Children Hospital of Eastern Ontario

Ottawa, Canada

Children Hospital of Eastern Ontario

Ottawa, Canada
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Hadano S.,Tokai University | Yoshii Y.,Toho University | Otomo A.,Tokai University | Kunita R.,Tokai University | And 7 more authors.
Neuroscience Research | Year: 2010

Loss-of-function mutations in human ALS2 account for several juvenile recessive motor neuron diseases (MNDs). To understand the molecular basis underlying motor dysfunction in ALS2-linked MNDs, several lines of Als2-/- mice with a mixed genetic background were thus far generated, and their phenotypes were thoroughly characterized. However, several phenotypic discrepancies among different Als2-deficient lines became evident. To investigate whether genetic backgrounds are associated with such discrepancies, we here generated congenic lines of Als2-/- mice on two different genetic backgrounds; C57BL/6 (B6) and FVB/N (FVB), and investigated their gross phenotypes. Both B6 and FVB congenic lines were viable and fertile with no evidences for obvious abnormalities. There were no differences in growth curves between wild-type and Als2-/- mice on each genetic background. Remarkably, Als2-/- mice on a FVB, but not a B6, background exhibited a shorter life span than wild-type litters. Further, B6 female, but not male, Als2-/- mice showed a significantly lower spontaneous rearing activity than wild-type litters. These genetic background- and/or gender-specific findings suggest the presence of modifiers for life span and motor activities in Als2-/- mice. These congenic mice should provide a useful means to understand the molecular and genetic basis for variable expression of pathological phenotypes in MNDs. © 2010 Elsevier Ireland Ltd.


Lafay-Cousin L.,Alberta Childrens Hospital | Hawkins C.,Hospital for Sick Children | Carret A.S.,Hospital Sainte Justine | Johnston D.,Children Hospital of Eastern Ontario | And 12 more authors.
European Journal of Cancer | Year: 2012

Background: Atypical teratoid rhabdoid tumours (ATRT) are aggressive brain tumours mostly occurring in early childhood. Largest published series arise from registries and institutional experiences (1-4). The aim of this report is to provide population-based data to further characterise this rare entity and to delineate prognostic factors. Patients and methods: A national retrospective study of children ≤18 years diagnosed with a central nervous system (CNS) ATRT between 1995 and 2007 was undertaken. All cases underwent central pathology review. Results: There were 50 patients (31 males; median age at diagnosis of 16.7 months). Twelve patients were >36 months. Infratentorial location accounted for 52% of all cases. Nineteen patients (38%) had metastatic disease. Fifteen (30%) underwent gross total resection (GTR). Ten patients (20%) underwent palliation. Among the 40 remaining patients, 22 received conventional chemotherapy and 18 received high dose chemotherapy regimens (HDC); nine received intrathecal chemotherapy and 15 received adjuvant radiation. Thirty of the 40 treated patients relapsed/progressed at a median time of 5.5 months (0-32). The median survival time of the entire cohort was 13.5 months (1-117.5 months). Age, tumour location and metastatic status were not prognostic. Patients with GTR had a better survival (2 years overall survival (OS): 60% ± 12.6 versus 21.7% ± 8.5, p = 0.03). HDC conferred better outcome (2 years OS 47.9% ± 12.1 versus 27.3% ± 9.5, p = 0.036). Upfront radiation did not provide survival benefit. Six of the 12 survivors (50%) did not receive radiation. Conclusion: The outcome of CNS ATRT remains poor. However, the use of HDC provides encouraging results. GTR is a significant prognostic factor. The role of adjuvant radiation remains unclear. © 2011 Elsevier Ltd. All rights reserved.


Turner D.,Hebrew University of Jerusalem | Griffiths A.M.,Hospital for Sick Children | Mack D.,Children Hospital of Eastern Ontario | Otley A.R.,Izaak Walton Killam Hospital | And 5 more authors.
Inflammatory Bowel Diseases | Year: 2010

Background: We aimed to determine the optimal approach to assess disease activity (i.e., biological inflammation) in ulcerative colitis (UC) by comparing patients' and physicians' rating of the disease. Methods: This was a prospective, multicenter, double-cohort study. The first cohort was composed of 94 children with UC (parent proxy when required) and their physicians who provided independent clinical report and global assessment of disease, rated on a 100 mm visual analog scale. Constructs of disease activity (including mucosal inflammation, laboratory tests, Mayo score, and the Pediatric UC Activity Index), were scored by an independent blinded physician and used to compare validity of the assessment. Of the 94 children, 43 were seen at a follow-up visit and provided a global rating of change in disease activity. To ascertain whether age influences assessment accuracy, a second cohort of 86 adult UC patients were analyzed in a similar way. Results: In both cohorts the physician global assessment had higher correlations with all constructs of disease activity than did the patient' global assessment (for colonoscopic score r = 0.76 vs. r = 0.29, P = 0.002). Even with abdominal pain, a subjective item, the physician's rating had higher correlation than the patient's rating. Similarly, the physician rating of change better reflected change in disease activity than that of the patient rating. Conclusions: For indirect measurement of biological activity on the basis of symptoms and signs, clinician assessments are superior to those of patients. Patient assessments, physician assessments, and direct measurement of disease activity provide complementary information in clinical research. Copyright © 2009 Crohn's & Colitis Foundation of America, Inc.


