Browsing by Author "Mount Sinai Hospital of University of Toronto"

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    Assessing the Safety of Human Pluripotent Stem Cells and Their Derivatives for Clinical Applications
    (2017-07-11) Peter W. Andrews; Uri Ben-David; Nissim Benvenisty; Peter Coffey; Kevin Eggan; Barbara B. Knowles; Andras Nagy; Martin Pera; Benjamin Reubinoff; Peter J. Rugg-Gunn; Glyn N. Stacey; University of Sheffield; Broad Institute; Hebrew University of Jerusalem; UCL Institute of Ophthalmology; University of California, Santa Barbara; Harvard University; Harvard Stem Cell Institute; Jackson Laboratory; Mahidol University; Mount Sinai Hospital of University of Toronto; Monash University; University of Melbourne; The Florey Institute of Neuroscience and Mental Health; Walter and Eliza Hall Institute of Medical Research; Hadassah University Medical Centre; The Babraham Institute; Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute; Medicines and Health Care products Regulatory Agency
    © 2017 Pluripotent stem cells may acquire genetic and epigenetic variants during culture following their derivation. At a conference organized by the International Stem Cell Initiative, and held at The Jackson Laboratory, Bar Harbor, Maine, October 2016, participants discussed how the appearance of such variants can be monitored and minimized and, crucially, how their significance for the safety of therapeutic applications of these cells can be assessed. A strong recommendation from the meeting was that an international advisory group should be set up to review the genetic and epigenetic changes observed in human pluripotent stem cell lines and establish a framework for evaluating the risks that they may pose for clinical use.
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    Attitudes towards truth-telling about cancer: A survey from Thailand [5]
    (2008-03-13) Darin Jaturapatporn; Albert J. Kirshen; Mahidol University; Mount Sinai Hospital of University of Toronto
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    Correlation of circulating full-length visfatin (PBEF/NAMPT) with metabolic parameters in subjects with and without diabetes: A cross-sectional study
    (2008-12-01) Ravi Retnakaran; Byung Soo Youn; Ying Liu; Anthony J G Hanley; Nam Seok Lee; Ji Woo Park; Eun Sun Song; Vivian Vu; Wi Kim; Rungsunn Tungtrongchitr; Peter J. Havel; Michael M. Swarbrick; Collin Shaw; Gary Sweeney; York University; Mount Sinai Hospital of University of Toronto; University of Toronto; Korea University; Mahidol University; University of California, Davis; ALPCO Diagnostics
    Objective: Here we use a novel ELISA that is specific for full-length visfatin (PBEF/NAMPT), compare it with the existing C-terminal based assay and use it to investigate associations of visfatin with metabolic parameters. Design, patients and measurements: We established the specificity and effectiveness of the new ELISA and evaluated the associations of full-length visfatin with clinical, anthropometric and metabolic parameters in a cross-sectional study of 129 Thai subjects, consisting of 50 outpatients with type 2 diabetes and 79 healthy volunteers. Results: The new ELISA accurately recovered full-length recombinant visfatin and detected visfatin secreted by primary human and rat adipocytes. We found serum full-length visfatin was significantly higher in subjects with diabetes compared to their nondiabetic peers (median 2.75 vs. 2.22 ng/ml, P = 0.0142). After adjustment for age, gender and traditional metabolic risk factors, adjusted mean visfatin remained significantly higher in the diabetes group (3.80 vs. 2.10 ng/ml, P = 0.0021). On Spearman univariate correlation analysis, visfatin was significantly associated with resistin (r = 0.30, P = 0.0011), but not with any other anthropometric or metabolic variables, including adiponectin multimers. On multiple linear regression analysis, the only covariates independently associated with visfatin were diabetes (t = 3.11, P = 0.0024) and log resistin (t = 2.68, P = 0.0086). Conclusions: Circulating visfatin is independently associated with diabetes and resistin concentration, but is not related to adiponectin multimers or other metabolic covariates. These data are suggestive of a potential role of visfatin in subclinical inflammatory states. © 2008 The Authors.
