Showing papers by "Sunnybrook Health Sciences Centre published in 2004"

Predisposition to abacavir hypersensitivity conferred by HLA-B*5701 and a haplotypic Hsp70-Hom variant

Abstract: Susceptibility to a clinically significant drug hypersensitivity syndrome associated with abacavir use seems to have a strong genetic component. We have previously shown that the presence of HLA-B*5701 strongly predicts abacavir hypersensitivity and have identified a potential susceptibility locus within a 300-kb region between the MEGT1 and C4A6 loci in the central MHC. We now report the results of fine recombinant genetic mapping in an expanded patient population of 248 consecutive, fully ascertained, abacavir-exposed individuals in the Western Australian HIV Cohort Study, in which 18 cases of definite abacavir hypersensitivity (7.3%) and 230 tolerant controls were identified. Haplotype mapping within patients with allelic markers of the 57.1 ancestral haplotype suggests a susceptibility locus within the 14-kb Hsp70 gene cluster. HLA-B*5701 was present in 94.4% of hypersensitive cases compared with 1.7% of controls (odds ratio, 960; P < 0.00001). A haplotypic nonsynonymous polymorphism of Hsp70-Hom (HspA1L, resulting from the substitution of residue M493T in the peptide-binding subunit) was found in combination with HLA-B*5701 in 94.4% of hypersensitive cases and 0.4% of controls (odds ratio, 3,893; P < 0.00001). Individuals with abacavir hypersensitivity demonstrated increased monocyte tumor necrosis factor expression in response to ex vivo abacavir stimulation, which was abrogated with CD8+ T cell depletion. These data indicate that the concurrence of HLA-B*5701 and Hsp70-Hom M493T alleles is necessary for the development of abacavir hypersensitivity, which is likely to be mediated by an HLA-B*5701-restricted immune response to abacavir.

Long-term efficacy of bivalirudin and provisional glycoprotein IIb/IIIa blockade vs heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary revascularization: REPLACE-2 randomized trial.

Abstract: ContextIn the Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE)-2 trial, bivalirudin with provisional glycoprotein IIb/IIIa (Gp IIb/IIIa) inhibition was found to be noninferior to heparin plus planned Gp IIb/IIIa blockade in the prevention of acute ischemic end points and was associated with significantly less bleeding by 30 days after percutaneous coronary intervention (PCI)ObjectiveTo determine whether the efficacy of bivalirudin remains comparable with that of heparin plus Gp IIb/IIIa blockade over 6 months and 1 yearDesign, Setting, and ParticipantsFollow-up study to 1 year of a randomized, double-blind trial conducted among 6010 patients undergoing urgent or elective PCI at 233 community or referral hospitals in 9 countries from October 2001 through August 2002InterventionsPatients were randomly assigned to receive intravenously bivalirudin (075 mg/kg bolus, 175 mg/kg per hour for the duration of PCI), with provisional Gp IIb/IIIa inhibition, or to receive heparin (65 U/kg bolus), with planned Gp IIb/IIIa inhibition (abciximab or eptifibatide) Both groups received daily aspirin and a thienopyridine for at least 30 days after PCIMain Outcome MeasuresIncidence of death, myocardial infarction, or repeat revascularization by 6 months and death by 12 months after enrollmentResultsAt 6 months, death occurred in 14% of patients in the heparin plus Gp IIb/IIIa group and in 10% of patients in the bivalirudin group (hazard ratio [HR], 070; 95% confidence interval [CI], 043-114; P = 15) Myocardial infarction occurred in 74% and 82% of patients, respectively (HR, 112; 95% CI, 093-134; P = 24), and repeat revascularization was required in 114% and 121% of patients, respectively (HR, 106; 95% CI, 091-123; P = 45) By 1 year, death occurred in 246% of patients treated with heparin plus Gp IIb/IIIa blockade and in 189% of patients treated with bivalirudin (HR, 078; 95% CI, 055-111; P = 16) Nonsignificant trends toward lower 1-year mortality with bivalirudin were present in all patient subgroups analyzed and were of greatest magnitude among high-risk patientsConclusionLong-term clinical outcome with bivalirudin and provisional Gp IIb/IIIa blockade is comparable with that of heparin plus planned Gp IIb/IIIa inhibition during contemporary PCI