Hadano S.,Tokai University | Otomo A.,Tokai University | Kunita R.,Tokai University | Suzuki-Utsunomiya K.,Tokai University | And 7 more authors.
PLoS ONE | Year: 2010

Background: ALS2/alsin is a guanine nucleotide exchange factor for the small GTPase Rab5 and involved in macropinocytosis-associated endosome fusion and trafficking, and neurite outgrowth. ALS2 deficiency accounts for a number of juvenile recessive motor neuron diseases (MNDs). Recently, it has been shown that ALS2 plays a role in neuroprotection against MND-associated pathological insults, such as toxicity induced by mutant Cu/Zn superoxide dismutase (SOD1). However, molecular mechanisms underlying the relationship between ALS2-associated cellular function and its neuroprotective role remain unclear. Methodology/Principal Findings: To address this issue, we investigated the molecular and pathological basis for the phenotypic modification of mutant SOD1-expressing mice by ALS2 loss. Genetic ablation of Als2 in SOD1H46R, but not SOD1G93A, transgenic mice aggravated the mutant SOD1-associated disease symptoms such as body weight loss and motor dysfunction, leading to the earlier death. Light and electron microscopic examinations revealed the presence of degenerating and/or swollen spinal axons accumulating granular aggregates and autophagosome-like vesicles in early- and even pre-symptomatic SOD1H46R mice. Further, enhanced accumulation of insoluble high molecular weight SOD1, polyubiquitinated proteins, and macroautophagy-associated proteins such as polyubiquitin-binding protein p62/SQSTM1 and a lipidated form of light chain 3 (LC3-II), emerged in ALS2-deficient SOD1H46R mice. Intriguingly, ALS2 was colocalized with LC3 and p62, and partly with SOD1 on autophagosome/endosome hybrid compartments, and loss of ALS2 significantly lowered the lysosome-dependent clearance of LC3 and p62 in cultured cells. Conclusions/Significance: Based on these observations, although molecular basis for the distinctive susceptibilities to ALS2 loss in different mutant SOD1-expressing ALS models is still elusive, disturbance of the endolysosomal system by ALS2 loss may exacerbate the SOD1H46R-mediated neurotoxicity by accelerating the accumulation of immature vesicles and misfolded proteins in the spinal cord. We propose that ALS2 is implicated in endolysosomal trafficking through the fusion between endosomes and autophagosomes, thereby regulating endolysosomal protein degradation in vivo. © 2010 Hadano et al.


Aziz K.,University of Alberta | Chinnery H.,Stollery Childrens Hospital | Lacaze-Masmonteil T.,Children Hospital of Eastern Ontario
Advances in Neonatal Care | Year: 2012

OBJECTIVE: To describe the implementation and outcomes of delayed cord clamping (DCC) in preterm babies. STUDY DESIGN: Following staff orientation, a policy of DCC for 45 seconds was instituted for all eligible babies born between 28 and 32 weeks' gestational age, and later to all those younger than 33 weeks. RESULTS: Of 480 babies, 349 (73%) were eligible for DCC. Of these, 236 (68%) received DCC. Monthly compliance rates to DCC protocol in eligible babies ranged from 18% to 93%. There was no significant difference in demographic measures or rates of delivery room ventilation between eligible babies who did or did not receive DCC. Delayed cord clamping was associated with less hypothermia, higher initial hemoglobin levels, and less necrotizing enterocolitis, with a trend toward lower 1-minute Apgar scores and less blood pressure support. CONCLUSIONS: The DCC protocol is feasible in preterm babies with reinforcement and education. It appears practical, safe, and applicable, and has minimal impact on immediate neonatal transition, with possible early neonatal benefits. Copyright © 2012 by The National Association of Neonatal Nurses.


Hing M.M.,University of Ottawa | Michalowski M.,Adventium Labs. | Wilk S.,Poznan University of Technology | Michalowski W.,University of Ottawa | Farion K.,Children Hospital of Eastern Ontario
2010 IEEE International Conference on Bioinformatics and Biomedicine Workshops, BIBMW 2010 | Year: 2010

This paper describes a methodological approach to identifying inconsistencies when reconciling multiple clinical practice guidelines. The need to address these inconsistencies arises when a patient with co-morbidity has to be managed according to different treatment regimens. Starting with a well-known flowchart representation we discuss how to create a formal guideline model that allows for easy manipulations of its components. For this model we present how to identify conflicting actions that are manifested by treatment-treatment and treatment-disease interactions, and how to reconcile these conflicting actions. ©2010 IEEE.


