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1.  Pancreatic β-Cell Death in Response to Pro-Inflammatory Cytokines Is Distinct from Genuine Apoptosis 
PLoS ONE  2011;6(7):e22485.
A reduction in functional β-cell mass leads to both major forms of diabetes; pro-inflammatory cytokines, such as interleukin-1beta (IL-1β) and gamma-interferon (γ-IFN), activate signaling pathways that direct pancreatic β-cell death and dysfunction. However, the molecular mechanism of β-cell death in this context is not well understood. In this report, we tested the hypothesis that individual cellular death pathways display characteristic phenotypes that allow them to be distinguished by the precise biochemical and metabolic responses that occur during stimulus-specific initiation. Using 832/13 and INS-1E rat insulinoma cells and isolated rat islets, we provide evidence that apoptosis is unlikely to be the primary pathway underlying β-cell death in response to IL-1β+γ-IFN. This conclusion was reached via the experimental results of several different interdisciplinary strategies, which included: 1) tandem mass spectrometry to delineate the metabolic differences between IL-1β+γ-IFN exposure versus apoptotic induction by camptothecin and 2) pharmacological and molecular interference with either NF-κB activity or apoptosome formation. These approaches provided clear distinctions in cell death pathways initiated by pro-inflammatory cytokines and bona fide inducers of apoptosis. Collectively, the results reported herein demonstrate that pancreatic β-cells undergo apoptosis in response to camptothecin or staurosporine, but not pro-inflammatory cytokines.
doi:10.1371/journal.pone.0022485
PMCID: PMC3146470  PMID: 21829464
2.  Sensitivity of computed tomography performed within six hours of onset of headache for diagnosis of subarachnoid haemorrhage: prospective cohort study 
Objective To measure the sensitivity of modern third generation computed tomography in emergency patients being evaluated for possible subarachnoid haemorrhage, especially when carried out within six hours of headache onset.
Design Prospective cohort study.
Setting 11 tertiary care emergency departments across Canada, 2000-9.
Participants Neurologically intact adults with a new acute headache peaking in intensity within one hour of onset in whom a computed tomography was ordered by the treating physician to rule out subarachnoid haemorrhage.
Main outcome measures Subarachnoid haemorrhage was defined by any of subarachnoid blood on computed tomography, xanthochromia in cerebrospinal fluid, or any red blood cells in final tube of cerebrospinal fluid collected with positive results on cerebral angiography.
Results Of the 3132 patients enrolled (mean age 45.1, 2571 (82.1%) with worst headache ever), 240 had subarachnoid haemorrhage (7.7%). The sensitivity of computed tomography overall for subarachnoid haemorrhage was 92.9% (95% confidence interval 89.0% to 95.5%), the specificity was 100% (99.9% to 100%), the negative predictive value was 99.4% (99.1% to 99.6%), and the positive predictive value was 100% (98.3% to 100%). For the 953 patients scanned within six hours of headache onset, all 121 patients with subarachnoid haemorrhage were identified by computed tomography, yielding a sensitivity of 100% (97.0% to 100.0%), specificity of 100% (99.5% to 100%), negative predictive value of 100% (99.5% to 100%), and positive predictive value of 100% (96.9% to 100%).
Conclusion Modern third generation computed tomography is extremely sensitive in identifying subarachnoid haemorrhage when it is carried out within six hours of headache onset and interpreted by a qualified radiologist.
doi:10.1136/bmj.d4277
PMCID: PMC3138338  PMID: 21768192
3.  High risk clinical characteristics for subarachnoid haemorrhage in patients with acute headache: prospective cohort study 
Objective To identify high risk clinical characteristics for subarachnoid haemorrhage in neurologically intact patients with headache.
Design Multicentre prospective cohort study over five years.
Setting Six university affiliated tertiary care teaching hospitals in Canada. Data collected from November 2000 until November 2005.
Participants Neurologically intact adults with a non-traumatic headache peaking within an hour.
Main outcome measures Subarachnoid haemorrhage, as defined by any of subarachnoid haemorrhage on computed tomography of the head, xanthochromia in the cerebrospinal fluid, or red blood cells in the final sample of cerebrospinal fluid with positive results on angiography. Physicians completed data collection forms before investigations.
