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Background: Although chronic kidney disease (CKD) is associated with worse stroke outcomes, data regarding the influence of CKD on intravenous thrombolysis outcomes are scarce. We sought to assess the efficacy and safety of intravenous thrombolysis for acute ischemic stroke with unknown onset time in patients with CKD. Methods: Patients with an acute stroke of unknown onset time from the EOS trials (Evaluation of Unknown Onset Stroke Thrombolysis) collaboration were evaluated using an individual patient-level database of randomized controlled trials comparing intravenous thrombolysis with placebo/standard treatment. CKD was defined as baseline estimated glomerular filtration rate of 2 Mixed-effect logistic-regression analysis was performed to evaluate treatment effects. A favorable outcome was defined as a modified Rankin Scale score of 0 to 1 at 90 days. Safety outcomes were symptomatic intracranial hemorrhage at 22 to 36 hours and 90-day mortality. Results: Baseline data on renal function were available for 688 of 843 patients. Of these, CKD was present in 146 (21%), including 69 of 351 patients receiving alteplase and 77 of 337 patients receiving placebo/standard treatment. Overall, treatment with alteplase was associated with higher odds of favorable outcome, and CKD did not modify the treatment effect ( P interaction =0.834). A favorable outcome was observed in 31 of 69 (46%) patients with CKD in the alteplase group and in 28 of 77 (36%) patients with CKD in the control group (adjusted odds ratio, 1.19 [95% CI, 0.55–2.58]). Among patients with CKD, symptomatic intracranial hemorrhage occurred in 2 patients (3%) in the alteplase group but in none of the controls ( P =0.133). At 90 days, death was reported in 3 patients (4%) in the alteplase group compared with 2 patients (3%) in the controls ( P =0.539). Conclusions: The present analysis indicates that the benefit of alteplase does not differ between stroke patients with unknown onset time with and without CKD, although the statistical power was lacking to confirm the efficacy in subgroups. This study only applies to mild-to-moderate or predialysis CKD.

Background: We evaluated the effect of persistent hyperglycemia on outcomes in 1000 patients with intracerebral hemorrhage enrolled within 4.5 hours of symptom onset. Methods: We defined moderate and severe hyperglycemia based on serum glucose levels ≥140 mg/dL— Results: In the multivariate analysis, both moderate (odds ratio, 1.8 [95% CI, 1.1–2.8]) and severe (odds ratio, 1.8 [95% CI, 1.2–2.7]) hyperglycemia were associated with higher 90-day death or disability after adjusting for Glasgow Coma Scale score, hematoma volume, presence or absence of intraventricular hemorrhage, hyperlipidemia, cigarette smoking, and hypertension (no interaction between hyperglycemia and preexisting diabetes, P =0.996). Among the patients without preexisting diabetes, both moderate (odds ratio, 1.8 [95% CI, 1.0–3.2]) and severe (odds ratio, 2.0 [95% CI, 1.1–3.7]) hyperglycemia were associated with 90-day death or disability after adjusting for above mentioned potential confounders. Among the patients with preexisting diabetes, moderate and severe hyperglycemia were not associated with 90-day death or disability. Conclusions: Persistent hyperglycemia, either moderate or severe, increased the risk of death or disability in nondiabetic patients with intracerebral hemorrhage. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01176565.

Both ischemic heart disease (IHD) and stroke are major causes of death worldwide. We investigated the effects of combined Traditional Chinese medicine (TCM) and western medicine (WM) on stroke risk in IHD patients.Taiwanese patients with IHD were enrolled in the TCM study during their outpatient visit. Stroke events after TCM or non-TCM treatment were examined. Chi-square tests and Student t-tests were used to examine differences between patients using and not using TCM. The Cox proportional hazards regression model was used to estimate hazard ratios (HRs). Sex, age, and comorbidities were included in a multivariable Cox model to estimate the adjusted HR (aHR). The survival probability and the probability free of stroke were calculated by the Kaplan-Meier method.There were 733 IHD patients using TCM and 733 using non-TCM treatment, with the same proportion of sex and age within each cohort. Using single Chinese herb such as Dan Shen, San Qi, or Chuan Xiong would have lower stroke events and lower aHR than non-TCM in IHD patients. There was 0.3-fold lower stroke risk in IHD patients with combination TCM and non-TCM treatment (95% CI = 0.11-0.84, P = .02). Moreover, the survival rate was higher (P < .001) and the incidence of hemorrhagic stroke was significantly lower (P = .04) in IHD patients with TCM treatment.IHD patients using combined TCM and WM had a higher survival rate and lower risk of new onset stroke, especially hemorrhagic stroke than those who did not use TCM treatment.

