitations that could have influenced their results, and say pulling observational evidence together in a systematic review and meta-analysis is a good way to consider all the evidence at once, ‘but we cannot make statements about cause and effect. We would need to look at experimental evidence for that.’
However, they say their findings ‘strongly support’ the lower cut-off point for impaired fasting glucose and raised haemoglobin levels proposed by the ADA guideline.
And they conclude that lifestyle change — eating a healthy balanced diet, keeping weight under control, and doing regular physical activity — is the most effective treatment.
EurekAlert www.eurekalert.org/pub_releases/2016-11/b-ssl112216.php
More than 3,000 medical laboratory industry professionals expected to attend the launch edition of MEDLAB Europe at the Fira Gran Via in Barcelona, Spain.
After many years of operating successful MEDLAB events around Africa, Asia and the Middle East, Informa Life Sciences Exhibitions has announced that the MEDLAB Series will be expanding its presence into Europe. Taking place at the Fira Gran Via in Barcelona, Spain, from 13-15 September 2017, more than 3,000 industry professionals are expected to attend Europe’s leading event for laboratory management and diagnosis.
With the European medical laboratory market expected to reach USD 15.5 billion (€ 14.2 billion) by 2024[1], a platform such as MEDLAB presents a huge opportunity for global laboratory industry leaders, including manufacturers, dealers and distributors, to make inroads into the European market. Housing international exhibitors and covering 2,000 sqm of exhibition space, MEDLAB Europe will give visitors from across the world an opportunity to access cutting-edge laboratory products, next-generation technology, innovative services and world-class educational content.
According to Tom Coleman, Group Exhibition Director, MEDLAB Series: “The launch of MEDLAB Europe is in line with our global expansion strategy for our MEDLAB series of events. The increasing prevalence of chronic diseases, rising geriatric population coupled with the rising awareness towards early diagnosis, has positioned the European medical laboratory market as a critical market for manufacturers, services providers, and dealers and distributors from across the globe. MEDLAB Europe will generate substantial value for our customers and partners by driving further product innovation and deeper engagement in these specific markets.”
Over the three-day event, MEDLAB Europe will also offer a multi-disciplinary congress tackling current challenges and developments key to the European market, and leveraging the true potential of laboratory testing to dramatically improve patient outcomes across the continent.
The conference programme covers five main tracks including Point of Care Testing (POCT), Histopathology, Lab Management, Microbiology and Hematology. From new methods of effective lab management to the development of techniques in detecting diseases, the conferences will also review the expanding role of the laboratory medicine and discuss partnership between a clinician and a lab professional in providing delivery of care to every patient.
“The scientific programme at MEDLAB has been carefully designed in collaboration with some of the brightest minds in the medical laboratory industry in order to have a real impact on improving the health and wellbeing of patients across the region,” said Coleman.
www.medlabeurope.com
The molecular causes of diseases such as Parkinson’s need to be understood as a first step towards combating them. University of Konstanz chemists working alongside Professor Malte Drescher recently succeeded in analysing what happens when selective mutations of the alpha-synuclein protein occur – a protein that is closely linked to Parkinson’s disease. In a complex series of experiments they examined what the effects were of changing a single amino acid in the protein. The physicochemists were able to prove how this tiny change disturbs the binding of alpha-synuclein to membranes. “We hope that the finding of this selectively defective membrane binding will help us to understand how Parkinson’s develops on a molecular level. Ultimately, this will facilitate the devising of therapeutic strategies,” outlines Julia Cattani, a doctoral student, who played a major role in the success of the research.
The human brain contains large quantities of the small alpha-synuclein protein. Its exact biological function is still unknown, yet it is closely linked to Parkinson’s disease; the protein “clumps together” in the nerve cells of Parkinson patients. Alpha-synuclein consists of a chain of 140 amino acids. In rare cases Parkinson’s disease is hereditary; where this occurs one of these 140 components has been replaced. Malte Drescher and his working group in the Department of Chemistry at the University of Konstanz have now found out the influence these selective changes in the protein sequence can have on the behaviour of alpha-synuclein. “We can show that the selective mutations disturb the membrane binding of alpha-synuclein on a local level,” explains Malte Drescher.
