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Guilcher S.J.T.,University of TorontoOntario | Guilcher S.J.T.,St Michaels Hospital | Guilcher S.J.T.,Institute for Clinical Evaluative science | Kaufman-Shriqui V.,Ariel University | And 14 more authors.
Preventive Medicine | Year: 2017

Overweight and obesity are major global public health concerns. Obesity is multifactorial in origin and influenced by genetics, psychosocial factors, eating and physical activity behaviors, as well as the environment. The objective of this study is to examine the impact of social cohesion on gender differences in body mass index (BMI) for urban-dwelling Canadians. Cross-sectional data were used from the Neighborhood Effects on Health and Well-being Study (NEHW) in Toronto, Canada (n = 2300). Our main outcome, BMI, was calculated from self-reported height and weight (weight (kg)/height (m)2). Using multi-level logistic regression models, we identified a significant interaction between social cohesion and gender on being overweight/obese. Women with higher social cohesion had slightly lower odds of being overweight/obese (OR: 0.96, 95%CI: 0.94 to 0.99) compared to men, after adjusting for other sociodemographic factors (e.g., age, income, education), and neighborhood characteristics (e.g., walkability, neighborhood safety and material deprivation). Future public health research and interventions should consider the differential mechanisms involved in overweight/obesity by gender. The exact mechanisms behind how the social environment influences these pathways are still unclear and require future research. © 2017 Elsevier Inc.


Sarswat A.,Toronto General Research Institute | Wasilewski E.,Toronto General Research Institute | Wasilewski E.,University of TorontoOntario | Chakka S.K.,Toronto General Research Institute | And 9 more authors.
Bioorganic and Medicinal Chemistry | Year: 2017

Protein arginine deiminases (PAD) are implicated in a variety of inflammatory and neurodegenerative diseases including multiple sclerosis (MS). Following the discovery of an in silico hit containing hydantoin and a piperidine moiety, we hypothesized that a 2-carbon linker on the hydantoin would be necessary for a 5-membered heterocycle for optimal PAD inhibitory activity. We designed thirteen compounds as potential inhibitors of PAD2 and PAD4 enzymes—two important PAD enzymes implicated in MS. Two compounds, one with an imidazole moiety (22) and the other with a tetrazole moiety (24) showed good inhibition of PAD isozymes in vitro and in the EAE mouse model of MS in vivo. Further experiments suggested that compound 22, a non-covalent inhibitor of PAD2 and PAD4, exhibits dose-dependent efficacy in the EAE mouse model and in the cuprizone-mediated demyelination model. © 2017 Elsevier Ltd


Bagai A.,University of TorontoOntario | Peterson E.D.,Duke Clinical Research Institute | McCoy L.A.,Duke Clinical Research Institute | Effron M.B.,Lilly United States LLC | And 7 more authors.
American Heart Journal | Year: 2017

Background Little is known about the use of platelet function testing to guide choice of P2Y12 receptor inhibitor therapy in routine clinical practice. Methods We studied 671 myocardial infarction (MI) patients treated with percutaneous coronary intervention in the TRANSLATE-ACS Registry who had VerifyNow platelet function testing performed while on clopidogrel treatment during their index hospitalization (April 2010–October 2012). Results High platelet reactivity (>208 platelet reactivity units [PRU]) was present in 261 (38.9%) patients. Clopidogrel was switched in-hospital to prasugrel in 80 (30.7%) patients with high platelet reactivity and 18 (4.4%) patients with therapeutic platelet reactivity (≤208 PRU). Among high platelet reactivity patients, switch to prasugrel was associated with lower major adverse cardiovascular events (death, MI, stroke, or unplanned revascularization) at 1 year (10.0% vs 22.7%, P = 02 adjusted odds ratio [OR] 0.39, 95% CI 0.18-0.85, P = 02) and no significant difference in Bleeding Academic Research Consortium type 2 or higher bleeding (23.8% vs 22.1%, P = 77 adjusted OR 0.91, 95% CI 0.48-1.7, P = 77) compared with patients continued on clopidogrel. No significant differences in major adverse cardiovascular event (22.2% vs 12.8%, P = 25 adjusted OR 1.8, 95% CI 0.47-7.3, P = 38) or bleeding (22.2% vs 19.4%, P = 77 adjusted OR 1.3, 95% CI 0.27-6.8, P = 72) were observed among therapeutic platelet reactivity patients between switching and continuation on clopidogrel. Conclusions Only one-third of percutaneous coronary intervention–treated MI patients with high on-clopidogrel platelet reactivity were switched to a more potent P2Y12 receptor inhibitor. Intensification of antiplatelet therapy was associated with lower risk of ischemic events at 1 year among HPR patients. © 2017 Elsevier Inc.


