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Wan Y.,Fudan University | Wang Q.,Fudan University | Wang Q.,Keenan Research Center For Biomedical Science Of St Michaels Hospital | Prud'homme G.J.,University of Toronto | Prud'homme G.J.,Keenan Research Center for Biomedical Science
Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy | Year: 2015

Excessive loss of functional pancreatic β-cell mass, mainly due to apoptosis, is a major factor in the development of hyperglycemia in both type 1 and type 2 diabetes (T1D and T2D). In T1D, β-cells are destroyed by immunological mechanisms. In T2D, while metabolic factors are known to contribute to β-cell failure and subsequent apoptosis, mounting evidence suggests that islet inflammation also plays an important role in the loss of β-cell mass. Therefore, it is of great importance for clinical intervention to develop new therapies. γ-Aminobutyric acid (GABA), a major neurotransmitter, is also produced by islet β-cells, where it functions as an important intraislet transmitter in regulating islet-cell secretion and function. Importantly, recent studies performed in rodents, including in vivo studies of xenotransplanted human islets, reveal that GABA exerts β-cell regenerative effects. Moreover, it protects β-cells against apoptosis induced by cytokines, drugs, and other stresses, and has anti-inflammatory and immunoregulatory activities. It ameliorates the manifestations of diabetes in preclinical models, suggesting potential applications for the treatment of diabetic patients. This review outlines the actions of GABA relevant to β-cell regeneration, including its signaling mechanisms and potential interactions with other mediators. These studies increase our understanding of the regenerative processes of pancreatic β-cells, and help pave the way for the development of regenerative medicine for diabetes. © 2015 Wan et al.


Berger D.,University of Bern | Bloechlinger S.,University of Bern | Takala J.,University of Bern | Sinderby C.,University of Toronto | And 2 more authors.
Critical Care | Year: 2014

Introduction: Assist in unison to the patient's inspiratory neural effort and feedback-controlled limitation of lung distension with neurally adjusted ventilatory assist (NAVA) may reduce the negative effects of mechanical ventilation on right ventricular function.Methods: Heart-lung interaction was evaluated in 10 intubated patients with impaired cardiac function using esophageal balloons, pulmonary artery catheters and echocardiography. Adequate NAVA level identified by a titration procedure to breathing pattern (NAVAal), 50% NAVAal, and 200% NAVAal and adequate pressure support (PSVal, defined clinically), 50% PSVal, and 150% PSVal were implemented at constant positive end-expiratory pressure for 20 minutes each.Results: NAVAal was 3.1 ± 1.1cmH2O/μV and PSVal was 17 ± 2 cmH20. For all NAVA levels negative esophageal pressure deflections were observed during inspiration whereas this pattern was reversed during PSVal and PSVhigh. As compared to expiration, inspiratory right ventricular outflow tract velocity time integral (surrogating stroke volume) was 103 ± 4%, 109 ± 5%, and 100 ± 4% for NAVAlow, NAVAal, and NAVAhigh and 101 ± 3%, 89 ± 6%, and 83 ± 9% for PSVlow, PSVal, and PSVhigh, respectively (p < 0.001 level-mode interaction, ANOVA). Right ventricular systolic isovolumetric pressure increased from 11.0 ± 4.6 mmHg at PSVlow to 14.0 ± 4.6 mmHg at PSVhigh but remained unchanged (11.5 ± 4.7 mmHg (NAVAlow) and 10.8 ± 4.2 mmHg (NAVAhigh), level-mode interaction p = 0.005). Both indicate progressive right ventricular outflow impedance with increasing pressure support ventilation (PSV), but no change with increasing NAVA level.Conclusions: Right ventricular performance is less impaired during NAVA compared to PSV as used in this study. Proposed mechanisms are preservation of cyclic intrathoracic pressure changes characteristic of spontaneous breathing and limitation of right-ventricular outflow impedance during inspiration, regardless of the NAVA level. © 2014 Berger et al.; licensee BioMed Central Ltd.


