Mitochondrial defects arise from nucleoside/nucleotide reverse transcriptase inhibitors in neurons: Potential contribution to HIV-associated neurocognitive disorders.

The cornerstone of current HIV treatment is a class of drugs called nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs). However, patients who receive long term treatment with NRTIs often develop severe side effects, which are related to mitochondrial toxicity. The potential contribution of NRTI-mediated toxicity to HIV-associated neurocognitive disorders (HAND) has not been fully explored. NRTI toxicity is thought to be mediated through mitochondrial DNA polymerase γ (pol γ) inhibition, which impairs mitochondrial DNA (mtDNA) synthesis and leads to various mitochondrial dysfunctions. To evaluate the relationship between NRTI-mediated pol γ inhibition and mitochondrial toxicity in neurons, we systematically investigated mitochondrial regulation in NRTI-treated primary cortical neurons by measuring parameters related to mtDNA content, retrograde signaling responses and mitochondrial homeostasis. The effects of four different NRTIs with variable pol γ inhibitory activity and mitochondrial toxicity were assessed. The strong pol γ inhibitor, ddI, abolished mtDNA synthesis and greatly reduced mtDNA content. However, mtDNA transcription was not as severely affected, and no defects in oxidative phosphorylation were observed. Detrimental effects on mitochondrial respiration and motility were observed after AZT treatment in the absence of mtDNA depletion or inhibition of mtDNA synthesis. The results suggest that individual NRTIs, such as ddI and AZT, have the potential to cause mitochondrial toxicity in neurons. This mitochondrial toxicity would be expected to contribute to neurotoxicity in the central nervous system, and therefore, HAND etiology may be affected by NRTI treatment.

Safety and Effectiveness of Intravenous Thrombolysis for Acute Ischemic Stroke Outside the Coverage of National Health Insurance in Taiwan.

PURPOSE: Only a small percentage of ischemic stroke patients were treated with intravenous thrombolysis in Taiwan, partly because of the narrow reimbursement criteria of the National Health Insurance (NHI). We aimed to assess the safety and effectiveness of intravenous thrombolysis not covered by the NHI. METHODS: This is a retrospective analysis of register data from four hospitals. All patients who received intravenous tissue plasminogen activator and fulfilled the American Heart Association/American Stroke Association (AHA/ASA) thrombolysis guidelines between January 2007 and June 2012 were distinguished into two groups: those in accordance (reimbursement group) and those not in accordance (non-reimbursement group) with the NHI reimbursement criteria. Primary outcome was symptomatic intracerebral hemorrhage (SICH). Secondary outcomes were dramatic improvement in the National Institutes of Health Stroke Scale (NIHSS) score at discharge, good functional outcome (modified Rankin Scale ≤2) at discharge, and all-cause in-hospital mortality. RESULTS: In 569 guideline-eligible patients, 177 (31%) were treated without reimbursement. The reasons for exclusion from reimbursement included age >80 (n=42), baseline NIHSS less than 6 (n=29), baseline NIHSS >25 (n=15), thrombolysis beyond 3 hours (n=49), prior stroke with diabetes (n=28), use of oral anticoagulant (n=2), and more than one contraindication (n=12). Overall, we observed no differences between the reimbursement and non-reimbursement groups in the rate of SICH (7% versus 6%), dramatic improvement (36% versus 36%), good functional outcome (39% versus 37%), and in-hospital mortality (8% versus 6%) Conclusion: In stroke patients treated with intravenous thrombolysis according to the AHA/ASA guidelines, the outcomes were comparable between the reimbursement and non-reimbursement groups.

Does renal dysfunction modify the effect of intravenous thrombolysis for acute ischemic stroke within 4.5 hours of onset? A multicenter observational study.

BACKGROUND: About one third of stroke patients have renal dysfunction. Effect of renal dysfunction on outcome of intravenous thrombolysis (IVT) for acute ischemic stroke (AIS) has not been determined in Asia using patients without IVT as comparators. The aim of this study was to examine the interaction between renal dysfunction and IVT on the outcomes in AIS patients admitted within 4.5 hours of onset in a multicenter stroke registry of Taiwan. METHODS: We identified all consecutive AIS patients admitted within 4.5 hours of onset between 2007 and 2013. Renal dysfunction was defined by an estimated glomerular filtration rate less than 60 mL/minute/1.73 m(2) on initial admission. Patients older than 80 years of age and a National Institute of Health Stroke Scale score less than 4 or greater than 25 were excluded. The primary outcome was a modified Rankin Scale score 3-6 at 3 months. We determined the effect of IVT and renal dysfunction on outcome in a multivariate analysis. RESULTS: Of the 929 patients analyzed, 39% had renal dysfunction, and 51% received IVT. Primary outcomes occurred in 45% versus 41% of patients with and without renal dysfunction, respectively, (P = .197). In a multivariate analysis, the odds ratios (95% confidence interval; P value) of IVT and renal dysfunction for primary outcome were .70 (.51-.96; P = .029) and .97 (.71-1.33; P = .865), respectively. No significant interaction was noted between IVT and renal dysfunction (P = .218). CONCLUSIONS: Renal dysfunction did not modify the effect of IVT for AIS and should not be a reason for withholding treatment from otherwise-eligible patients.

