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London, Canada

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London, Canada
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Kernohan K.D.,00 Commissioners Road East | Kernohan K.D.,Childrens Health Research Institute | Jiang Y.,00 Commissioners Road East | Jiang Y.,Childrens Health Research Institute | And 11 more authors.
Developmental Cell | Year: 2010

Human developmental disorders caused by chromatin dysfunction often display overlapping clinical manifestations, such as cognitive deficits, but the underlying molecular links are poorly defined. Here, we show that ATRX, MeCP2, and cohesin, chromatin regulators implicated in ATR-X, RTT, and CdLS syndromes, respectively, interact in the brain and colocalize at the H19 imprinting control region (ICR) with preferential binding on the maternal allele. Importantly, we show that ATRX loss of function alters enrichment of cohesin, CTCF, and histone modifications at the H19 ICR, without affecting DNA methylation on the paternal allele. ATRX also affects cohesin, CTCF, and MeCP2 occupancy within the Gtl2/Dlk1 imprinted domain. Finally, we show that loss of ATRX interferes with the postnatal silencing of the maternal H19 gene along with a larger network of imprinted genes. We propose that ATRX, cohesin, and MeCP2 cooperate to silence a subset of imprinted genes in the postnatal mouse brain. © 2010 Elsevier Inc. All rights reserved.


Kotsopoulos J.,Womens College Research Institute | Lubinski J.,Pomeranian Medical University | Neuhausen S.L.,City of Hope National Medical Center | Gronwald J.,Pomeranian Medical University | And 9 more authors.
Women's Health | Year: 2015

Aim: To measure weight gain among unaffected women with a BRCA1 or BRCA2 mutation after undergoing an oophorectomy. Patients & methods: We compared the bodyweight of women with (n = 405) and without an oophorectomy (n = 741) at baseline as well as the rate of weight change prior to and following surgery among 1454 BRCA mutation carriers who had an oophorectomy. Results: There was a small and non-significant difference in bodyweight between BRCA mutation carriers who had an oophorectomy compared with those women who did not (151.5 vs 149.1 pounds; p = 0.26). There was an increase in bodyweight with increasing age, but this relationship did not differ prior to and following surgery (p comparing the slope parameters = 0.78). Conclusion: Oophorectomy is not associated with significant weight gain in high-risk women. © 2015 Future Medicine Ltd.


Balvert M.,University of Tilburg | Van Hoof S.J.,Maastricht University | Granton P.V.,Maastricht University | Granton P.V.,00 Commissioners Road East | And 5 more authors.
Physics in Medicine and Biology | Year: 2015

Advances in precision small animal radiotherapy hardware enable the delivery of increasingly complicated dose distributions on the millimeter scale. Manual creation and evaluation of treatment plans becomes difficult or even infeasible with an increasing number of degrees of freedom for dose delivery and available image data. The goal of this work is to develop an optimisation model that determines beam-on times for a given beam configuration, and to assess the feasibility and benefits of an automated treatment planning system for small animal radiotherapy. The developed model determines a Pareto optimal solution using operator-defined weights for a multiple-objective treatment planning problem. An interactive approach allows the planner to navigate towards, and to select the Pareto optimal treatment plan that yields the most preferred trade-off of the conflicting objectives. This model was evaluated using four small animal cases based on cone-beam computed tomography images. Resulting treatment plan quality was compared to the quality of manually optimised treatment plans using dose-volume histograms and metrics. Results show that the developed framework is well capable of optimising beam-on times for 3D dose distributions and offers several advantages over manual treatment plan optimisation. For all cases but the simple flank tumour case, a similar amount of time was needed for manual and automated beam-on time optimisation. In this time frame, manual optimisation generates a single treatment plan, while the inverse planning system yields a set of Pareto optimal solutions which provides quantitative insight on the sensitivity of conflicting objectives. Treatment planning automation decreases the dependence on operator experience and allows for the use of class solutions for similar treatment scenarios. This can shorten the time required for treatment planning and therefore increase animal throughput. In addition, this can improve treatment standardisation and comparability of research data within studies and among different institutes. © 2015 Institute of Physics and Engineering in Medicine.


Manjoo A.,00 Commissioners Road East | Sanders D.,00 Commissioners Road East | Lawendy A.,00 Commissioners Road East | Gladwell M.,00 Commissioners Road East | And 3 more authors.
Journal of Orthopaedic Trauma | Year: 2010