Michalowski M.,Adventium Labs. | Mainegra Hing M.,University of Ottawa | Wilk S.,Poznan University of Technology | Michalowski W.,University of Ottawa | Farion K.,Children Hospital of Eastern Ontario
Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics) | Year: 2011

This paper describes a novel methodological approach to identifying inconsistencies when concurrently using multiple clinical practice guidelines. We discuss how to construct a formal guideline model using Constraint Logic Programming, chosen for its ability to handle relationships between patient information, diagnoses, and treatment suggestions. We present methods to identify inconsistencies that are manifested by treatment-treatment and treatment-disease interactions associated with comorbidity. Using an open source constraint programming system (ECLiPSe), we demonstrate the ability of our approach to find treatment given incomplete patient data and to identify possible inconsistencies. © 2011 Springer-Verlag.


Dankar F.K.,IBM | Dankar F.K.,Sidra Medical and Research Center | El Emam K.,Children Hospital of Eastern Ontario | Matwin S.,Polish Academy of Sciences | Matwin S.,Dalhousie University
Procedia Computer Science | Year: 2014

Knowledge of patients' location information (postal/zip codes) is critical in public health research. However, the inclusion of location information makes it easier to determine the identity of the individuals in the data sets. An efficient way to anonymize location information is through aggregation. In order to aggregate the locations efficiently, the data holder needs to know the locations' adjacency information. A location adjacency matrix is big, and requires constant updates, thus it cannot be stored at the data holder's end. A possible solution would be to have the adjacency matrix stored on a cloud server, the data holder can then query the required adjacency records. However, queries reveal information on patients' locations, thus, we need to privately query the cloud server's database. Existing private information retrieval protocols are inefficient for our context, therefore, in this paper, we present an efficient protocol to privately query the server's database for adjacency information and thus preserving patients' privacy. © 2014 The Authors.


Richer J.,Childrens Hospital of Eastern Ontario | Milewicz D.M.,University of Texas Health Science Center at Houston | Gow R.,Children Hospital of Eastern Ontario | de Nanassy J.,Children Hospital of Eastern Ontario | And 5 more authors.
American Journal of Medical Genetics, Part A | Year: 2012

Mutations in ACTA2 (smooth muscle cell-specific isoform of α-actin) lead to a predisposition to thoracic aortic aneurysms and other vascular diseases. More recently, the ACTA2 R179H mutation has been described in individuals with global smooth muscle dysfunction. We report a patient heterozygous for the mutation in ACTA2 R179H who presented with megacystis at 13 weeks gestational age and, at birth, with prune-belly sequence. He also had deep skin dimples and creases on his palms and soles, a finding not previously described but possibly related to ACTA2. To our knowledge, this is the first report of the R179H mutation in ACTA2 in a child with prune-belly sequence. We think the R179H mutation in ACTA2 should be included in the differential diagnosis of individuals presenting with the sequence without an identified mechanical obstruction. Furthermore, as ACTA2 R179H has been reported in patients with severe vasculomyopathy and premature death, we recommend that molecular testing for this mutation be considered in fetuses presenting with fetal megacystis with a normal karyotype, particularly if the bladder diameter is 15mm or more, to allow expectant parents to make an informed decision. © 2012 Wiley Periodicals, Inc.


Otomo A.,Tokai University | Kunita R.,Tokai University | Suzuki-Utsunomiya K.,Tokai University | Ikeda J.-E.,Tokai University | And 2 more authors.
FEBS Letters | Year: 2011

Loss of ALS2/alsin function accounts for several recessive motor neuron diseases. ALS2 is a Rab5 activator and its endosomal localization is regulated by Rac1 via macropinocytosis. Here, we show that the pathogenic missense ALS2 mutants fail to be localized to Rac1-induced macropinosomes as well as endosomes, which leads to loss of the ALS2 function as a Rab5 activator on endosomes. Further, these mutants lose the competence to enhance the formation of amphisomes, the hybrid-organelle formed upon fusion between autophagosomes and endosomes. Thus, Rac1-induced relocalization of ALS2 might be crucial to exert the ALS2 function associated with the autophagy-endolysosomal degradative pathway. Structured summary: Rac1 physically interacts with ALS2 by pull down (View interaction) Rab5A physically interacts with ALS2 by pull down (View Interaction 1, 2) ALS2 and EEA1 colocalize by fluorescence microscopy (View Interaction 1, 2, 3) ALS2 physically interacts with ALS2 by anti tag coimmunoprecipitation (View interaction) © 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

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