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Chinnakkannu Vijayakumar S.,Ryerson University | Venkatakrishnan K.,Ryerson University | Venkatakrishnan K.,Keenan Research Center For Biomedical Science Of St Michaels Hospital | Tan B.,Ryerson University
Materials Science and Engineering C | Year: 2017

Cellular interactions are regulated by various mechanical, physical and chemical factors that are either introduced to or are pre-existing in their local microenvironments. These factors include geometric confinement, cell-substrate interactions and cell-cell contacts. The systematic elucidation of these dictating mechanisms is crucial for fundamental understanding of regenerative medicine and for designing biomedical devices. Here, we have developed an elegant multi-photon ionization based mechanism, which accomplishes selective surface bio-functionalization of native titanium substrates, to achieve stable cellular confinements. In particular, we applied selective titanium phase activation for cellular confinement of mouse fibroblasts and osteoblast cells in an effort to examine their directionality and proliferative behavior under confinement. The experimental results suggest, both mouse fibroblasts and osteoblasts can be manipulated, guided and aligned along an induced orientation by selective hongquiite phase activation. The cell viability of both fibroblast and osteoblast cells were observed through fluorescent assays and SEM techniques. The phase activated surface fabricated influenced both nuclei and actin cytoskeletal re-arrangement of cell structures. © 2017 Elsevier B.V.


Kneyber M.C.J.,Keenan Research Center For Biomedical Science Of St Michaels Hospital | Kneyber M.C.J.,University of Groningen | Zhang H.,Keenan Research Center For Biomedical Science Of St Michaels Hospital | Zhang H.,University of Toronto | And 2 more authors.
American Journal of Respiratory and Critical Care Medicine | Year: 2014

It is well established that mechanical ventilation can injure the lung, producing an entity known as ventilator-induced lung injury (VILI). There are various forms of VILI, including volutrauma (i.e., injury caused by overdistending the lung), atelectrauma (injury due to repeated opening/closing of lung units), and biotrauma (release of mediators that can induce lung injury or aggravate pre-existing injury, potentially leading to multiple organ failure). Experimental data in the pediatric context are in accord with the importance of VILI, and appear to show age-related susceptibility to VILI, although a conclusive link between use of large VTs and mortality has not been demonstrated in this population. The relevance of VILI in the pediatric intensive care unit population is thus unclear. Given the physiological and biological differences in the respiratory systems of infants, children, and adults, it is difficult to directly extrapolate clinical practice from adults to children. This Critical Care Perspective analyzes the relevance of VILI to the pediatric population, and addresses why pediatric patients might be less susceptible than adults to VILI. Copyright © 2014 by the American Thoracic Society.


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.,St Michaels Hospital
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.


Prud'homme G.J.,University of Toronto | Prud'homme G.J.,St Michaels Hospital | Glinka Y.,St Michaels Hospital | Wang Q.,Fudan University | And 2 more authors.
Autoimmunity Reviews | Year: 2015

Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain. However, it is also produced in other sites; notably by pancreatic β cells and immune cells. The function of GABA in the immune system is at an early stage of study, but it exerts inhibitory effects that are relevant to autoimmune diseases. The study of GABAergic interactions in the immune system has centered on three main aspects: 1) the expression of GABA and the relevant GABAergic molecular machinery; 2) the in vitro response of immune cells; and 3) therapeutic applications in autoimmune diseases. T cells and macrophages can produce GABA, and express all the components necessary for a GABAergic response. There are two types of GABA receptors, but lymphocytes appear to express only type A (GABAAR); a ligand-gated chloride channel. Other immune cells may also express the type B receptor (GABABR); a G-protein coupled receptor. Activation of GABA receptors on T cells and macrophages inhibits responses such as production of inflammatory cytokines. In T cells, GABA blocks the activation-induced calcium signal, and it also inhibits NF-κB activation. In preclinical models, therapeutic application of GABA, or GABAergic (agonistic) drugs, protects against type 1 diabetes (T1D), experimental autoimmune encephalomyelitis (EAE), collagen-induced arthritis (CIA) and contact dermatitis. In addition, GABA exerts anti-apoptotic and proliferative effects on islet β cells, which may be applicable to islet transplantation. Autoimmunity against glutamic acid decarboxylase 65 (GAD65; synthesizes GABA) occurs in T1D. Antigen therapy of T1D with GAD65 or proinsulin in mice has protective effects, which are markedly enhanced by combined GABA therapy. Clinically, autoantibodies against GAD65 and/or GABA receptors play a pathogenic role in several neurological conditions, including stiff person syndrome (SPS), some forms of encephalitis, and autoimmune epilepsy. GABAergic drugs are widely used in medicine, and include benzodiazepines, barbiturates, anticonvulsants, and anesthetic drugs such as propofol. Native GABA can be administered orally to humans as a drug, and has few adverse effects. However, the immune effects of GABAergic drugs in patients are not well documented. GABAergic immunobiology is a recent area of research, which shows potential for the development of new therapies for autoimmune diseases. © 2015 Elsevier B.V.