Is renal dysfunction associated with adverse stroke outcome after thrombolytic therapy?

BACKGROUND: Renal dysfunction is a prevalent comorbidity in acute stroke patients requiring thrombolytic therapy. Reports studying the relationship between renal dysfunction and risk of postthrombolytic symptomatic intracerebral hemorrhage (SICH) are contradictory. We aimed to compare the safety and effectiveness of thrombolytic therapy in acute stroke patients with and without renal dysfunction. METHODS: Based on the prospective stroke registries of 4 hospitals in Taiwan from 2007-2012, we identified acute stroke patients who received thrombolytic therapy. Clinically significant renal dysfunction was defined as an estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m(2). Renal dysfunction was further defined as stage 3 (30 ≤ eGFR < 60 ml/min/ 1.73 m(2)), stage 4 (15 ≤ eGFR < 30 ml/min/1.73 m(2)) and stage 5 (<15 ml/min/1.73 m(2)). The rates of SICH and poor outcome (defined as modified Rankin scale score ≥4) at 3 months after thrombolytic therapy were compared in patients with and without renal dysfunction. SICH was determined according to the definition of the National Institute of Neurological Disorders and Stroke. Multivariable logistic regression was used to determine the effect of renal dysfunction on outcome. Patients with different stages of renal dysfunction were further analyzed to determine the effect of disease severity on outcome. RESULTS: Of the 657 stroke patients with thrombolysis, 239 (36%) had renal dysfunction, including 212 patients in stage 3, 17 patients in stage 4 and 10 patients in stage 5 of renal dysfunction. Patients with renal dysfunction were older and more likely to have hypertension, ischemic heart disease, congestive heart failure and prior antiplatelet use than those without. There were no differences in SICH (8 vs. 7%, p = 0.580) and poor outcome (41 vs. 39%, p = 0.758) between patients with and without renal dysfunction. After multivariable analysis, renal dysfunction was not associated with SICH (odds ratio: 1.03, 95% confidence interval: 0.55-1.92) and poor outcome. Pretreatment stroke severity was the only factor significantly associated with both SICH and poor outcome at 3 months. When stratifying renal dysfunction into stage 3 and stage ≥4, there was no significant increase in SICH as the severity of renal dysfunction increased after multivariable adjustment. CONCLUSIONS: Renal dysfunction did not increase the risk of SICH and poor outcome at 3 months after stroke thrombolysis. Further study comparing directly the risk and benefit of thrombolytic therapy versus no therapy in stroke patients with renal dysfunction is warranted.

Development of an educational program for staffs of emergency medical service to improve their awareness of stroke within 3 hours of symptom onset: a pilot study.

PURPOSE: Timely identification and transport are crucial for the pre-hospital management of stroke by emergency medical service (EMS) providers. In this preliminary study, our aim was to develop an educational program which can improve 1) stroke knowledge and 2) triage accuracy of identifying acute stroke within 3 hours of symptom onset by dedicated EMS providers in Tainan city. METHODS: A total of 33 providers received a written test before, immediately after, and 3 months after completing the educational program, which was about stroke knowledge, diagnosis, and management. The test (total score, 39) contained three sections: two on stroke knowledge (consisting of true-false and choice questions) and one on clinical scenarios (situational descriptions and videos). RESULTS: The mean total score improved significantly immediately after the program. An increase in mean score was also noted for all three sections. The increase in total score lasted 3 months. The linear regression model showed greater improvement on scores correlated with lower pretest total score only, not correlated with age, gender, work year and the learning or working experience. CONCLUSION: The educational program increased knowledge about stroke and improved the accuracy of triage by dedicated EMS providers. Further investigation is needed to determine the effectiveness of similar educational programs for non-dedicated EMS responders.

Outcome of acute ischemic stroke in very elderly patients: is intravenous thrombolysis beneficial?

BACKGROUND/AIMS: Intravenous tissue plasminogen activator (tPA) treatment is recommended in acute stroke within 3 h of onset; however, the benefit of its use in the elderly remains uncertain. We assessed the safety and efficacy of tPA treatment in elderly patients. METHODS: We recruited 97 elderly Chinese patients aged ≥80 years with cerebral ischemia presenting within 3 h of onset. Favorable outcomes were defined as discharge to home and modified Rankin Scale (mRS) ≤2 at discharge. RESULTS: For moderate to severe patients (NIHSS ≥6), the baseline characteristics between the tPA (n = 30) and non-tPA (n = 41) group were not different. The proportion of patients discharged home was 56.7 and 61%, respectively (p = 0.72). For patients with baseline mRS ≤2, the frequency of discharged mRS ≤2 was not different (27.3% of the tPA group and 26.9% of the non-tPA group; p = 1.00). Symptomatic intracranial hemorrhage was 6.7 and 2.4%, respectively (p = 0.31). For minor stroke patients (NIHSS ≤5), tPA was not considered and the outcome of those discharged home and mRS ≤2 was 73 and 88%, respectively. CONCLUSION: Elderly patients can be treated safely with intravenous tPA, whereas our data did not support routine thrombolysis. Further randomized trials in the elderly are encouraged.