Izaak Walton Killam Health Center

Halifax, Canada

Izaak Walton Killam Health Center

Halifax, Canada
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Girirajan S.,Howard Hughes Medical Institute | Rosenfeld J.A.,Perkin Elmer Corporation | Coe B.P.,Howard Hughes Medical Institute | Parikh S.,Cleveland Clinic | And 37 more authors.
New England Journal of Medicine | Year: 2012

BACKGROUND: Some copy-number variants are associated with genomic disorders with extreme phenotypic heterogeneity. The cause of this variation is unknown, which presents challenges in genetic diagnosis, counseling, and management. METHODS: We analyzed the genomes of 2312 children known to carry a copy-number variant associated with intellectual disability and congenital abnormalities, using array comparative genomic hybridization. RESULTS: Among the affected children, 10.1% carried a second large copy-number variant in addition to the primary genetic lesion. We identified seven genomic disorders, each defined by a specific copy-number variant, in which the affected children were more likely to carry multiple copy-number variants than were controls. We found that syndromic disorders could be distinguished from those with extreme phenotypic heterogeneity on the basis of the total number of copy-number variants and whether the variants are inherited or de novo. Children who carried two large copy-number variants of unknown clinical significance were eight times as likely to have developmental delay as were controls (odds ratio, 8.16; 95% confidence interval, 5.33 to 13.07; P = 2.11×10 -38). Among affected children, inherited copy-number variants tended to co-occur with a second-site large copy-number variant (Spearman correlation coefficient, 0.66; P<0.001). Boys were more likely than girls to have disorders of phenotypic heterogeneity (P<0.001), and mothers were more likely than fathers to transmit second-site copy-number variants to their offspring (P = 0.02). CONCLUSIONS: Multiple, large copy-number variants, including those of unknown pathogenic significance, compound to result in a severe clinical presentation, and secondary copy-number variants are preferentially transmitted from maternal carriers. (Funded by the Simons Foundation Autism Research Initiative and the National Institutes of Health.) Copyright © 2012 Massachusetts Medical Society. All rights reserved.