Objective: Smokers with stroke were reported to have a better survival than nonsmokers, and this phenomenon was labeled as “smoking paradox”. This study is to assess its validity from a national stroke registry data. Methods: A total of 88,925 cases of stroke registered in the nationwide stroke registry system of Taiwan between 2006 and 2016, with 4,169 deaths, were analyzed. Age-specific mortality rate for current, ex- and non-smokers were calculated. NIHSS score (National Institutes of Health Stroke Scale) was measured at 3 months and 6 months Cox model was used to compare complications, mortality and outcomes between smoker and non-smoker ground. Results: Smokers constituted more than half of the men (55%) but only 5% of the women. The median age for current smokers was 60.2, for nonsmokers, 71.6, and for ex-smokers, 72.5. Smokers, with nearly 12 years younger than nonsmokers, had smaller mortality rate at younger age groups with fewer deaths, but much larger mortality after age 60, and doubled the mortality rate at the largest group after age 70. Smokers, who quit early, had similar outcome as nonsmokers. When age was controlled, current smokers had worse functional outcome (NIHSS) even at 3 months (adjusted OR, 1.08; 95% CI, 1.02-1.14). Conclusion: Smokers, but not ex-smokers, developed stroke 12 years younger than nonsmokers, an ominous sign for smokers. They had higher age-specific mortality rate and poorer outcome than nonsmokers. Quitting early nearly reversed the harms. Smoking paradox does not exist.

Background: This study describes the availability and characteristics of databases in Asian-Pacific countries and assesses the feasibility of a distributed network approach in the region. Methods: A web-based survey was conducted among investigators using healthcare databases in the Asia-Pacific countries. Potential survey participants were identified through the Asian Pharmacoepidemiology Network. Results: Investigators from a total of 11 databases participated in the survey. Database sources included four nationwide claims databases from Japan, South Korea, and Taiwan; two nationwide electronic health records from Hong Kong and Singapore; a regional electronic health record from western China; two electronic health records from Thailand; and cancer and stroke registries from Taiwan. Conclusions: We identified 11 databases with capabilities for distributed network approaches. Many country-specific coding systems and terminologies have been already converted to international coding systems. The harmonization of health expenditure data is a major obstacle for future investigations attempting to evaluate issues related to medical costs.

Background: American Stroke Association has listed hypertension, smoking, diabetes, high cholesterol, physical inactivity and atrial fibrillation as the major risk factors for stroke. We developed a new model to predict stroke mortality using the 15-year prospective data of half a million adults in Taiwan. The model identified additional important risk factors. Method: In a health surveillance program conducted from 1994 to 2008, a cohort of 541,047 adults were recruited. Among them, we identified 18,296 deaths, including 946 deaths from Ischemic stroke and 597 deaths from hemorrhagic stroke. We developed a prediction model for stroke mortality, with the area under ROC curve of 0.921 for all stroke, of 0.949 for ischemic stroke or of 0.936 for hemorrhagic stroke. As many as 14 variables or confounders were controlled by Cox model in calculating hazard ratios (HR). Results: In addition to hypertension, smoking, diabetes, inactivity and high cholesterol, this prediction model revealed that chronic kidney disease (CKD), either proteinuria or low GFR, low total cholesterol (3 mg/dL), Aspartate Aminotransferase (AST) (≧40 IU/L), and uric acid (≧7 mg/dL) were also important risk factors associated with stroke deaths. In contrast, physical activity reduced mortality from total stroke by 29%, from ischemic stroke by 32% and from hemorrhagic stroke by 22%. Conclusion: In addition to commonly known risk factors, we identified from this Chinese population at least 6 additional risk factors for stroke: (1) CKD, either proteinuria or low GFR, (2) low total or HDL cholesterol, (3) rapid heart rate, (4) elevated CRP, (5) elevated AST and (6) elevated uric acid. Being physically active is a powerful modifier, which could reduce stroke mortality by one third. Primary prevention of stroke should extend our consideration to controlling these additional risk factors and encourage regular exercise.