Martin L.J.,Ontario Cancer Institute | Melnichouk O.,Ontario Cancer Institute | Huszti E.,Ontario Cancer Institute | Connelly P.W.,Keenan Research Center For Biomedical Science Of St Michaels Hospital | And 4 more authors.
Journal of the National Cancer Institute | Year: 2015

Background: There is strong evidence that breast cancer risk is influenced by environmental factors. Blood lipid and lipoprotein levels are also influenced by environmental factors and are associated with some breast cancer risk factors. We examined whether serial measures of serum lipids and lipoproteins were associated with breast cancer risk. Methods: We carried out a nested case-control study within a randomized long-term dietary intervention trial with 4690 women with extensive mammographic density followed for an average of 10 years for breast cancer incidence. We measured lipids in an average of 4.2 blood samples for 279 invasive breast cancer case subjects and 558 matched control subjects. We calculated subaverages of lipids for each subject based on menopausal status and use of hormone replacement therapy (HRT) at blood collection and analyzed their association with breast cancer using generalized estimating equations. All statistical tests were two-sided. Results: High-density lipoprotein-cholesterol (HDL-C) (P =. 05) and apoA1 (P =. 02) levels were positively associated with breast cancer risk (75th vs 25th percentile: HDL-C, 23% higher; apoA1, 28% higher) and non-HDL-C (P =. 03) and apoB (P =. 01) levels were negatively associated (75th vs 25th percentile: non-HDL-C, 19% lower; apoB, 22% lower). These associations were observed only when lipids were measured when HRT was not used. Total cholesterol and triglyceride levels were not statistically significantly associated with breast cancer risk. Conclusions: These results demonstrate that serum lipids are associated with breast cancer risk in women with extensive mammographic density. The possibility that interventions for heart disease prevention, which aim to reduce non-HDL-C or raise HDL-C, may have effects on breast cancer risk merits examination. © 2015 The Author.


Curley G.F.,Keenan Research Center For Biomedical Science Of St Michaels Hospital | Curley G.F.,Kings College | Slutsky A.S.,St Michaels Hospital and the Keenan Research Center for Biomedical Science | Slutsky A.S.,Kings College
Critical Care | Year: 2014

This review documents important progress made in 2013 in the field of critical care respirology, in particular with regard to acute respiratory failure and acute respiratory distress syndrome. Twenty-five original articles published in the respirology and critical care sections of Critical Care are discussed in the following categories: pre-clinical studies, protective lung ventilation - how low can we go, non-invasive ventilation for respiratory failure, diagnosis and prognosis in acute respiratory distress syndrome and respiratory failure, and promising interventions for acute respiratory distress syndrome. © 2014 Curley and Slutsky; licensee BioMed Central Ltd.


Hutchison M.G.,University of Toronto | Lawrence D.W.,University of Toronto | Cusimano M.D.,University of Toronto | Cusimano M.D.,Injury Prevention Research Office | And 2 more authors.
American Journal of Sports Medicine | Year: 2014

Background: Mixed martial arts (MMA) is a full combative sport with a recent global increase in popularity despite significant scrutiny from medical associations. To date, the empirical research of the risk of head injuries associated with this sport is limited. Youth and amateur participation is growing, warranting investigation into the burden and mechanism of injuries associated with this sport. Purpose: (1) To determine the incidence, risk factors, and characteristics of knockouts (KOs) and technical knockouts (TKOs) from repetitive strikes in professional MMA; and (2) to identify the mechanisms of head trauma and the situational factors that lead to KOs and TKOs secondary to repetitive strikes through video analysis. Study Design: Descriptive epidemiology study. Methods: Competition data and video records for all KOs and TKOs from numbered Ultimate Fighting Championship MMA events (n = 844) between 2006 to 2012. Analyses included (1) multivariate logistic regression to investigate factors associated with an increased risk of sustaining a KO or TKO secondary to repetitive strikes and (2) video analysis of all KOs and TKOs secondary to repetitive strikes with descriptive statistics. Results: During the study period, the KO rate was 6.4 per 100 athlete-exposures (AEs) (12.7% of matches), and the rate of TKOs secondary to repetitive strikes was 9.5 per 100 AEs (19.1% of matches), for a combined incidence of match-ending head trauma of 15.9 per 100 AEs (31.9% of matches). Logistic regression identified that weight class, earlier time in a round, earlier round in a match, and older age were risk factors for both KOs and TKOs secondary to repetitive strikes. Match significance and previously sustained KOs or TKOs were also risk factors for KOs. Video analysis identified that all KOs were the result of direct impact to the head, most frequently a strike to the mandibular region (53.9%). The average time between the KO-strike and match stoppage was 3.5 seconds (range, 0-20 seconds), with losers sustaining an average of 2.6 additional strikes (range, 0-20 strikes) to the head. For TKOs secondary to strikes, in the 30-second interval immediately preceding match stoppage, losers sustained, on average, 18.5 strikes (range, 5-46 strikes), with 92.3% of these being strikes to the head. Conclusion: Rates of KOs and TKOs in MMA are higher than previously reported rates in other combative and contact sports. Public health authorities and physicians should be cognizant of the rates and mechanisms of head trauma. Preventive measures to lessen the risks of head trauma for those who elect to participate in MMA are described. © 2014 The Author(s).

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