News Article | November 22, 2016
Site: www.prweb.com

Cubresa Inc., a medical imaging company that develops and markets molecular imaging systems, today announced that their compact SPECT (Single-Photon Emission Computed Tomography) scanner was used in a study by Dalhousie University and Mount Saint Vincent University researchers in Halifax, Nova Scotia to help evaluate the diagnostic potential of a new molecular label that could lead to the early detection of Alzheimer’s disease in living patients. Alzheimer’s disease (AD) is a progressive neurological condition that causes dementia and for which there is no FDA-approved treatment for the underlying disease. There is a need for a non-invasive way to detect and diagnose the disease in living patients because definitive diagnosis still requires post mortem examination. The study was performed by Dr. Sultan Darvesh and his research group at BIOTIC (Biomedical Translational Imaging Centre) at the Izaak Walton Killam Health Centre in Halifax, and was partially funded by TREVENTIS™ Corporation of which Dr. Darvesh is a scientific co-founder. SPECT imaging provides 3D information with a high degree of sensitivity and specificity for detecting the presence of a particular radiolabeled enzyme, in this case the BChE (butyrylcholinesterase) enzyme. Prior research has shown that elevated BChE expression levels are associated with abnormal ß-amyloid (Aß) plaques in the brains of Alzheimer’s patients. The novel molecular label, TRV6001, was synthesized and determined to bind to BChE with high specificity before being injected into 5XFAD mouse models of Alzheimer’s Disease. TRV6001 is still under development and has not yet been shown to be safe or effective in humans. “SPECT imaging has provided us the first direct in vivo evidence that the TRV6001 label can cross the blood-brain barrier and actually exhibits higher retention in the brains of AD mice (whose BChE level is markedly elevated) than in normal control brains,” said lead author Drew DeBay, Ph.D. candidate at the Department of Medical Neuroscience, Dalhousie University. In addition, the retention in BChE-associated brain structures was shown to closely follow the known histochemical distribution of BChE that has been previously established in AD mouse models. “Up to now there have been many false-positives,” said Dr. Sultan Darvesh, FRCPC, Professor at the Department of Medical Neuroscience, Dalhousie University. “Previous labels were able to bind to Aß plaque–but Aß is also present in cognitively normal people. BChE, which we are detecting, is notably absent in the non-Alzheimer’s brain.” “Alzheimer’s disease affects so many people and causes such pain and suffering for individuals and their families,” said George Abe, CEO of Cubresa. “We’re pleased to know that our SPECT scanner has contributed to a big step towards developing effective treatments and monitoring their effect.” The research was presented this year at the Alzheimer's Association International Conference® (AAIC®), the world's largest forum for the dementia research community, in Toronto, Canada. Detailed caption for associated image: Representative WT (wild-type, left column) and 5XFAD (Alzheimer’s model, right column) brains at the mid-coronal level. Row A: Histochemical staining of BChE, revealing marked elevation of BChE in AD, notably in the cerebral cortex. C = cerebral cortex, H = hippocampus, BG = basal ganglia, Th = thalamus, A = amygdala. Scale bar = 1mm. Row B: CT with co-registered MR at the same level as Row A. Row C: SPECT images acquired at 4 mins post-injection with co-registered CT/MR and ROIs. Marked retention in the cerebral cortex is evident in the 5XFAD brain compared to the WT brain and to a lesser extent in amygdala, hippocampus, basal ganglia and thalamus. Images courtesy of the Darvesh group and BIOTIC. About Cubresa Inc. Cubresa is a medical imaging company that develops and markets nuclear imaging systems that enable researchers at leading universities, hospitals and pharmaceutical companies to non-invasively visualize and measure biochemical processes at the molecular level. Applications for Cubresa’s products include preclinical drug development, disease research in oncology, neurology, and cardiology, as well as clinical diagnostics. Cubresa has operations in Boston, Massachusetts and Winnipeg, Manitoba. Visit http://www.cubresa.com for more information. About Dalhousie University Dalhousie University is internationally known as one of North America’s most welcoming universities. Founded in 1818, Dalhousie is one of Canada’s oldest universities, attracting more than 18,500 students from around the world. Located on Canada’s East Coast, the university blends world-class academic programs with leading-edge research. Visit http://www.dal.ca for more information. About Mount Saint Vincent University Recognized as a leader in distance and experiential learning, and based on a strong tradition of social responsibility, Mount Saint Vincent University takes a personalized approach to education to nurture socially responsible global citizens. Founded in 1873, the Mount has been nationally recognized for having one of the lowest student-to-professor ratios, for providing students early access to valuable research opportunities, for its legacy in the advancement of women, and for facilitating critical advancements in food security, healthy aging, literacy, and childhood development. Visit http://www.msvu.ca for more information. About Izaak Walton Killam Health Centre and the Biomedical Translational Imaging Centre The IWK Health Centre is the Maritime region's leading health care and research centre dedicated to the well-being of women, children, youth and families. In addition to providing highly specialized and complex care, the IWK provides certain primary care services and is a strong advocate for the health of families. The IWK is a global leader in research and knowledge sharing, and a partner in educating the next generation of health professionals. As part of the IWK Health Centre, the Biomedical Translational Imaging Centre (BIOTIC) has an explicit mandate to translate medical science innovations with industry partners using clinical and preclinical imaging tools to produce next-generation healthcare advances. Visit http://www.iwk.nshealth.ca for more information. About TREVENTIS™ Corporation TREVENTIS is headquartered in Southeastern Pennsylvania and has research operations in Halifax and Toronto, Canada. The company is focused on the discovery and development of disease-modifying small molecule drugs for a variety of dementias including Alzheimer’s. In addition to its therapeutic programs, TREVENTIS has a novel approach to the development of diagnostics for early diagnosis and monitoring treatment effects in Alzheimer’s disease. Visit http://www.treventis.com for more information.