Dres M.,Keenan Research Center For Biomedical Science Of St Michaels Hospital | Mancebo J.,Hospital Of Sant Pau | Curley G.F.,Keenan Research Center For Biomedical Science Of St Michaels Hospital | Curley G.F.,University of Toronto
American Journal of Respiratory and Critical Care Medicine | Year: 2016

This review documents important progress made in 2015 in the field of critical care. Significant advances in 2015 included further evidence for early implementation of low tidal volume ventilation as well as new insights into the role of open lung biopsy, diaphragmatic dysfunction, and a potential mechanism for ventilator-induced fibroproliferation. New therapies, including a novel low-flow extracorporeal CO2 removal technique and mesenchymal stem cell-derived microparticles, have also been studied. Several studies examining the role of improved diagnosis and prevention of ventilator-Associated pneumonia also showed relevant results. This review examines articles published in the American Journal of Respiratory and Critical Care Medicine and other major journals that have made significant advances in the field of critical care in 2015. Copyright © 2016 by the American Thoracic Society.


Samaan S.,Keenan Research Center For Biomedical Science Of St Michaels Hospital | Lichner Z.,Keenan Research Center For Biomedical Science Of St Michaels Hospital | Ding Q.,Keenan Research Center For Biomedical Science Of St Michaels Hospital | Saleh C.,Keenan Research Center For Biomedical Science Of St Michaels Hospital | And 5 more authors.
Biological Chemistry | Year: 2014

MicroRNAs (miRNAs) are short RNA nucleotides that negatively regulate their target genes. They are differentially expressed in prostate cancer. Kallikreins are genes that encode serine proteases and are dysregulated in cancer. We elucidated a miRNA-kallikrein network that can be involved in prostate cancer progression. Target prediction identified 23 miRNAs that are dysregulated between high and low risk biochemical failure and are predicted to target five kallikreins linked to prostate cancer; KLK2, KLK3, KLK4, KLK14 and KLK15. We also identified 14 miRNAs that are differentially expressed between Gleason grades and are predicted to target these kallikreins. This demonstrates that kallikreins are downstream effectors through which miRNAs influence tumor progression. We show, through in-silico and experimental analysis, that miR-378/422a and its gene targets PIK3CG, GRB2, AKT3, KLK4 and KLK14 form an integrated circuit in prostate cancer. Our analysis shows that a minisatellite sequence in the kallikrein locus consists of a number of microsatellite repeats that represent predicted miRNA response elements. A number of kallikrein and non-kallikrein prostate cancer-related genes share these microsatellite repeats. We validated some of these interactions in prostate cancer cell lines. Finally, we provide preliminary evidence on the presence of a miRNA-mediated cross-talk between kallikreins, including a kallikrein pseudogene. © 2014, WDG. All rights reserved.


Hutchison M.G.,University of Toronto | Lawrence D.W.,University of Toronto | Cusimano M.D.,University of Toronto | Cusimano M.D.,St Michaels Hospital | 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).


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.


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.


Strohm E.M.,Ryerson University | Strohm E.M.,Keenan Research Center For Biomedical Science Of St Michaels Hospital | Moore M.J.,Ryerson University | Moore M.J.,Keenan Research Center For Biomedical Science Of St Michaels Hospital | And 2 more authors.
Photoacoustics | Year: 2016

High resolution ultrasound and photoacoustic images of stained neutrophils, lymphocytes and monocytes from a blood smear were acquired using a combined acoustic/photoacoustic microscope. Photoacoustic images were created using a pulsed 532 nm laser that was coupled to a single mode fiber to produce output wavelengths from 532 nm to 620 nm via stimulated Raman scattering. The excitation wavelength was selected using optical filters and focused onto the sample using a 20× objective. A 1000 MHz transducer was co-aligned with the laser spot and used for ultrasound and photoacoustic images, enabling micrometer resolution with both modalities. The different cell types could be easily identified due to variations in contrast within the acoustic and photoacoustic images. This technique provides a new way of probing leukocyte structure with potential applications towards detecting cellular abnormalities and diseased cells at the single cell level. © 2016 The Authors.

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