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    Global phylogenomic analysis of nonencapsulated Streptococcus pneumoniae reveals a deep-branching classic lineage that is distinct from multiple sporadic lineages
    (2014-01-01) Markus Hilty; Daniel Wüthrich; Susannah J. Salter; Hansjürg Engel; Samuel Campbell; Raquel Sá-Leão; Hermínia De Lencastre; Peter Hermans; Ewa Sadowy; Paul Turner; Claire Chewapreecha; Mathew Diggle; Gerd Pluschke; Lesley McGee; Özgen Köseoʇlu Eser; Donald E. Low; Heidi Smith-Vaughan; Andrea Endimiani; Marianne Kü Ffer; Mélanie Dupasquier; Emmanuel Beaudoing; Johann Weber; Rémy Bruggmann; William P. Hanage; Julian Parkhill; Lucy J. Hathaway; Kathrin Mü Hlemann; Stephen D. Bentley; University of Bern; UniversitatsSpital Bern; Swiss Institute of Bioinformatics; Wellcome Trust Sanger Institute; Instituto de Tecnologia Quimica e Biologica - Univesidade Nova de Lisboa; Rockefeller University; Radboud University Nijmegen; National Medicines Institute, Warsaw; Mahidol University; Nuffield Department of Clinical Medicine; Queen's Medical Centre; Universitat Basel; National Center for Immunization and Respiratory Diseases; Hacettepe Universitesi; Mount Sinai Hospital of University of Toronto; Menzies School of Health Research; Universitat Lausanne Schweiz; Harvard School of Public Health; University of Cambridge
    © The Author(s) 2014. The surrounding capsule of Streptococcus pneumoniae has been identified as a major virulence factor and is targeted by pneumococcal conjugate vaccines (PCV). However, nonencapsulated S. pneumoniae (non-Ec-Sp) have also been isolated globally, mainly in carriage studies. It is unknown if non-Ec-Sp evolve sporadically, if they have high antibiotic nonsusceptiblity rates and a unique, specific gene content. Here, whole-genome sequencing of 131 non-Ec-Sp isolates sourced from 17 different locations around the world was performed. Results revealed a deep-branching classic lineage that is distinct from multiple sporadic lineages. The sporadic lineages clustered with a previously sequenced, global collection of encapsulated S. pneumoniae (Ec-Sp) isolates while the classic lineage is comprised mainly of the frequently identified multilocus sequences types (STs) ST344 (n = 39) and ST448 (n = 40). All ST344 and nine ST448 isolates had high nonsusceptiblity rates to β-lactams and other antimicrobials. Analysis of the accessory genome reveals that the classic non-Ec-Sp contained an increased number of mobile elements, than Ec-Sp and sporadic non-Ec-Sp. Performing adherence assays to human epithelial cells for selected classic and sporadic non-Ec-Sp revealed that the presence of a integrative conjugative element (ICE) results in increased adherence to human epithelial cells (P = 0.005). In contrast, sporadic non-Ec-Sp lacking the ICE had greater growth in vitro possibly resulting in improved fitness. In conclusion, non-Ec-Sp isolates from the classic lineage have evolved separately. They have spread globally, are well adapted to nasopharyngeal carriage and are able to coexist with Ec-Sp. Due to continued use of PCV, non-Ec-Sp may become more prevalent.
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    Immunohistochemical analysis based Ep-ICD subcellular localization index (ESLI) is a novel marker for metastatic papillary thyroid microcarcinoma
    (2012-11-15) Tada Kunavisarut; Ipshita Kak; Christina MacMillan; Ranju Ralhan; Paul G. Walfish; The Lunenfeld-Tanenbaum Research Institute of University of Toronto; Mount Sinai Hospital of University of Toronto; University of Toronto Faculty of Medicine; University of Toronto; Mahidol University