Bardouille T.,National Research Council Canada | Krishnamurthy S.V.,Izaak Walton Killam Health Center | Hajra S.G.,National Research Council Canada | Darcy R.C.N.,National Research Council Canada | Darcy R.C.N.,Dalhousie University
IEEE Transactions on Biomedical Engineering | Year: 2012

Brain source localization accuracy in magnetoencephalography (MEG) requires accuracy in both digitizing anatomical landmarks and coregistering to anatomical magnetic resonance images (MRI). We compared the source localization accuracy and MEG-MRI coregistration accuracy of two head digitization systemsa laser scanner and the current standard electromagnetic digitization system (Polhemus)using a calibrated phantom and human data. When compared using the calibrated phantom, surface and source localization accuracy for data acquired with the laser scanner improved over the Polhemus by 141 and 132, respectively. Laser scan digitization reduced MEG source localization error by 1.38mm on average. In human participants, a laser scan of the face generated a 1000-fold more points per unit time than the Polhemus head digitization. An automated surface-matching algorithm improved the accuracy of MEG-MRI coregistration over the equivalent manual procedure. Simulations showed that the laser scan coverage could be reduced to an area around the eyes only while maintaining coregistration accuracy, suggesting that acquisition time can be substantially reduced. Our results show that the laser scanner can both reduce setup time and improve localization accuracy, in comparison to the Polhemus digitization system. © 2012 IEEE.

Guernsey D.L.,Dalhousie University | Jiang H.,Dalhousie University | Bedard K.,Dalhousie University | Evans S.C.,Dalhousie University | And 14 more authors.
PLoS Genetics | Year: 2010

Charcot-Marie-Tooth disease (CMT) represents a family of related sensorimotor neuropathies. We studied a large family from a rural eastern Canadian community, with multiple individuals suffering from a condition clinically most similar to autosomal recessive axonal CMT, or AR-CMT2. Homozygosity mapping with high-density SNP genotyping of six affected individuals from the family excluded 23 known genes for various subtypes of CMT and instead identified a single homozygous region on chromosome 9, at 122,423,730-129,841,977 Mbp, shared identical by state in all six affected individuals. A homozygous pathogenic variant was identified in the gene encoding leucine rich repeat and sterile alpha motif 1 (LRSAM1) by direct DNA sequencing of genes within the region in affected DNA samples. The single nucleotide change mutates an intronic consensus acceptor splicing site from AG to AA. Direct analysis of RNA from patient blood demonstrated aberrant splicing of the affected exon, causing an obligatory frameshift and premature truncation of the protein. Western blotting of immortalized cells from a homozygous patient showed complete absence of detectable protein, consistent with the splice site defect. LRSAM1 plays a role in membrane vesicle fusion during viral maturation and for proper adhesion of neuronal cells in culture. Other ubiquitin ligases play documented roles in neurodegenerative diseases. LRSAM1 is a strong candidate for the causal gene for the genetic disorder in our kindred. © 2010 Guernsey et al.

Lin L.-T.,Taipei Medical University | Richardson C.D.,Dalhousie University | Richardson C.D.,Izaak Walton Killam Health Center
Viruses | Year: 2016

The hemagglutinin (H) protein of measles virus (MeV) interacts with a cellular receptor which constitutes the initial stage of infection. Binding of H to this host cell receptor subsequently triggers the F protein to activate fusion between virus and host plasma membranes. The search for MeV receptors began with vaccine/laboratory virus strains and evolved to more relevant receptors used by wild-type MeV. Vaccine or laboratory strains of measles virus have been adapted to grow in common cell lines such as Vero and HeLa cells, and were found to use membrane cofactor protein (CD46) as a receptor. CD46 is a regulator that normally prevents cells from complement-mediated self-destruction, and is found on the surface of all human cells, with the exception of erythrocytes. Mutations in the H protein, which occur during adaptation and allow the virus to use CD46 as a receptor, have been identified. Wild-type isolates of measles virus cannot use the CD46 receptor. However, both vaccine/laboratory and wild-type strains can use an immune cell receptor called signaling lymphocyte activation molecule family member 1 (SLAMF1; also called CD150) and a recently discovered epithelial receptor known as Nectin-4. SLAMF1 is found on activated B, T, dendritic, and monocyte cells, and is the initial target for infections by measles virus. Nectin-4 is an adherens junction protein found at the basal surfaces of many polarized epithelial cells, including those of the airways. It is also over-expressed on the apical and basal surfaces of many adenocarcinomas, and is a cancer marker for metastasis and tumor survival. Nectin-4 is a secondary exit receptor which allows measles virus to replicate and amplify in the airways, where the virus is expelled from the body in aerosol droplets. The amino acid residues of H protein that are involved in binding to each of the receptors have been identified through X-ray crystallography and site-specific mutagenesis. Recombinant measles “blind” to each of these receptors have been constructed, allowing the virus to selectively infect receptor specific cell lines. Finally, the observations that SLAMF1 is found on lymphomas and that Nectin-4 is expressed on the cell surfaces of many adenocarcinomas highlight the potential of measles virus for oncolytic therapy. Although CD46 is also upregulated on many tumors, it is less useful as a target for cancer therapy, since normal human cells express this protein on their surfaces. © 2016 by the authors; licensee MDPI, Basel, Switzerland.

