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Drolet C.,McGill University | Miro J.,Hopital Ste Justine | Cote J.-M.,Center Hospitalier Of Luniversite Laval | Finley J.,Izaak Walton Killam Health Center | And 2 more authors.
Canadian Journal of Cardiology | Year: 2011

Background: The management of pediatric discrete subaortic stenosis remains controversial. Objectives: Document the natural history and surgical outcomes for discrete subaortic stenosis to adolescence. Methods: Retrospective review of clinical and echocardiographic findings in 74 patients diagnosed in childhood between 1985 and 1998. Results: Twenty-five patients were followed only medically for 9.4 ± 0.9 years to 15.9 ± 0.6 years of age. Their echocardiographic left ventricular outflow peak gradient did not progress, 19 ± 1.4 (SEM) vs 20 ± 2.3 mm Hg. The proportion with aortic insufficiency (AI) increased (4% to 52%). Forty-nine patients were operated for discrete subaortic stenosis at 7.8 ± 0.6 years. Their peak gradient at diagnosis was 36 ± 3 mm Hg with AI in 33%. Preoperatively their peak gradient progressed to 60 ± 5 mm Hg with AI in 82%. Assessment 6.2 ± 0.5 years postoperativly showed a peak gradient of 14 ± 2 mm Hg with AI in 88%. Ten patients required reoperation for recurrent discrete subaortic stenosis, 3 acquired complete heart block, and 1 developed endocarditis. There was no mortality. At diagnosis, surgical patients were younger, had greater peak gradients, and greater incidence of AI, than those followed only medically. The progression of discrete subaortic stenosis was positively associated with severity of obstruction and negatively associated with older age at diagnosis. The risk of having surgery over time was associated with greater preoperative obstruction and presence of AI. Conclusions: Many pediatric patients with mild discrete subaortic stenosis exhibit little progression of obstruction and need not undergo immediate surgery. Others with more severe stenosis may progress precipitously and will benefit from early resection. © 2011 Canadian Cardiovascular Society. Source

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. Source

Yee W.H.,University of Calgary | Soraisham A.S.,University of Calgary | Shah V.S.,University of Toronto | Aziz K.,University of Alberta | And 28 more authors.
Pediatrics | Year: 2012

OBJECTIVES: To examine the variation in the incidence and to identify the timing of the presentation of necrotizing enterocolitis (NEC) in a cohort of preterm infants within the Canadian Neonatal Network (CNN). METHODS: This was a population-based cohort of 16 669 infants with gestational age (GA) <33 weeks, admitted to 25 NICUs participating in the CNN between January 1, 2003, and December 31, 2008. Variations in NEC incidence among the participating NICUs for the study period were examined. We categorized early-onset NEC as occurring at <14 days of age and late-onset NEC occurring at ≥14 days. Multivariate logistic regression analysis was performed to identify risk factors for early-onset NEC. RESULTS: The overall incidence of NEC was 5.1%, with significant variation in the risk adjusted incidence among the participating NICUs in the CNN. Early-onset NEC occurred at a mean of 7 days compared with 32 days for late-onset NEC. Early-onset NEC infants had lower incidence of respiratory distress syndrome, patent ductus treated with indomethacin, less use of postnatal steroids, and shorter duration of ventilation days. Multivariate logistic regression analysis identified that greater GA and vaginal delivery were associated with increased risk of early-onset NEC. CONCLUSIONS: Among infants <33 weeks' gestation, NEC appears to present at mean age of 7 days in more mature infants, whereas onset of NEC is delayed to 32 days of age in smaller, lower GA infants. Further studies are required to understand the etiology of this disease process. Copyright © 2012 by the American Academy of Pediatrics. Source

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. Source

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. Source

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