    Background: Thyroid cancer is among the fastest growing malignancies; almost fifty-percent of these rapidly increasing incidence tumors are less than or equal to 1cm in size, termed papillary thyroid microcarcinoma (PTMC). The management of PTMC remains a controversy due to differing natural history of these patients. Epithelial cell adhesion molecule (EpCAM) is comprised of an extracellular domain (EpEx), a single transmembrane domain and an intracellular domain (Ep-ICD). Our group reported nuclear Ep-ICD correlated with poor prognosis in thyroid cancer (Ralhan et al., BMC Cancer 2010,10:331). Here in, we hypothesized nuclear and cytoplasmic accumulation of Ep-ICD and loss of membranous EpEx may aid in distinguishing metastatic from non-metastatic PTMC, which is an important current clinical challenge. To test our hypothesis, Ep-ICD and EpEx expression levels were analyzed in PTMC and the staining was correlated with metastatic potential of these carcinomas.Methods: Thirty-six PTMC patients (tumor size 0.5 - 1cm; metastatic 8 cases and non-metastatic 28 cases) who underwent total thyroidectomy were selected. The metastatic group consisted of patients who developed lymph node or distant metastasis at diagnosis or during follow up. The patients' tissues were stained for Ep-ICD and EpEx using domain specific antibodies by immunohistochemistry and evaluated.Results: PTMC patients with metastasis had higher scores for nuclear and cytoplasmic Ep-ICD immunostaining than the patients without metastasis (1.96 ± 0.86 vs. 1.22 ± 0.45; p = 0.007 and 5.37 ± 0.33 vs. 4.72 ± 1.07; p = 0.016, respectively). Concomitantly, the former had lower scores for membrane EpEx than the non-metastatic group (4.64 ± 1.08 vs. 5.64 ± 1.51; p = 0.026). An index of aggressiveness, Ep-ICD subcellular localization index (ESLI), was defined as sum of the IHC scores for accumulation of nuclear and cytoplasmic Ep-ICD and loss of membranous EpEx; ESLI = [Ep - ICD nuc + Ep - ICD cyt + loss of membranous EpEx]. Notably, ESLI correlated significantly with lymph node metastasis in PTMC (p = 0.008).Conclusion: Nuclear and cytoplasmic Ep-ICD expression and loss of membranous EpEx were found to correlate positively with metastasis in PTMC patients. In addition, ESLI had the potential to identify metastatic behavior in PTMC which could serve as a valuable tool for solving a current dilemma in clinical practice. © 2012 Kunavisarut et al.; licensee BioMed Central Ltd.
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    A new role for monocytes in modulating myometrial inflammation during human labor
    (2014-01-01) Khetsopon Srikhajon; Oksana Shynlova; Anyarin Preechapornprasert; Boonsri Chanrachakul; Stephen Lye; Mahidol University; Mount Sinai Hospital of University of Toronto; University of Toronto; Bumrungrad International Hospital
    Here we fully characterize the cytokine profile of laboring human myometrium using Luminex analysis of 48 cytokine proteins, and stereologically quantified infiltration of monocytes and neutrophils into the myometrium. We hypothesized that monocytes can regulate their accumulation in the myometrium by disruption of proinflammatory cytokines to prevent an uncontrolled inflammatory response after labor onset. We isolated primary human myometrial cells (HMCs) from term, nonlaboring myometrial biopsies. Confluent HMCs were cocultured directly with human monocytic (THP-1) or lymphocytic (U937) cells, and with the same cells spatially separated by a membrane insert. After 72 h, HMCs and THP-1 were harvested separately, and RNA was extracted and analyzed by quantitative PCR. Coculture supernatants were collected and analyzed by Luminex assay and ELISA. We found that the laboring human myometrium produces significantly higher amounts of interleukin (IL) 6, IL9, IL18, IL1RA, CCL2, CCL7, CXCL8, CSF3, and tumor necrosis factor alpha, which coincides with the influx of immune cells. The direct contact or presence of THP-1 monocytes (but not U937 cells) significantly decreased CCL2 protein levels and increased IL1RA protein levels secreted by HMCs. This time-dependent decrease of CCL2 was greater with increasing number of monocytes being in direct contact with HMCs. We suggest a novel mechanism by which monocytes are first recruited to the myometrium by multiple cytokines and contribute to the physiologic inflammation of labor. After completing transmigration, activated monocytes disrupt locally established CCL2 gradients (possible by CCR2-mediated consumption) to limit their accumulation in the uterus. This mechanism may serve as a negative feedback loop to control the local inflammation and promote a return to homeostasis. © 2014 by the Society for the Study of Reproduction, Inc.