Noyce R.S.,Dalhousie University | Noyce R.S.,Izaak Walton Killam Health Center | Richardson C.D.,Dalhousie University | Richardson C.D.,Izaak Walton Killam Health Center
Trends in Microbiology | Year: 2012

Measles virus (MV) causes acute respiratory disease, infects lymphocytes and multiple organs, and produces immune suppression leading to secondary infections. In rare instances it can also cause persistent infections in the brain and central nervous system. Vaccine and laboratory-adapted strains of MV use CD46 as a receptor, whereas wild-type strains of MV (wtMV) cannot. Both vaccine and wtMV strains infect lymphocytes, monocytes, and dendritic cells (DCs) using the signaling lymphocyte activation molecule (CD150/SLAM). In addition, MV can infect the airway epithelial cells of the host. Nectin 4 (PVRL4) was recently identified as the epithelial cell receptor for MV. Coupled with recent observations made in MV-infected macaques, this discovery has led to a new paradigm for how the virus accesses the respiratory tract and exits the host. Nectin 4 is also a tumor cell marker which is highly expressed on the apical surface of many adenocarcinoma cell lines, making it a potential target for MV oncolytic therapy. © 2012 Elsevier Ltd.

Tuschl K.,University College London | Clayton P.T.,University College London | Gospe Jr. S.M.,University of Washington | Gulab S.,Aga Khan University | And 14 more authors.
American Journal of Human Genetics | Year: 2012

Environmental manganese (Mn) toxicity causes an extrapyramidal, parkinsonian-type movement disorder with characteristic magnetic resonance images of Mn accumulation in the basal ganglia. We have recently reported a suspected autosomal recessively inherited syndrome of hepatic cirrhosis, dystonia, polycythemia, and hypermanganesemia in cases without environmental Mn exposure. Whole-genome mapping of two consanguineous families identified SLC30A10 as the affected gene in this inherited type of hypermanganesemia. This gene was subsequently sequenced in eight families, and homozygous sequence changes were identified in all affected individuals. The function of the wild-type protein and the effect of sequence changes were studied in the manganese-sensitive yeast strain Δpmr1. Expressing human wild-type SLC30A10 in the Δpmr1 yeast strain rescued growth in high Mn conditions, confirming its role in Mn transport. The presence of missense (c.266T>C [p.Leu89Pro]) and nonsense (c.585del [p.Thr196Profs17]) mutations in SLC30A10 failed to restore Mn resistance. Previously, SLC30A10 had been presumed to be a zinc transporter. However, this work has confirmed that SLC30A10 functions as a Mn transporter in humans that, when defective, causes Mn accumulation in liver and brain. This is an important step toward understanding Mn transport and its role in neurodegenerative processes. © 2012 The American Society of Human Genetics.

Liu Y.,Harvard University | Liu Y.,Cambridge Broad Institute | Asnani A.,Harvard University | Asnani A.,Cambridge Broad Institute | And 19 more authors.
Science Translational Medicine | Year: 2014

Doxorubicin is a highly effective anticancer chemotherapy agent, but its use is limited by its cardiotoxicity. To develop a drug that prevents this toxicity, we established a doxorubicin-induced cardiomyopathy model in zebrafish that recapitulates the cardiomyocyte apoptosis and contractility decline observed in patients. Using this model, we screened 3000 compounds and found that visnagin (VIS) and diphenylurea (DPU) rescue the cardiac performance and circulatory defects caused by doxorubicin in zebrafish. VIS and DPU reduced doxorubicin-induced apoptosis in cultured cardiomyocytes and in vivo in zebrafish and mouse hearts. VIS treatment improved cardiac contractility in doxorubicin-treated mice. Further, VIS and DPU did not reduce the chemotherapeutic efficacy of doxorubicin in several cultured tumor lines or in zebrafish and mouse xenograft models. Using affinity chromatography, we found that VIS binds to mitochondrial malate dehydrogenase (MDH2), a key enzyme in the tricarboxylic acid cycle. As with VIS, treatment with the MDH2 inhibitors mebendazole, thyroxine, and iodine prevented doxorubicin cardiotoxicity, as did treatment with malate itself, suggesting that modulation of MDH2 activity is responsible for VIS' cardioprotective effects. Thus, VIS and DPU are potent cardioprotective compounds, and MDH2 is a previously undescribed, druggable target for doxorubicin-induced cardiomyopathy.