Hybrid imaging method to monitor medical device delivery and patient support for use in the method

Abstract: This invention discloses a method and apparatus to deliver medical devices to targeted locations within human tissues using imaging data. The method enables the target location to be obtained from one imaging system, followed by the use of a second imaging system to verify the final position of the device. In particular, the invention discloses a method based on the initial identification of tissue targets using MR imaging, followed by the use of ultrasound imaging to verify and monitor accurate needle positioning. The invention can be used for acquiring biopsy samples to determine the grade and stage of cancer in various tissues including the brain, breast, abdomen, spine, liver, and kidney. The method is also useful for delivery of markers to a specific site to facilitate surgical removal of diseased tissue, or for the targeted delivery of applicators that destroy diseased tissues in-situ.

Hypoxia and hypoxia-inducible factor-1 target genes in central nervous system radiation injury: a role for vascular endothelial growth factor.

Abstract: Purpose: Microvascular permeability changes and loss of blood-brain barrier integrity are important features of central nervous system (CNS) radiation injury. Expression of vascular endothelial growth factor (VEGF), an important determinant of microvascular permeability, was examined to assess its role in CNS radiation damage. Because hypoxia mediates VEGF up-regulation through hypoxia-inducible factor-1α (HIF1α) induction, we studied the relationships of hypoxia, HIF1α expression, and expression of VEGF in this damage pathway. Experimental Design: Expression of HIF1α, VEGF, and another hypoxia-responsive gene, glucose transporter-1, was assessed in the irradiated rat spinal cord using immunohistochemistry and in situ hybridization. Hypoxic areas were identified using the nitroimidazole 2-(2-nitro-1 H -imidazole-l-yl)- N -(2,2,3,3,3,-pentafluoropropyl) acetamide. To determine the causal importance of VEGF expression in radiation myelopathy, we studied the response of transgenic mice with greater (VEGF-A hi/+ ), reduced (VEGF-A lo/+ ), and wild-type VEGF activity to thoracolumbar irradiation. Results: In rat spinal cord, the number of cells expressing HIF1α and VEGF increased rapidly from 16 to 20 weeks after radiation, before white matter necrosis and forelimb paralysis. A steep dose response was observed in expression of HIF1α and VEGF. HIF1α and VEGF expressing cells were identified as astrocytes. Hypoxia was present in regions where up-regulation of VEGF and glucose transporter-1 and increased permeability was observed. VEGF-A lo/+ mice had a longer latency to development of hindlimb weakness and paralysis compared with wild-type or VEGF-A hi/+ mice. Conclusions: VEGF expression appears to play an important role in CNS radiation injury. This focuses attention on VEGF and other genes induced in response to hypoxia as targets for therapy to reduce or prevent CNS radiation damage.

Device and process for manipulating real and virtual objects in three-dimensional space

Abstract: A device and software system with input and output capability for manipulating real and virtual objects in 3-dimensional space. The device consists of a six degree-of-freedom mechanical armature that has sensors to determine the location and orientation of a stylus and planar surface. In the input mode, manipulation of the physical armature will result in a corresponding two-dimensional, virtual image of the stylus and surface on a computer screen. The armature also has motors to automatically change the armature location and orientation in order to generate a physical representation in the real world of the location and orientation of a virtual object. The armature is built so that it maintains balance at any location and orientation to statically maintain the armature location and orientation without drifting to a null rest position.

Pharmacologic therapies for adults with acute lung injury and acute respiratory distress syndrome