Ng E.,Sunnybrook Health science Center | Ng E.,University of TorontoOntario | Schurr P.,Sunnybrook Health science Center | Reilly M.,Sunnybrook Health science Center | And 4 more authors.
Early Human Development | Year: 2016

Background In preterm infants, it is unknown whether feeding affects neural breathing pattern. Objectives By measuring the diaphragm electrical activity (Edi) waveform, we evaluated the effect of enteral feeding and compared the effects of feeding methods on neural breathing pattern and central apnea in very low birth weight preterm infants. Methods In a prospective, randomized, crossover study, ten non-ventilated preterm infants with birth weights < 1250 g and tolerating full feeds were randomized to either bolus feeding (BF) or slow infusion feeding (SF) over 90 min, followed by crossover to the other method at the next feed. Edi was continuously measured by a feeding catheter with miniaturized sensors. Five 15-min epochs were chosen [Baseline (BL), first 15 min and 90 min after BF/SF started] for breath-by-breath analyses of neural breathing pattern, including Edi peak, Edi min (end-expiratory), neural inspiratory and expiratory times, neural respiratory rate, and central apnea. Primary outcome was change in Edi min with feed. Secondary outcomes include change in Edi peak, frequency and duration of central apnea with feeding. Results Although intrasubject coefficient of variation was not significantly different, individual responses to feeding and feeding method were variable. No significant difference in Edi timing, Edi min, Edi peak, or apnea was observed for the different epochs. Conclusions In this study cohort, neural breathing pattern does not appear to be consistently affected by enteral feeding or the feeding method. Compared with BF, SF does not appear to reduce the number or duration of apneas. © 2016 Elsevier Ireland Ltd


Gray E.J.,University of TorontoOntario | Gray E.J.,Sinai University | Gray E.J.,Center for Addiction and Mental Health Hospital | Petsalaki E.,Sinai University | And 10 more authors.
Journal of Biological Chemistry | Year: 2014

SH2D5 is a mammalian-specific, uncharacterized adaptorlike protein that contains an N-terminal phosphotyrosine-binding domain and a C-terminal Src homology 2 (SH2) domain.We show that SH2D5 is highly enriched in adult mouse brain, particularly in Purkinjie cells in the cerebellum and the cornu ammonis of the hippocampus. Despite harboring two potential phosphotyrosine (Tyr(P)) recognition domains, SH2D5 binds minimally to Tyr(P) ligands, consistent with the absence of a conserved Tyr(P)-binding arginine residue in the SH2 domain. Immunoprecipitation coupled to mass spectrometry (IP-MS) from cultured cells revealed a prominent association of SH2D5 with breakpoint cluster region protein, a RacGAP that is also highly expressed in brain. This interaction occurred between the phosphotyrosine-binding domain of SH2D5 and an NxxF motif located within the N-terminal region of the breakpoint cluster region. siRNA-mediated depletion of SH2D5 in a neuroblastoma cell line, B35, induced a cell rounding phenotype correlated with low levels of activated Rac1-GTP, suggesting that SH2D5 affects Rac1-GTP levels. Taken together, our data provide the first characterization of the SH2D5 signaling protein. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.


Wasade V.S.,Ford Motor Company | Balki I.,University of TorontoOntario | Bowyer S.M.,Ford Motor Company | Gaddam S.,Ford Motor Company | And 7 more authors.
Epilepsy and Behavior Case Reports | Year: 2016

Excessive yawning was described in some neurological conditions as part of periictal or ictal manifestations of epilepsy, most commonly temporal lobe. We present the first case of controllable yawning as a primary seizure semiology with dominant frontal lobe involvement in a 20-year-old man. Video electroencephalography recorded 8 yawning episodes accompanied with right arm movement correlating with rhythmic diffuse theta range activity with left hemispheric predominance. Magnetoencephalography coherence source imaging was consistent with persistent neuronal networks with areas of high coherence reliably present over the left lateral orbitofrontal region. Epileptogenic areas may have widespread networks involving the dominant frontal lobe in unique symptomatogenic areas. © 2016 The Authors


MacMillan T.E.,University of Toronto | MacMillan T.E.,University of TorontoOntario | Kamali R.,University of Toronto | Cavalcanti R.B.,University of Toronto | Cavalcanti R.B.,University of TorontoOntario
American Journal of Medicine | Year: 2016