Background Pulse pressure (PP) is related to cardiac function, arterial stiffness, fluid status, and vascular events. This study aimed to explore the prognostic role of PP upon admission in patients with acute ischemic stroke (AIS) based on a nation‐wide stroke registry. Methods and Results We evaluated the association between PP upon admission and outcomes 3 months after a stroke in patients who had an AIS registered in the Taiwan Stroke Registry, including 56 academic and community hospitals between 2006 and 2013. Three months after the stroke, unfavorable outcomes were defined using a modified Rankin scale of 3 to 6. Of 33 530 patients (female, 40.6%; mean age, 68.8±13.3 years) who had an AIS, PP upon admission had a reverse J‐curve association with an unfavorable outcome. After adjusting for clinical variables, including AIS subtypes, initial National Institutes of Health Stroke Scale, and systolic and diastolic blood pressure upon admission, a PP of P Conclusions Low PP upon admission was associated with unfavorable patient outcomes in AIS.

Background and Purpose— The study aimed to assess whether onset headache is an ominous sign in patients with first-ever ischemic stroke. Methods— A large population of ischemic stroke patients was obtained from the Taiwan Stroke Registry. Stroke subtypes were classified by the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) criteria. On the basis of the International Classification of Headache Disorders, second version, onset headache was defined as a new headache that developed at the onset of ischemic stroke. Clinical features and impact on stroke outcomes, including in-hospital stroke in evolution, changes in National Institutes of Health Stroke Scale on discharge, and Barthel index and modified Rankin scale ≤6 months after stroke were compared between those with and without onset headache. Results— Among 11 523 patients with first-ever ischemic stroke, 848 had onset headache (7.4%). Patients with specific cause, large-artery atherosclerosis, or cardioembolism were more likely to have onset headache. Patients with onset headache were younger, predominantly female, and more likely to have posterior circulation ischemic lesions. Compared with patients without onset headache, those with onset headache had a lower frequency of stroke in evolution (4.5% versus 6.7%; adjusted relative risk, 0.64; 95% confidence interval, 0.52–0.79), greater improvement in National Institutes of Health Stroke Scale score on discharge (0.08 versus −0.20; P =0.02), higher mean Barthel index scores (86.5±20.0 versus 83.9±23.3; adjusted difference, 1.43; 95% confidence interval, 0.28–2.89), and a lower frequency of modified Rankin scale higher than 2 (27.6% versus 31.5%; adjusted relative risk, 0.85; 95% confidence interval, 0.72–0.95) at 1-month follow-up. There was also a trend for better functional outcome in 3- and 6-month follow-ups. Conclusions— By adopting standard classification criteria, this large-scale study demonstrated that onset headache was associated with modest but significantly better outcomes after ischemic stroke.

Background / Purpose: Little is known about the role of receptor for advanced glycation end products (RAGE) -mediated signaling in the development of vascular cognitive impairment (VCI). The study aimed to investigate the associations of various RAGE signaling related plasma biomarkers and the development of VCI in chronic ischemic stroke (IS) patients. Methods: This cross-sectional study recruited patients with IS at an university medical center stroke clinic. VCI was defined as the scale of Clinical Dementia Ranking (CDR) ≥1. Standard enzyme-linked immunosorbent assay was used to measure the plasma concentration of soluble form of RAGE (sRAGE), endogenous soluble form of RAGE (esRAGE), high mobility group box 1 (HMGB1) and matrix metallopeptidase 9 (MMP9) in IS patients with and without VCI. Results: Between November 2014 to October 2015, a total of 172 IS patients (mean age 72.1±7.5 years, 64.5% male) were recruited, including 73 with CDR=0, 63 with CDR=0.5 and 36 with CDR ≥1. In univariate analysis, IS patients with VCI were older, and had more diabetes mellitus, fewer atrial fibrillation, and higher post-stroke modified Rankin Scales than those without. Plasma levels of sRAGE and esRAGE, but not HMGB1 or MMP9 were significantly higher in IS patients with VCI than those without (1.44±1.29 versus 1.03±0.48 and 0.39±0.40 versus 0.24±0.13 ng/ml, both p Conclusion: Among IS patients, plasma levels of both sRAGE and esRAGE were elevated in those with VCI.