Results In the 1999 patients enrolled there were 130 cases of subarachnoid haemorrhage. Mean (range) age was 43.4 (16-93), 1207 (60.4%) were women, and 1546 (78.5%) reported that it was the worst headache of their life. Thirteen of the variables collected on history and three on examination were reliable and associated with subarachnoid haemorrhage. We used recursive partitioning with different combinations of these variables to create three clinical decisions rules. All had 100% (95% confidence interval 97.1% to 100.0%) sensitivity with specificities from 28.4% to 38.8%. Use of any one of these rules would have lowered rates of investigation (computed tomography, lumbar puncture, or both) from the current 82.9% to between 63.7% and 73.5%.
Conclusion Clinical characteristics can be predictive for subarachnoid haemorrhage. Practical and sensitive clinical decision rules can be used in patients with a headache peaking within an hour. Further study of these proposed decision rules, including prospective validation, could allow clinicians to be more selective and accurate when investigating patients with headache.
doi:10.1136/bmj.c5204
PMCID: PMC2966872  PMID: 21030443
4.  A prospective cluster-randomized trial to implement the Canadian CT Head Rule in emergency departments 
Background
The Canadian CT Head Rule was developed to allow physicians to be more selective when ordering computed tomography (CT) imaging for patients with minor head injury. We sought to evaluate the effectiveness of implementing this validated decision rule at multiple emergency departments.
Methods
We conducted a matched-pair cluster-randomized trial that compared the outcomes of 4531 patients with minor head injury during two 12-month periods (before and after) at hospital emergency departments in Canada, six of which were randomly allocated as intervention sites and six as control sites. At the intervention sites, active strategies, including education, changes to policy and real-time reminders on radiologic requisitions were used to implement the Canadian CT Head Rule. The main outcome measure was referral for CT scan of the head.
Results
Baseline characteristics of patients were similar when comparing control to intervention sites. At the intervention sites, the proportion of patients referred for CT imaging increased from the “before” period (62.8%) to the “after” period (76.2%) (difference +13.3%, 95% CI 9.7%–17.0%). At the control sites, the proportion of CT imaging usage also increased, from 67.5% to 74.1% (difference +6.7%, 95% CI 2.6%–10.8%). The change in mean imaging rates from the “before” period to the “after” period for intervention versus control hospitals was not significant (p = 0.16). There were no missed brain injuries or adverse outcomes.
Interpretation
Our knowledge–translation-based trial of the Canadian CT Head Rule did not reduce rates of CT imaging in Canadian emergency departments. Future studies should identify strategies to deal with barriers to implementation of this decision rule and explore more effective approaches to knowledge translation. (ClinicalTrials.gov trial register no. NCT00993252)
doi:10.1503/cmaj.091974
PMCID: PMC2950184  PMID: 20732978
5.  Implementation of the Canadian C-Spine Rule: prospective 12 centre cluster randomised trial 
Objective To evaluate the effectiveness of an active strategy to implement the validated Canadian C-Spine Rule into multiple emergency departments.
Design Matched pair cluster randomised trial.
Setting University and community emergency departments in Canada.
Participants 11 824 alert and stable adults presenting with blunt trauma to the head or neck at one of 12 hospitals.
Interventions Six hospitals were randomly allocated to the intervention and six to the control. At the intervention sites, active strategies were used to implement the Canadian C-Spine Rule, including education, policy, and real time reminders on radiology requisitions. No specific intervention was introduced to alter the behaviour of doctors requesting cervical spine imaging at the control sites.
Main outcome measure Diagnostic imaging rate of the cervical spine during two 12 month before and after periods.
Results Patients were balanced between control and intervention sites. From the before to the after periods, the intervention group showed a relative reduction in cervical spine imaging of 12.8% (95% confidence interval 9% to 16%; 61.7% v 53.3%; P=0.01) and the control group a relative increase of 12.5% (7% to 18%; 52.8% v 58.9%; P=0.03). These changes were significant when both groups were compared (P<0.001). No fractures were missed and no adverse outcomes occurred.
Conclusions Implementation of the Canadian C-Spine Rule led to a significant decrease in imaging without injuries being missed or patient morbidity. Final imaging rates were much lower at intervention sites than at most US hospitals. Widespread implementation of this rule could lead to reduced healthcare costs and more efficient patient flow in busy emergency departments worldwide.
Trial registration Clinical trials NCT00290875.
doi:10.1136/bmj.b4146
PMCID: PMC2770593  PMID: 19875425

Results 1-5 (5)