Background Hospital admissions provide an opportunity to deprescribe ineffective medications and reduce pill burden. Docusate sodium is a stool softener that is frequently prescribed to treat constipation despite poor evidence for efficacy, thus providing a good target for deprescription. The aims of this study were to characterize rates of use and discontinuation of docusate among internal medicine inpatients, as well as use of other laxatives. Methods We conducted a retrospective observational study over 1 year on all patients admitted to internal medicine at 2 urban academic hospitals to determine rates of docusate use. We also evaluated laxative and opioid medication use on a random sample of 500 inpatients who received docusate to characterize patterns of prescription and deprescription. Results Fifteen percent (1169/7581) of all admitted patients received 1 or more doses of docusate. Among our random sample, 53% (238/452) received docusate before admission, and only 13% (31/238) had docusate deprescribed. Among patients not receiving docusate before admission, 33.2% (71/214) received a new prescription for docusate on discharge. Patients receiving opioids were frequently prescribed no laxatives or given docusate monotherapy (28%, 51/185). Conclusions Docusate was frequently prescribed to medical inpatients despite its known ineffectiveness, with low deprescription and high numbers of new prescriptions. Docusate use was common even among patients at high risk of constipation. One third of patients not receiving docusate before admission were prescribed docusate on discharge, potentially exacerbating polypharmacy. Among patients already receiving docusate, 80% had it continued on discharge, indicating significant missed opportunities for deprescribing. Given the availability of effective alternatives, our results suggest that quality-improvement initiatives are needed to promote evidence-based laxative use in hospitalized patients. © 2016 Elsevier Inc.


Padilla N.,Aix - Marseille University | Maraninchi M.,Aix - Marseille University | Beliard S.,Aix - Marseille University | Beliard S.,La Timone Hospital | And 13 more authors.
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2014

Objective - The dyslipidemia of obesity and other insulin-resistant states is characterized by the elevation of plasma triglyceride-rich lipoproteins (TRL) of both hepatic (apoB-100-containing very low-density lipoprotein) and intestinal (apoB-48-containing chylomicrons) origin. Bariatric surgery is a well-established and effective modality for the treatment of obesity and is associated with improvements in several metabolic abnormalities associated with obesity, including a reduction in plasma triglycerides. Here, we have investigated the effect of bariatric surgery on TRL metabolism.Approach and Results - Twenty-two nondiabetic, obese subjects undergoing bariatric surgery: sleeve gastrectomy (n=12) or gastric bypass (n=10) were studied. Each subject underwent 1 lipoprotein turnover study 1 month before surgery followed by a second study, 6 months after surgery, using established stable isotope enrichment methodology, in constant fed state. TRL-apoB-100 concentration was significantly reduced after sleeve gastrectomy, explained by a decrease (P<0.05) in TRL-apoB-100 production rate and an increase (P<0.05) in TRL-apoB-100 fractional catabolic rate. TRLapoB- 48 concentration was also significantly reduced after sleeve gastrectomy, explained by reduction in TRL-apoB-48 production rate (P<0.05). For gastric bypass, although TRL-apoB-100 concentration declined after surgery (P<0.01), without a significant decline in TRL-apoB-48, there was no significant change in either TRL-apoB-100 or TRL-apoB-48 production rate or fractional catabolic rate. The reduction in TRL-apoB-100 concentration was significantly associated with a reduction in plasma apoC-III in the pooled group of patients undergoing bariatric surgery.Conclusions - This is the first human lipoprotein kinetic study to explore the mechanism of improvement of TRL metabolism after bariatric surgery. These effects may contribute to the decrease of cardiovascular mortality after surgery. © 2014 American Heart Association, Inc.


Blackmore K.M.,Mount Sinai Hospital | Blackmore K.M.,University of TorontoOntario | Knight J.A.,Mount Sinai Hospital | Walter J.,University of TorontoOntario | Lilge L.,University of TorontoOntario
PLoS ONE | Year: 2015