Introduction: Indomethacin may preserve tissue viability in compartment syndrome. The mechanism of improved tissue viability is unclear, but the anti-inflammatory effects may alter the relative contribution of tissue necrosis versus apoptosis to cellular injury. Existing studies have only considered indomethacin administration before induction of elevated intracompartment pressure. The purpose of this study was to determine the effect of timing of indomethacin administration on muscle damage in elevated intracompartment pressure and to assess apoptosis as a cause of tissue demise. Methods: Twenty-four Wistar rats were randomized to elevated intracompartmental pressure (EICP) for either 45 or 90 minutes (30 mmHg). In the 45-minute cohort, indomethacin was withheld in Group 1 (CS45), given before induction of EICP in Group 2 (CS45Indo0), or given after 30 minutes of EICP/15 minutes before fasciotomy in Group 3 (CS45Indo30). In the 90-minute cohort, indomethacin was withheld in Group 4 (CS90) or given after 30 or 60 minutes of EICP in Groups 5 (CS90Indo30) and 6 (CS90Indo60). Intravital microscopy and fluorescent staining assessed capillary perfusion, cell damage, and inflammatory activation within extensor digitorum longus muscle. Apoptosis was assessed using spectrophotometric assessment of caspase levels. Groups 1 to 3 and 4 to 6 were compared using analysis of variance with P < 0.05 deemed significant. Results: Perfusion and tissue viability improved in indomethacin-treated groups. Nonperfused capillaries decreased from Group 1 (CS45) (50.1 ± 2.5) to Group 2 (CS45Indo0) (38.4 ± 1.8) and Group 3 (CS45Indo30) (14.13 ± 1.73) (P < 0.05). Similarly, Group 5 (CS90Indo30) and Group 6 (CS90Indo60) had 25% fewer nonperfused capillaries compared with Group 4 (CS90) (P < 0.0001). Group 2 (CS45Indo0) and Group 3 (CS45Indo30) showed fewer damaged cells (1% ± 0.5% and 8.7% ± 2%) compared with Group 1 (CS45) (20% ± 14%) (P < 0.0001). Group 5 (CS90Indo30) showed decreased cell damage (13% ± 1%) compared with Group 4 (CS90) (18% ± 1%) (P < 0.01). Group 6 (CS90Indo60) also showed decreased cell damage (11% ± 1%) compared with Group 4 (CS90) (18% ± 1%); however, this difference was not significant (P > 0.05). Apoptotic activity was present with elevated intracompartment pressure. At 30 minutes, there were elevated caspase levels in Group 4 and Group 6 EICP groups (0.47 ± 0.08) compared with control subjects (0.19 ± 0.02) (P < 0.003). However, indomethacin-treated groups did not differ from control subjects with regard to caspase levels (P > 0.05). Conclusion: Indomethacin decreased cell damage and improved perfusion in elevated intracompartment pressure. The benefits of indomethacin were partially time-dependent; some improvement in tissue viability occurred regardless of timing of administration. Although apoptosis was common in elevated intracompartment pressure, the protective effect of indomethacin does not appear to be related to apoptosis. Clinical Relevance: Adjuvant treatment with indomethacin may improve outcome in compartment syndrome. © 2010 by Lippincott Williams & Wilkins.


Filler G.,University of Western Ontario | Filler G.,00 Commissioners Road East | Huang S.-H.S.,University of Western Ontario | Lindsay R.M.,University of Western Ontario
Pediatric Nephrology | Year: 2011

Su Jin Kim and coworkers from Korea published an important study on the relationship of residual renal function (RRF) and cystatin in pediatric peritoneal dialysis (PD) patients in this issue of Pediatric Nephrology, both in anuric patients and patients with RRF. Based on a lack of correlation between cystatin C and standard small solute-based dialysis adequacy parameters such as Kt/Vurea but a significant correlation with RRF, the authors concluded that cystatin C may be a good tool to monitor RRF. The editorial reviews the available literature in adults, the different handing between urea and cystatin C, and the determinants of cystatin C clearance in dialysis patients. In adults, cystatin C levels are determined predominantly by RRF, but not exclusively. In anephric hemodialysis and PD patients, there is a correlation with standard weekly Kt/Vurea. Cystatin C levels will also depend on ultrafiltration. Despite these factors that affect cystatin C levels beyond RRF, cystatin C is a useful parameter for monitoring PD patients that may be more closely related to long-term outcomes than small solute adequacy parameters. © 2010 IPNA.


Bax K.C.,00 Commissioners Road East | Norozi K.,00 Commissioners Road East | Sharma A.P.,00 Commissioners Road East | Filler G.,00 Commissioners Road East
Health Economics Review | Year: 2011

Background: Electronic medical records (EMR) are considered the best solution to improved dissemination of health information for patients. The associated transcription caused a significant cost increase in an academic pediatric center. An educational campaign was implemented to achieve cost-effective transcriptions without compromising the number of EMR transcriptions. Methods: We analyzed the effect of seniority on transcription times over a 4-month period. We also compared the dictation volume before and 4 months after educational interventions. This study was performed in a pediatric academic center with both inpatient and outpatient transcription utilization analyzed. All clinicians providing pediatric care and utilizing the hospital-based transcription over the study time period were analyzed. Interventions included targeted education about efficiencies in transcription, time-based dictation costs, avoidance of lengthy pauses and unnecessary detail, shortening of total transcriptions, superfluous phrases as well as structured templates. Level of training by postgraduate year of training and seniority within faculty were measured for impact on dictation time and effect of education to improve times. Results: Learners in year one had an average dictation time of 7.5 ± 2.2 minutes, which decreased with seniority to an average of 4.1 ± 2.2 minutes for senior faculty (0.0007, ANOVA). After educational initiatives were implemented, there was progressive decline in dictation utilization. The total dictation time decreased from 8,750 minutes per month in August 2009 to 4,296 minutes in December of 2009 (p = 0.0045, unpaired t-test). Conclusion: We identified a substantial need for education in dictation utilization and demonstrated that relatively simple interventions can result in substantial costs savings. © 2011 Bax et al; licensee Springer.


PubMed | 00 Commissioners Road East
Type: Journal Article | Journal: Developmental cell | Year: 2010

Human developmental disorders caused by chromatin dysfunction often display overlapping clinical manifestations, such as cognitive deficits, but the underlying molecular links are poorly defined. Here, we show that ATRX, MeCP2, and cohesin, chromatin regulators implicated in ATR-X, RTT, and CdLS syndromes, respectively, interact in the brain and colocalize at the H19 imprinting control region (ICR) with preferential binding on the maternal allele. Importantly, we show that ATRX loss of function alters enrichment of cohesin, CTCF, and histone modifications at the H19 ICR, without affecting DNA methylation on the paternal allele. ATRX also affects cohesin, CTCF, and MeCP2 occupancy within the Gtl2/Dlk1 imprinted domain. Finally, we show that loss of ATRX interferes with the postnatal silencing of the maternal H19 gene along with a larger network of imprinted genes. We propose that ATRX, cohesin, and MeCP2 cooperate to silence a subset of imprinted genes in the postnatal mouse brain.

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