Abstract: Background Multiple pharmacologic treatments have been studied for acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Objectives Our objective was to determine the effects of pharmacologic treatments on clinical outcomes in adults with ALI or ARDS. Search methods We searched OVID versions of CENTRAL (The Cochrane Library Issue 3, 2003), MEDLINE (1966 to week 2, January 2004), EMBASE (1980 to week 4, 2004), CINAHL (1982 to week 2, January 2004), and HEALTHSTAR (1995 to December 2003); proceedings from four conferences (1994 to 2003); and bibliographies of review articles and included studies. Selection criteria Randomized controlled trials of pharmacologic treatments compared to no therapy or placebo for established ALI or ARDS in adults admitted to an intensive care unit, with measurement of early mortality (primary outcome), late mortality, duration of mechanical ventilation, ventilator-free days to day 28, or adverse events. We excluded trials of nitric oxide, partial liquid ventilation, fluid and nutritional interventions, oxygen, and trials in other populations reporting outcomes in subgroups of patients with ALI or ARDS. Data collection and analysis Two reviewers independently screened titles and abstracts, rated studies for inclusion, extracted data and assessed methodologic quality of included studies. Disagreements were resolved by consensus in consultation with a third reviewer. For each pharmacologic therapy, we quantitatively pooled the results of studies using random effects models where permitted by the available data. We contacted study authors when clarification of the primary outcome was required. Main results Thirty three trials randomizing 3272 patients met our inclusion criteria. Pooling of results showed no effect on early mortality of prostaglandin E1 (seven trials randomizing 697 patients; relative risk [RR] 0.95, 95% confidence interval [CI] 0.77 to 1.17), N-acetylcysteine (five trials randomizing 239 patients; RR 0.89, 95% CI 0.65 to 1.21), early high-dose corticosteroids (two trials randomizing 187 patients; RR 1.12, 95% CI 0.72 to 1.74), or surfactant (nine trials randomizing 1441 patients; RR 0.93, 95% CI 0.77 to 1.12). Two interventions were beneficial in single small trials; corticosteroids given for late phase ARDS reduced hospital mortality (24 patients; RR 0.20, 95% CI 0.05 to 0.81), and pentoxifylline reduced one-month mortality (RR 0.67, 95% CI 0.47 to 0.95) in 30 patients with metastatic cancer and ARDS. Individual trials of nine additional interventions failed to show a beneficial effect on prespecified outcomes. Authors' conclusions Effective pharmacotherapy for ALI and ARDS is extremely limited, with insufficient evidence to support any specific intervention.

Carpal tunnel syndrome: cross-sectional and outcome study in Ontario workers.

Abstract: Purpose To carry out an analytic cross-sectional study of Ontario workers with carpal tunnel syndrome (CTS) and to assess workers' symptoms, functional disabilities, recreational difficulties, and work capability 4 years after treatment of their CTS. Methods Data were obtained by review of Ontario Workers Safety and Insurance Board (WSIB) files and by completion of self-assessment questionnaires. Inclusion criteria included all workers registered with the Ontario WSIB who were off work with newly diagnosed carpal tunnel syndrome in 1996. Results There are 3 million workers covered by the WSIB in the province of Ontario. In 1996, 964 of them developed work-related CTS that required time off for treatment. Of these patients 53% were women and 75% had bilateral CTS. Eighty-one percent of the unilateral cases involved the dominant extremity. The average age at the time of claim was 41 years and workers were at the same job type for an average of 7.4 years (unilateral) and 8.5 years (bilateral), respectively. Thirty-nine percent of workers had a history of another tendonitis or epicondylitis. Seventy-five percent of workers had surgery and on average returned to work 3 months later. Four years after treatment, outcome was assessed by self-administered questionnaires, for which there was a 73% response rate. Forty-six percent of workers experienced moderate to severe pain, 47% had moderate to severe numbness, and 40% had difficulty grasping and using small objects. Only 14% were symptom free. Successful return to work was considered to be a return to the same job with or without modifications, and it occurred in 64% of cases. Better clinical outcome scores were found to occur with surgery and abnormal nerve conduction study results. Worse clinical outcome scores were present with repeat surgery and surgical complications. Concurrent diagnoses of either tendonitis or epicondylitis also resulted in worse clinical outcome scores and worse return-to-work outcomes. The average total cost in Canadian dollars to the WSIB exceeded $13,700 per worker for a total cost in excess of $13,200,000 per year. (In 1996, $1 Canadian=$1.365 US.) Conclusions These outcomes indicate that Canadian workers have a large amount of permanent pain and suffering, a large loss of work productivity, and incur a considerable financial cost as a result of work-related CTS.

Severe Acute Respiratory Syndrome and the Delivery of Continuing Medical Education: Case Study from Toronto.

