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Annich G.M.,The Hospital for Sick Children
Journal of Thrombosis and Haemostasis | Year: 2015

Extracorporeal life support is by far the most extraordinary and complex form of extracorporeal technology used in the practice of critical care medicine. It is used to support critically ill patient who suffer acute respiratory or cardiac failure unresponsive to conventional support. As extracorporeal technologies have refined the pathophysiologic reaction that occurs at the blood/biomaterial interface has not been conquered; a new set of physiologic responses/derangements occur with the patient's exposure to the artificial circuit. Without this support mortality is near certain and with support if management is not precise and judicious the complications can be catastrophic. The management of a patient on ECLS is the same as for any critically ill patient with the added need for anticoagulation to maintain patency of the extracorporeal circuit without causing bleeding within the patient and thrombosis within the circuitry or the patient. This is the precarious balance of hemostasis during ECLS. © 2015 International Society on Thrombosis and Haemostasis.

Canton J.,The Hospital for Sick Children
Journal of Leukocyte Biology | Year: 2014

Macrophages are capable of assuming distinct, metastable, functional phenotypes in response to environmental cues—a process referred to as macrophage polarization. The identity and plasticity of polarized macrophage subsets as well as their functions in the maintenance of homeostasis and the progression of various pathologies have become areas of intense interest. Yet, the mechanisms by which they achieve subset-specific functions at the cellular level remain unclear. It is becoming apparent that phagocytosis and phagosome maturation differ depending on the polarization of macrophages. This minireview summarizes recent progress in this field, highlighting developing trends and discussing the molecular mechanisms that underlie subset-specific functions. © Society for Leukocyte Biology.

Recent advances in molecular neurooncology provide unique opportunities for targeted molecular-based therapies. However, the blood-brain barrier (BBB) remains a major limitation to the delivery of tumor-specific therapies directed against aberrant signaling pathways in brain tumors. Given the dismal prognosis of patients with malignant brain tumors, novel strategies that overcome the intrinsic limitations of the BBB are therefore highly desirable. Focused ultrasound BBB disruption is emerging as a novel strategy for enhanced delivery of therapeutic agents into the brain via focal, reversible, and safe BBB disruption. This review examines the potential role and implications of focused ultrasound in molecular neurooncology.

Simpson E.,The Hospital for Sick Children
Cochrane database of systematic reviews (Online) | Year: 2012

Recombinant factor VIIa (rFVIIa) is licensed for use in patients with haemophilia and inhibitory allo-antibodies and for prophylaxis and treatment of patients with congenital factor VII deficiency. It is also used for off-license indications to prevent bleeding in operations where blood loss is likely to be high, and/or to stop bleeding that is proving difficult to control by other means. This is the third version of the 2007 Cochrane review on the use of recombinant factor VIIa for the prevention and treatment of bleeding in patients without haemophilia, and has been updated to incorporate recent trial data. To assess the effectiveness of rFVIIa when used therapeutically to control active bleeding or prophylactically to prevent (excessive) bleeding in patients without haemophilia. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and other medical databases up to 23 March 2011. Randomised controlled trials (RCTs) comparing rFVIIa with placebo, or one dose of rFVIIa with another, in any patient population (except haemophilia). Outcomes were mortality, blood loss or control of bleeding, red cell transfusion requirements, number of patients transfused and thromboembolic adverse events. Two authors independently assessed potentially relevant studies for inclusion, extracted data and examined risk of bias. We considered prophylactic and therapeutic rFVIIa studies separately. Twenty-nine RCTs were included: 28 were placebo-controlled, double-blind RCTs and one compared different doses of rFVIIa. In the 'Risk of bias' assessment, most studies were found to have some threats to validity although therapeutic RCTs were found to be less prone to bias than prophylactic RCTs.Sixteen trials involving 1361 participants examined the prophylactic use of rFVIIa; 729 received rFVIIa. There was no evidence of mortality benefit (risk ratio (RR) 1.04; 95% confidence interval (CI) 0.55 to 1.97). There was decreased blood loss (mean difference (MD) -297 mL; 95% CI -416 to -178) and decreased red cell transfusion requirements (MD -261 mL; 95% CI -367 to -154) with rFVIIa treatment; however, these values were likely overestimated due to the inability to incorporate data from trials (four RCTs in the outcome of blood loss and three RCTs in the outcome of transfusion requirements) showing no difference of rFVIIa treatment compared to placebo. There was a trend in favour of rFVIIa in the number of participants transfused (RR 0.85; 95% CI 0.72 to 1.01). However, there was a trend against rFVIIa with respect to thromboembolic adverse events (RR 1.35; 95% CI 0.82 to 2.25).Thirteen trials involving 2929 participants examined the therapeutic use of rFVIIa; 1878 received rFVIIa. There were no outcomes where any observed advantage or disadvantage of rFVIIa over placebo could not have been observed by chance alone. There was a trend in favour of rFVIIa for reducing mortality (RR 0.91; 95% CI 0.78 to 1.06). However, there was a trend against rFVIIa for increased thromboembolic adverse events (RR 1.14; 95% CI 0.89 to 1.47).When all trials were pooled together to examine the risk of thromboembolic events, a significant increase in total arterial events was observed (RR 1.45; 95% CI 1.02 to 2.05). The effectiveness of rFVIIa as a more general haemostatic drug, either prophylactically or therapeutically, remains unproven. The results indicate increased risk of arterial events in patients receiving rFVIIa. The use of rFVIIa outside its current licensed indications should be restricted to clinical trials.

Dragas R.,The Hospital for Sick Children
Documenta ophthalmologica. Advances in ophthalmology | Year: 2014

Vigabatrin (VGB), a treatment for the childhood epilepsy, infantile spasms (IS), is implicated in visual field constriction. Electroretinograms (ERGs) are used as a substitute for visual field testing in infants. We use the VGB-associated ERG reduction (VAER), defined as reduction in age-corrected light adapted 30 Hz flicker amplitude from a pre-treatment measurement in the absence of other retinal defects, as an indicator of retinal toxicity resulting from VGB use. The d-wave ERG response is predominantly the result of OFF-bipolar cell depolarization response to light offset. The purpose of this study is to evaluate the ERG d-wave response as a marker for VAER toxicity in an infant population. One hundred children with IS treated with VGB (median age at baseline: 7.6 months; range 1.7-38.4) were tested for the cone-OFF response elicited to a 250 cd s m(2) flash with 200 ms duration (long flash ERG). Diagnosis of VAER requires baseline testing of the flicker ERG and at least one follow up ERG; Fifty-one patients fulfilled this criteria. Fifty-eight children received the long flash ERG at baseline. Thirteen retinally normal controls with a median age of 32 months (5.7-65) were also tested. Amplitude and implicit time of the d-wave response were measured manually. Longer duration of treatment was associated with reduced d-wave amplitude (ANOVA p < 0.05) in patients taking VGB. Nine patients demonstrated VAER during the course of the study. D-wave amplitude was reduced in the IS group with VAER compared to those without VAER (p < 0.05). Vigabatrin associated retinal defects may be reflected in reduction of the cone d-wave amplitude.

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