Mammographic density (MD), associated with higher water and lower fat content in the breast, is strongly related to breast cancer risk. Optical attenuation spectroscopy (OS) is a non-imaging method of evaluating breast tissue composition by red and near-infrared light transmitted through the breast that, unlike mammography, does not involve radiation. OS provides information on wavelength dependent light scattering of tissue and on absorption by water, lipid, oxy-, deoxy-hemoglobin. We propose that OS could be an alternative marker of breast cancer risk and that OS breast tissue measures will be associated with MD. In the present analysis, we developed an algorithm to estimate breast tissue composition and light scattering parameters using a spectrally constrained global fitting procedure employing a diffuse light transport model. OS measurements were obtained from 202 pre- and post-menopausal women with normal mammograms. Percent density (PD) and dense area (DA) were measured using Cumulus. The association between OS tissue composition and PD and DA was analyzed using linear regression adjusted for body mass index. Among pre-menopausal women, lipid content was significantly inversely associated with square root transformed PD (β = -0.05, p = 0.0002) and DA (β = -0.05, p = 0.019); water content was significantly positively associated with PD (β = 0.06, p = 0.008). Tissue oxygen saturation was marginally inversely associated with PD (β = -0.03, p = 0.057) but significantly inversely associated with DA (β = -0.10, p = 0.002). Among post-menopausal women lipid and water content were significantly associated (negatively and positively, respectively) with PD (βlipid = -0.08, βwater = 0.14, both p<0.0001) and DA (βlipid = -0.10, p<0.0001; βwater = 0.11, p = 0.001). The association between OS breast content and PD and DA is consistent with more proliferation in dense tissue of younger women, greater lipid content in low density tissue and higher water content in high density tissue. OS may be useful for assessing physiologic tissue differences related to breast cancer risk, particularly when mammography is not feasible or easily accessible. © 2015 Blackmore et al.


Cai Z.,University of TorontoOntario | Chattopadhyay N.,University of TorontoOntario | Yang K.,University of TorontoOntario | Kwon Y.L.,University of TorontoOntario | And 4 more authors.
Nuclear Medicine and Biology | Year: 2016

Introduction Gold nanoparticles (AuNP; 30 nm) were modified with polyethylene glycol (PEG) chains linked to trastuzumab for binding to HER2-positive breast cancer (BC) cells and diethylenetriaminepentaacetic acid (DTPA) for complexing the Auger electron-emitter, 111In (trastuzumab-AuNP-111In). Our objective was to determine the cytotoxicity of trastuzumab-AuNP-111In on HER2-positive BC cells in vitro and evaluate its tumor growth inhibition properties and normal tissue toxicity in vivo following intratumoral (i.t.) injection in mice with s.c. HER2-overexpressing BC xenografts. Methods Binding and internalization of trastuzumab-AuNP-111In or non-targeted AuNP-111In in SK-BR-3 (1–2 × 106 HER2/cell) and MDA-MB-361 (5 × 105 HER2/cell) human BC cells were studied. The surviving fraction (SF) of SK-BR-3 or MDA-MB-361 cells exposed to trastuzumab-AuNP-111In or AuNP-111In was determined. DNA double-strand breaks (DSBs) were assayed by probing for γ-H2AX. Tumor growth was monitored over 70 days in CD1 athymic mice with s.c. MDA-MB-361 xenografts after i.t. injection of 10 MBq (0.7 mg; 2.6 × 1012 AuNP) of trastuzumab-AuNP-111In and normal tissue toxicity was assessed by monitoring body weight, complete blood cell (CBC) counts and serum alanine aminotransferase (ALT) and creatinine (Cr). Results Trastuzumab-AuNP-111In was specifically bound by SK-BR-3 and MDA-MB-361 cells. Trastuzumab-AuNP-111In was more efficiently internalized than AuNP-111In and localized to a peri-nuclear region. The SF fraction of SK-BR-3 cells was reduced by 1.8-fold by treatment with 3 nM (7 MBq/mL) of trastuzumab-AuNP-111In. The SF of MDA-MB-361 cells was reduced by 3.7-fold at 14.4 nM (33.6 MBq/mL). In comparison, non-targeted AuNP-111In at these concentrations reduced the SF of SK-BR-3 or MDA-MB-361 cells by 1.2-fold (P = 0.03) and 1.7-fold (P < 0.0001), respectively. DNA DSBs were greater in SK-BR-3 and MDA-MB-361 cells exposed to trastuzumab-AuNP-111In compared to AuNP-111In, but unlabeled trastuzumab-AuNP did not increase DNA DSBs. Local i.t. injection of trastuzumab-AuNP-111In in CD1 athymic mice with s.c. MDA-MB-361 tumors arrested tumor growth for 70 days. There was no apparent normal tissue toxicity. The radiation absorbed dose deposited in the tumor by trastuzumab-AuNP-111In was 60.5 Gy, while normal organs received <0.9 Gy. Conclusion These results are promising for further development of trastuzumab-AuNP-111In as a novel Auger electron-emitting radiation nanomedicine for local treatment of HER2-positive BC. Advances in knowledge and implications for patient care A local radiation treatment for HER2-positive BC based on AuNP modified with trastuzumab and labeled with the Auger electron-emitter, 111In was developed and shown to arrest tumor growth with no normal tissue toxicity. © 2016 Elsevier Inc.

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