Abstract: Introduction: Severe acute respiratory syndrome (SARS) struck Toronto in the spring of 2003, causing many deaths, serious morbidity, forced quarantine of thousands of individuals, and the closure of all provincial hospitals for several weeks. Given the direction by public health authorities to cancel or postpone all continuing medical education (CME) courses, including those sponsored by the University of Toronto Faculty of Medicine, SARS has had a profound effect on the delivery of CME in Toronto and beyond. Method: Case study design using existing documents and self-report. Results: The immediate, specific response of the University of Toronto CME program to SARS is described for the period from March 2003 to September 2003. Discussion: During major outbreaks of infectious disease, continuing education providers should maintain regular contact with public health authorities and learners, enact a rational process for postponing or canceling courses, and implement a disaster plan flexible enough to ensure the delivery of education using technological advances.

Biological effects of high-frequency ultrasound exposure during mouse organogenesis.

Abstract: Little has been reported on bioeffects of high-frequency ultrasound (US) and guidelines for US use do not necessarily apply to high frequencies. Pregnant CD-1 mice were exposed to Doppler or B-mode US biomicroscopy (UBM) on embryonic day (E) 8.5 or E10.5, during organogenesis. Operating frequency was 40 MHz with a free field I SPTA of 11.9 W/cm 2 (Doppler) and 2.6 mW/cm 2 (B-mode), peak negative pressures of 6.61 MPa and MI of 1.05 (B-mode). Offspring were assessed weekly from 1 day postnatally to euthanasia at 6 weeks, with no significant difference in pup weight, body length or crown-rump length observed. E8.5 Doppler-exposed mice showed a small reduction in weight and length at 3 weeks and in weight at 6 weeks. E10.5 Doppler-exposed animals exhibited slight growth reduction in weeks 2 to 4, but were not significantly different at 6 weeks. Our results indicate similar exposures of mice should not cause significant adverse bioeffects. (E-mail: aduckett@sten.sunnybrook.utoronto.ca )

Thermal assessment of 40-MHz ultrasound at soft tissue-bone interfaces.

Abstract: Tissue exposure to diagnostic ultrasound (US) can cause significant temperature rises. However, little has been reported on thermal effects of high-frequency US, and guidelines for the use of US do not necessarily apply to higher frequencies. Temperature rise induced by US biomicroscopy (UBM) was measured in phantoms containing mouse skulls and in anesthetized mice and mice post mortem, with a 50-μm K-type thermocouple. The operating frequency was 40 MHz with a free field ISPTA of 2.6 mW/cm2 (B-mode) and 11.9 W/cm2 (Doppler). Peak negative pressures were 5.22 MPa (B mode) and 7.32 MPa (Doppler), resulting in a mechanical index (MI) of 0.83 (B-mode) and 1.05 (Doppler mode). In Doppler mode, mean temperature rises of 1.80°C and 1.73°C were measured for proximal and distal skull phantom surfaces after a 3-min insonation. In vivo, the proximal mouse skull surface showed a mean temperature rise of 2.1°C, with no statistically significant differences post mortem. Our results indicate temperature rise from insonation of bone interfaces using similar exposure parameters should not cause adverse bioeffects. (E-mail: aduckett@sten.sunnybrook.utoronto.ca )

Hard times and good friends: negative life events and social support in patients with seasonal and nonseasonal depression.

Abstract: Objective: Although a relatively large body of research has now accumulated concerning the relation between negative life events, social support, and major depressive disorder (MDD), little is known about the relation between seasonal affective disorder and these psychosocial variables. This study aimed to compare baseline levels of negative life events (NLEs) and perceived social support (SS) in patients with seasonal and nonseasonal depression. Method: Canadian patients with winter seasonal affective disorder (SAD) (n = 26) and nonseasonal recurrent MDD (n = 66) completed measures of recent NLEs (the List of Threatening Experiences) and perceived SS (the Social Support Survey) prior to treatment. Results: No significant between-group differences were observed in mean number of NLEs experienced or in quality of SS. Perceived SS was impaired in both groups, compared with patients with chronic medical conditions. Conclusions: The results of this study complement those of previous research reporting increased incidence of NLEs and decreased SS in primary care patients with high seasonality in the UK. Future research is required to determine the causal relation between these psychosocial risk factors and SAD and to assess whether they have an effect on, or are affected by, treatment interventions for SAD. (Can J Psychiatry 2004;49:408–411)