Sunnybrook Health Sciences Centre

About: Sunnybrook Health Sciences Centre is a healthcare organization based out in Toronto, Ontario, Canada. It is known for research contribution in the topics: Population & Medicine. The organization has 7689 authors who have published 15236 publications receiving 523019 citations. The organization is also known as: Sunnybrook.

Sonoporation by ultrasound-activated microbubble contrast agents: effect of acoustic exposure parameters on cell membrane permeability and cell viability

Abstract: This work investigates the effect of ultrasound exposure parameters on the sonoporation of KHT-C cells in suspension by perflutren microbubbles. Variations in insonating acoustic pressure (0.05 to 3.5 MPa), pulse frequency (0.5 to 5.0 MHz), pulse repetition frequency (10 to 3000 Hz), pulse duration (4 to 32 micros) and insonation time (0.1 to 900 s) were studied. The number of cells permeabilised to a fluorescent tracer molecule (70 kDa FITC-dextran) and the number of viable cells were measured using flow cytometry. The effect of exposure on the microbubble population was measured using a Coulter counter. Cell viability and membrane permeability were found to depend strongly on the acoustic exposure conditions. Cell permeability increased and viability decreased with increasing peak negative pressure, pulse repetition frequency, pulse duration and insonation time and with decreasing pulse centre frequency. The highest therapeutic ratio (defined as the ratio of permeabilised to nonviable cells) achieved was 8.8 with 32 +/- 4% permeabilization and 96 +/- 1% viability at 570 kPa peak negative pressure, 8 micros pulse duration, 3 kHz pulse repetition frequency, 500 kHz centre frequency and 12 s insonation time with microbubbles at 3.3% volume concentration. These settings correspond to an acoustic energy density (E(SPPA)) of 3.12 J/cm(2). Cell permeability and viability did not correlate with bubble disruption. The results indicate that ultrasound exposure parameters can be optimized for therapeutic sonoporation and that bubble disruption is a necessary but insufficient indicator of ultrasound-induced permeabilization.

Warfarin Use and the Risk for Stroke and Bleeding in Patients With Atrial Fibrillation Undergoing Dialysis

Abstract: Background—Current observational studies on warfarin use and the risk for stroke and bleeding in patients with atrial fibrillation (AF) undergoing dialysis found conflicting results. Methods and Results—We conducted a population-based retrospective cohort study of patients aged ≥65 years admitted to a hospital with a primary or secondary diagnosis of AF, in Quebec and Ontario, Canada from 1998 to 2007. The AF cohort was grouped into dialysis (hemodialysis and peritoneal dialysis) and nondialysis patients and into warfarin and no-warfarin users according to the first prescription filled for warfarin within 30 days after AF hospital discharge. We determined the association between warfarin use and the risk for stroke and bleeding in dialysis and nondialysis patients. The cohort comprised 1626 dialysis patients and 204 210 nondialysis patients. Among dialysis patients, 46% (756/1626) patients were prescribed warfarin. Among dialysis patients, warfarin users had more congestive heart failure and diabetes mell...

Acquired multicellular-mediated resistance to alkylating agents in cancer.

Abstract: EMT-6 murine mammary tumor sublines highly resistant to cyclophosphamide, cis-diamminedichloro-platinum(II), or N,N',N"-triethylenethiophosphoramide were generated in vivo by sequential treatment of tumor-bearing mice with the respective drugs. Previous studies demonstrated the drug-resistant phenotypes of the sublines were not expressed in vitro when the cells were grown as monolayer cultures. We now show that expression of drug resistance--including patterns of cross-drug resistance observed in vivo--can be fully recapitulated in vitro when the cells are grown under in vivo-like, three-dimensional conditions--namely, as multicellular tumor spheroids. Moreover, the spheroids generated from all of the drug-resistant sublines manifested a much more compact structure. Immediate drug-sensitivity testing of single cells released by trypsin treatment from compact drug-resistant spheroids revealed that such cells lost much of their drug-resistant properties. The results suggest a possible mechanism of acquired drug resistance in tumors based on the response of a cell population (i.e., multicellular or tissue resistance) as opposed to classic (uni)cellular resistance mechanisms.

Signaling through beta-catenin and Lef/Tcf.

Abstract: Beta-catenin plays a structural role in cell adhesion by binding to cadherins at the intracellular surface of the plasma membrane and a signaling role in the cytoplasm as the penultimate downstream mediator of the wnt signaling pathway. The ultimate mediator of this pathway is a nuclear complex of beta-catenin acting as a coactivtor with lymphoid enhancer factor/T cell factor (Lef/Tcf) transcription factors to stimulate transcription of a variety of target genes. Signaling through beta-catenin is regulated by modulating its degradation and nuclear translocation. In the absence of an activating signal, phosphorylation of beta-catenin by glycogen synthase kinase 3 (GSK3) acting in conjunction with adenomatous polyposis coli and axin/conductin causes beta-catenin to interact with the beta-transducin repeat-containing protein which results in its ubiquitination and degradation. Signaling from the wnt pathway activates dishevelled which, in an as yet undefined manner, inhibits the activity of GSK3 resulting in an increase in the cytoplasmic free pool of beta-catenin, and translocation into the nucleus. The integrin-linked kinase (ILK) pathway also activates beta-catenin-Lef/Tcf signaling. ILK phosphorylates GSK3 to inhibit its activity and translocates beta-catenin into the nucleus. In addition, ILK downregulates the expression of E-cadherin and upregulates Lef-1 expression. In the final step of the beta-catenin-Lef/Tcf signaling pathway, nuclear beta-catenin binds pontin52-TATA binding protein and displaces Groucho-related gene or CREB-binding protein corepressors from Lef/Tcf resulting in stimulation of transcription. During development, beta-catenin-Lef/Tcf signaling is involved in the formation of dorsal mesoderm and dorsal axis. Furthermore, defects in the beta-catenin-Lef/Tcf pathway are involved in the development of several types of cancers.

Factors Determining the Decision To Institutionalize Dementing Individuals:A Prospective Study

Abstract: This longitudinal study of 196 caregiver/care receiver dyads was undertaken to determine the variables predictive of caregiver decision to institutionalize a dependent with dementia. Seven variables (use of services, enjoyment of caregiving, caregiver burden and health, caregiver rating and reaction to care receiver behavior and memory problems, and presence of troublesome behaviors) predicted the decision to institutionalize. Six variables (caregiver health and burden, use of services, care receiver cognitive function and troublesome behaviors, and caregiver reaction to behaviors) predicted actual institutionalization at 18 months.