To find out more about the influence of selective mutations, the Konstanz-based chemists Dr Marta Robotta and Julia Cattani applied tiny magnetic probe molecules to various places on the alpha-synuclein protein. With the help of electron paramagnetic resonance spectroscopy – a procedure similar in method to magnetic resonance imaging (MRI) used in the medical field – the researchers were able to measure the rotation of these nanomagnets. At every residue at which alpha-synuclein binds to a membrane, the rotation slows down. In this way they were able to find out precisely when and where a binding to the membranes takes place – and when it does not. In the case of the exchanged amino acids the physicochemists from Konstanz discovered a disturbance of the membrane binding of alpha-synuclein – an important clue for the molecular context of Parkinson’s disease.
“We went to great lengths, performing over 200 spectroscopic experiments, the results of which we compared with our models by means of a specially developed simulation algorithm. The outcome certainly compensated our efforts,” says Julia Cattani. Project leader Malte Drescher believes that alongside the huge commitment of his staff, an important prerequisite for the success of the research was, above all, the environment of the Collaborative Research Centre (SFB) 969, “Chemical and biological principles of cellular proteostasis” which formed the basis for sponsoring the project: “By networking on an interdisciplinary level and discussing with colleagues we managed to solve the many problems we faced,” emphasises Malte Drescher.
University of Konstanz
www.uni-konstanz.de/en/university/news-and-media/current-announcements/news/news-in-detail/parkinson-auf-der-spur/
With the medical laboratory market in the UAE expected to continue on a growth trajectory, innovative products and next-generation technology remains a focus for the region’s medical laboratory and IVD industry
Dubai, UAE, 25th January 2017: As the UAE gears up for a boom in the In-Vitro Diagnostics (IVD) market, expected to reach USD 0.83 billion by the end of 2020[1], the medical community has turned its focus towards exciting new products and technologies to keep up with the demand for new diagnostic capabilities that can have a real impact on improving the health of patients across the region.
MEDLAB Exhibition & Congress, the world’s leading event for laboratory management and diagnostics, which takes place on 6th – 9th February 2017 at the Dubai International Convention & Exhibition Centre, presents a huge opportunity for global laboratory industry leaders, including manufacturers, dealers and distributors, to showcase new innovations and to introduce some cutting-edge products to the UAE market. More than 30,000 visitors are expected to attend the four-day exhibition where they can explore over 400 products and services from more than 700 exhibitors from 38 countries.
A number of companies associated with ABIMO (Brazilian Medical Devices Manufacturers Association) will be at MEDLAB to showcase products and services including diagnosis and laboratory reagents, IVD, devices for medical tests, laboratory tests, laboratory refrigerators and products for hematology.
According to Clara Porto, ABIMO’s marketing and exports manager, “There is almost no national production of the sector and, as such, the region is quite dependent on imports. Generally, there is a great acceptance of Brazilian products so we expect to make good contacts and profitable deals at this year’s show.”
Binding Site, one of the largest independent providers for IVD tests and equipment in the United Kingdom, will be at MEDLAB to launch its latest protein system that can process complex protein assays 40% faster than current systems. Charles de Rohan, CEO from Binding Site commented: “We wanted to bring simplicity to complex analytical processes. The result is Optilite, the latest innovation in special protein testing, which offers laboratories reliable results without compromising speed and efficiency.”
Meanwhile, Sysmex Corporate, one of the leading international providers of solutions for systemising processes for medical laboratories, will be at MEDLAB to showcase their new urinalysis series. For the first time, they are offering an ‘all-in-one’ series of analysers that will allow you to examine both through chemistry and sediment, followed by imaging and validation.