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    Sleep and pathological wakefulness at the time of liberation from mechanical ventilation (SLEEWE) a prospective multicenter physiological study
    (2019-05-01) Martin Dres; Magdy Younes; Nuttapol Rittayamai; Tetyana Kendzerska; Irene Telias; Domenico Luca Grieco; Tai Pham; Detajin Junhasavasdikul; Edmond Chau; Sangeeta Mehta; M. Elizabeth Wilcox; Richard Leung; Xavier Drouot; Laurent Brochard; Li Ka Shing Knowledge Institute; AP-HP Assistance Publique - Hopitaux de Paris; Centre Hospitalier Universitaire de Poitiers; Saint Michael's Hospital University of Toronto; University of Toronto; Faculty of Medicine, Siriraj Hospital, Mahidol University; Mount Sinai Hospital of University of Toronto; Toronto Western Hospital University of Toronto; Ottawa Hospital Research Institute; YRT Ltd; Sleep Disorders Centre
    Copyright © 2019 by the American Thoracic Society. Rationale: Abnormal patterns of sleep and wakefulness exist in mechanically ventilated patients. Objectives: In this study (SLEEWE [Effect of Sleep Disruption on the Outcome of Weaning from Mechanical Ventilation]), we aimed to investigate polysomnographic indexes as well as a continuous index for evaluating sleep depth, the odds ratio product (ORP), to determine whether abnormal sleep or wakefulness is associated with the outcome of spontaneous breathing trials (SBTs). Methods: Mechanically ventilated patients from three sites were enrolled if an SBT was planned the following day. EEG was recorded using a portable sleep diagnostic device 15 hours before the SBT. The ORP was calculated from the power of four EEG frequency bands relative to each other, ranging from full wakefulness (2.5) to deep sleep (0). The correlation between the right and left hemispheres’ ORP (R/L ORP) was calculated. Measurements and Main Results: Among 44 patients enrolled, 37 had technically adequate signals: 11 (30%) passed the SBT and were extubated, 8 (21%) passed the SBT but were not deemed to be clinically ready for extubation, and 18 (49%) failed the SBT. Pathological wakefulness or atypical sleep were highly prevalent, but the distribution of classical sleep stages was similar between groups. The mean ORP and the proportion of time in which the ORP was .2.2 were higher in extubated patients compared with the other groups (P, 0.05). R/L ORP was significantly lower in patients who failed the SBT, and the area under the receiver operating characteristic curve of R/L ORP to predict failure was 0.91 (95% confidence interval, 0.75–0.98). Conclusions: Patients who pass an SBT and are extubated reach higher levels of wakefulness as indicated by the ORP, suggesting abnormal wakefulness in others. The hemispheric ORP correlation is much poorer in patients who fail an SBT.
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    Total and high molecular weight but not trimeric or hexameric forms of adiponectin correlate with markers of the metabolic syndrome and liver injury in Thai subjects
    (2007-01-01) Ying Liu; Ravi Retnakaran; Anthony Hanley; Rungsunn Tungtrongchitr; Collin Shaw; Gary Sweeney; University of Toronto; Mount Sinai Hospital of University of Toronto; Mahidol University; ALPCO Diagnostics; York University
    Context/Objective: Decreased total adiponectin has been associated with metabolic disorders, including obesity, diabetes, fatty liver, and the metabolic syndrome. Although circulating adiponectin is composed of trimers, hexamers, and high molecular weight (HMW) multimers, there has been limited study of the specific metabolic correlates of these isoforms in humans. Thus, our objective was to evaluate the associations of these adiponectin isoforms with metabolic and anthropometric parameters. Design/Participants/Setting: A total of 53 diabetic and 68 nondiabetic subjects attending outpatient clinics underwent cross-sectional metabolic characterization. Circulating levels of HMW, hexameric, and trimeric adiponectin were measured using a multimeric adiponectin ELISA based upon selective protease-mediated digestion. Results: On Spearman univariate analysis, both total and HMW adiponectin levels were inversely associated with body mass index, fasting glucose, homeostasis model of assessment of insulin resistance, triglycerides, and alanine aminotransferase (ALT) (all |r| ≥ 0.22; P < 0.05), with the HMW isoform also positively correlated with high-density lipoprotein cholesterol (r = 0.19; P = 0.036). In contrast, hexameric and trimeric adiponectin were significantly associated with only body mass index (r = -0.23; P = 0.0102) and mid-upper arm circumference (r = 0.21; P = 0.039), respectively. On separate forward stepwise multiple linear regression analyses, fasting glucose and ALT emerged as independent, negative covariates of both total and HMW adiponectin, whereas no independent covariates of hexameric and trimeric adiponectin were identified. Furthermore, after adjustment for age, gender, and diabetes, mean ALT was highest in subjects in the lowest tertile of HMW adiponectin, followed in turn by the middle and highest tertiles, respectively (trend P = 0.028). Conclusions: HMW adiponectin, but not hexameric or trimeric, tracks with the metabolic correlates of total adiponectin. Furthermore, an independent inverse association exists between ALT and HMW adiponectin. Copyright © 2007 by The Endocrine Society.