Schuh S.,University of Toronto | Zemek R.,Childrens Hospital of Eastern Ontario CHEO | Plint A.,Childrens Hospital of Eastern Ontario CHEO | Black K.J.L.,Izaak Walton Killam Health Center | And 5 more authors.
Pediatrics | Year: 2012

OBJECTIVES: To examine the use of intravenous magnesium in Canadian pediatric emergency departments (EDs) in children requiring hospitalization for acute asthma and association of administration of frequent albuterol/ipratropium and timely corticosteroids with hospitalization. METHODS: Retrospective medical record review at 6 EDs of otherwise healthy children 2 to 17 years of age with acute asthma. Data were extracted on history, disease severity, and timing of ED stabilization treatments with inhaled albuterol, ipratropium, corticosteroids, and magnesium. Primary outcome was the proportion of hospitalized children given magnesium in the ED. Secondary outcome was the ED use of "intensive therapy" in hospitalized children, defined as 3 albuterol inhalations with ipratropium and corticosteroids within 1 hour of triage. RESULTS: A total of 19 (12.3%) of 154 hospitalized children received magnesium (95% confidence interval 7.1, 17.5) versus 2 of 962 discharged patients. Children given magnesium were more likely to have been previously admitted to ICU (odds ratio [OR] 11.2), hospitalized within the past year (OR 3.8), received corticosteroids before arrival (OR 4.0), presented with severe exacerbation (OR 6.1), and to have been treated at 1 particular center (OR 14.9). Forty-two (53%) of 90 hospitalized children were not given "intensive therapy." Children receiving "intensive therapy" were more likely to present with severe disease to EDs by using asthma guidelines (ORs 8.9, 3.0). Differences in the frequencies of all stabilization treatments were significant across centers. CONCLUSIONS: Magnesium is used infrequently in Canadian pediatric EDs in acute asthma requiring hospitalization. Many of these children also do not receive frequent albuterol and ipratropium, or early corticosteroids. Significant variability in the use of these interventions was detected. Copyright © 2012 by the American Academy of Pediatrics.

PubMed | Izaak Walton Killam Health Center, Alberta Childrens Hospital and McMaster Childrens Hospital
Type: Journal Article | Journal: Pediatric blood & cancer | Year: 2016

Pediatric patients with chronic and/or refractory autoimmune multi-lineage cytopenias present challenges in both diagnosis and management. Increasing availability of diagnostic testing has revealed an underlying immune dysfunction in patients previously diagnosed with Evans Syndrome. However, the data are sparse and the majority of patients are adults.We performed a retrospective chart review to document the natural history of 23 pediatric patients with autoimmune multi-lineage cytopenias followed at three tertiary care pediatric hematology clinics.Investigations revealed seven patients (30.4%) with an autoimmune lymphoproliferative-like syndrome and six patients (26.1%) with other primary immunodeficiencies. Only one (4.3%) patient was suspected to have systemic lupus erythematosus and six patients (26.1%) had other types of autoimmunity. Treatment consisted of immunosuppressive therapy, intravenous gammaglobulin, and splenectomy. Supportive care included granulocyte-colony stimulating factor, and blood product transfusions. Two patients (8.7%) died. Complete remission was achieved in 3 patients (13.0%); of the remaining, 14 patients (60.9%) had chronic immune thrombocytopenic purpura, 10 patients (43.5%) chronic autoimmune neutropenia, and 4 patients (17.4%) chronic autoimmune hemolytic anemia with a median follow up of 5 years (2 months-12 years).These data suggest that pediatric patients presenting with autoimmune multi-lineage cytopenias should undergo investigation for underlying immune dysregulation, including autoimmune lymphoproliferative syndrome, other primary immunodeficiencies and autoimmune disorders. The development of an international registry for such patients is imperative to improve the understanding of their complex natural history.

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