Another exhibitor bringing something new to the market is American Medical Technologists (AMT), an internationally recognised certification agency for allied health professionals, who will promote a set of practice exams for its respected laboratory certifications including Medical Technologists (MTs), Medical Laboratory Technicians (MLTs) and Phlebotomists.
“With a new practice test for those preparing to take the certification exam for medical technologist through AMT, candidates have an important tool to take them a step closer to becoming certified members of the clinical laboratory community,” said Christopher Damon, JD, Executive Director of AMT.
This year at MEDLAB, a selection of free workshops will also be available for all industry professionals offering learning and training opportunities from leading international IVD and laboratory companies. The free workshops are an addition to MEDLAB’s conferences, which will span from blood transfusion medicine, laboratory informatics, clinical diagnostics of cardiology and diabetes, to laboratory management, microbiology, immunology and clinical chemistry.
Dr Mansour Al-Zarouni, Member, General Secretariat Committee at Sultan Bin Khalifa International Thalassemia Award (SITA) and Chair of MEDLAB said: “With new cutting edge innovations having a lifecycle of approximately 24-48 months, it’s crucial for this congress to play a role in connecting and merging pre-existing gaps between clinicians and laboratory professionals, through the conferences, to ensure everything is done to improve patient care outcomes.”
According to Simon Page, Managing Director of Informa Life Sciences Exhibitions, the Organiser of MEDLAB: “It is not enough for our visitors to simply view the new technologies from afar – we want them to get a hand-on experience of these products through the free workshops directly offered by the manufacturers. For example, LabCorp from the USA and National Reference Laboratory in the UAE are coming together to host a workshop on coagulation reference testing to discuss the significance of the coagulation reference laboratory.”
“Another example is Sidra’s workshop, the Pediatric Pathology symposium, which will address anatomical pathology, hematopathology, microbiology and molecular microbiology, clinical chemistry, and genetics, which will be led by international experts and attended by pathologists, lab physicians and scientists in the region, who work with pediatric specimens”, he added.
MEDLAB Exhibition & Congress is supported by the UAE Ministry of Health & Prevention, Health Authority Abu Dhabi, Dubai Health Authority, Dubai Healthcare City Authority, Jebel Ali Free Zone, College of American Pathologists, Clinical and Laboratory Standards Institute and the Saudi Society for Clinical Chemistry.
For more information about MEDLAB Exhibition & Congress, please visit www.medlabme.com
[1] UAE In-Vitro Diagnostics Market – Growth, Trends & Forecast (2015-2020), August 2016
In an effort to provide customers with expanded, more comprehensive solutions for molecular testing, Siemens Healthineers has announced a new strategic relationship with Fast-track Diagnostics (FTD) that includes the addition of FTD’s broad range of CE-marked kits and multisyndromic panels to the menu of the Siemens Healthineers VERSANT kPCR Molecular System. The addition of FTD’s broad menu of kits and panels – which cover conditions from respiratory to gastroenteritis to central nervous system (CNS) and childhood infections – increases the breadth of Siemens Healthineers’ complete molecular testing solution, ensuring leading-edge performance from extraction through detection and increasing workflow efficiency for molecular labs of all sizes.
“Over the past 24 months, Siemens Healthineers has made significant advancements in the delivery of molecular diagnostic applications and services,” says Fernando Beils, Head of Molecular Diagnostics, Siemens Healthineers. “We continue to strengthen and broaden our Molecular System by offering a comprehensive, scalable solution for accurate diagnosis and monitoring to our customers worldwide through our alliance with Fast-track Diagnostics.”
The VERSANT kPCR Molecular System, an established market player in molecular testing for HIV and Hepatitis, will now feature over 75 assays, consolidating testing for the infectious disease spectrum in a single molecular ecosystem.
“The VERSANT kPCR Molecular System is perfectly suited to our wide range of assays, which means laboratories can now diagnose nearly any infectious disease in one workflow,” says Bill Carman, CEO of Fast-track Diagnostics.
In offering customers the option of a single, consolidated system with a broad menu and virtually open platform, Siemens Healthineers enables healthcare providers to meet their current challenges, especially as an increasing push towards a value-based healthcare philosophy relies heavily on increased productivity and streamlined workflows. With this in mind, Siemens Healthineers has made its growth and enhancement within the molecular diagnostics space a key priority for its business strategy moving forward.
www.siemens.com/healthineerswww.fast-trackdiagnostics.com
Currently, testing for Zika requires that a blood sample be refrigerated and shipped to a medical centre or laboratory, delaying diagnosis and possible treatment. Although the new proof-of-concept technology has yet to be produced for use in medical situations, the test’s results can be determined in minutes. Further, the materials required for the test do not require refrigeration and may be applicable in testing for other emerging infectious diseases.
The researchers tested blood samples taken from four people who had been infected with Zika virus and compared it to blood from five people known not to have the virus. Blood from Zika-infected patients tested positive, but blood from Zika-negative controls did not. The assay produced no false-positive results.
Among the reasons such a test is needed, according to the researchers, is that many people infected with Zika don’t know they’re infected. Although symptoms include fever, joint pain, muscle pain and rash, many people don’t feel ill after being bitten by an infected mosquito. Testing is particularly important for pregnant women because Zika infection can cause congenital Zika syndrome, which contributes to several neurologic problems in the foetus or newborn infant.
“Zika infection is often either asymptomatic or mildly symptomatic,” said Evan D. Kharasch, MD, PhD, one of the study’s three senior investigators. “The most effective way to diagnose the disease is not to wait for people to develop symptoms but to do population screening.”
That strategy requires inexpensive, easy-to-use and easy-to-transport tests. Kharasch, the Russell D. and Mary B. Shelden Professor of Anesthesiology, collaborated with Srikanth Singamaneni, PhD, an associate professor of mechanical engineering & materials science, and Jeremiah J. Morrissey, PhD, a research professor of anesthesiology, to create the test, which uses gold nanorods mounted on paper to detect Zika infection within a few minutes.
“If an assay requires electricity and refrigeration, it defeats the purpose of developing something to use in a resource-limited setting, especially in tropical areas of the world,” said Singamaneni. “We wanted to make the test immune from variations in temperature and humidity.”
The test relies on a protein made by Zika virus that causes an immune response in infected individuals. The protein is attached to tiny gold nanorods mounted on a piece of paper. The paper then is completely covered with tiny, protective nanocrystals. The nanocrystals allow the diagnostic nanorods to be shipped and stored without refrigeration prior to use.
To use the test, a technician rinses the paper with slightly acidic water, removing the protective crystals and exposing the protein mounted on the nanorods. Then, a drop of the patient’s blood is applied. If the patient has come into contact with the virus, the blood will contain immunoglobulins that react with the protein.
“We’re taking advantage of the fact that patients mount an immune attack against this viral protein,” said Morrissey. “The immunoglobulins persist in the blood for a few months, and when they come into contact with the gold nanorods, the nanorods undergo a slight color change that can be detected with a hand-held spectrophotometer.
“With this test, results will be clear before the patient leaves the clinic, allowing immediate counselling and access to treatment.”
The colour change cannot be seen with the naked eye, but the scientists are working to change that. They’re also working on developing ways to use saliva rather than blood.
Although the test uses gold, the nanorods are very small. The researchers estimate that the cost of the gold used in one of the assays would be 10 to 15 cents.
As other infectious diseases emerge around the world, similar strategies potentially could be used to develop tests to detect the presence of viruses that may become problematic, according to the researchers.
Washington University School of Medicine
medicine.wustl.edu/news/test-uses-nanotechnology-quickly-diagnose-zika-virus/
March 2024
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