Background / Purpose: Pulse pressure (PP) is related to cardiac function, arterial stiffness, fluid status and vascular events. The impact of PP on stroke outcome remains to be delineated. The present study aimed to explore the prognostic role of admission PP in patients with acute ischemic stroke (AIS) based on a nationwide stroke registry. Methods: We evaluated the association between PP on admission and outcome at 3 months after stroke in AIS patients registered in the Taiwan Stroke Registry, including 56 academic and community hospitals, during 2006~2013.Unfavorable outcome was defined as modified Rankin Scale of 3~6 at 3 months after stroke. Results: Of 33,530 patients (female, 40.6%; mean age, 68.8±13.3 years) with AIS, PP on admission had a “reversed J-curve” association with unfavorable outcome. After adjustment for clinical variables including AIS subtypes, initial National Institutes of Health Stroke Scale, systolic and diastolic blood pressure on admission, PP Conclusion: Low PP on admission carries an unfavorable outcome in patients with AIS.

The association between tamoxifen use and risk of deep vein thrombosis or pulmonary embolism in women with breast cancer has been reported in the Western population. The study aimed to evaluate the association between tamoxifen use and deep vein thrombosis or pulmonary embolism in older women with breast cancer in Taiwan.We conducted a retrospective case-control study using the database of the Taiwan National Health Insurance Program. A total of 281 women subjects with breast cancer aged ≥65 years with newly diagnosed deep vein thrombosis/or pulmonary embolism from 2000 to 2011 were identified as the cases. Additionally, 907 women subjects with breast cancer aged ≥65 years without deep vein thrombosis or pulmonary embolism were randomly selected as the controls. The cases and the controls were matched with age and comorbidities. Ever use of tamoxifen was defined as subjects who had at least a prescription for tamoxifen before index date. Never use of tamoxifen was defined as subjects who never had a prescription for tamoxifen before index date. We used the multivariable logistic regression model to calculate the odds ratio (OR) and the 95% confidence interval (CI) of deep vein thrombosis or pulmonary embolism associated with tamoxifen use.After adjustment for confounding variables, the adjusted OR of deep vein thrombosis or pulmonary embolism was 1.95 for subjects with ever use of tamoxifen (95% CI 1.45, 2.62), as compared with never use of tamoxifen. In addition, atrial fibrillation (adjusted OR 3.73, 95% CI 1.89, 7.35) and chronic kidney disease (adjusted OR 1.72, 95% CI 1.06, 2.80) were also associated with deep vein thrombosis or pulmonary embolism.Tamoxifen use is associated with 1.95-fold increased odds of deep vein thrombosis or pulmonary embolism among older women with breast cancer in Taiwan.

Background— Stroke is a leading cause of death around the world. Improving the quality of stroke care is a global priority, despite the diverse healthcare economies across nations. The American Heart Association/American Stroke Association Get With the Guidelines-Stroke program (GWTG-Stroke) has improved the quality of stroke care in 790 US academic and community hospitals, with broad implications for the rest of the country. The generalizability of GWTG-Stroke across national and economic boundaries remains to be tested. The Taiwan Stroke Registry, with 30 599 stroke admissions between 2006 and 2008, was used to assess the applicability of GWTG-Stroke in Taiwan, which spends ≈1/10 of what the United States does in medical costs per new or recurrent stroke. Methods and Results— Taiwan Stroke Registry, sponsored by the Taiwan Department of Health, engages 39 academic and community hospitals and covers the entire country with 4 steps of quality control to ensure the reliability of entered data. Five GWTG-Stroke performance measures and 1 safety indicator are applicable to assess Taiwan Stroke Registry quality of stroke care. Demographic and outcome figures are comparable between GWTG-Stroke and Taiwan Stroke Registry. Two indicators (early and discharge antithrombotics) are close to GWTG-Stroke standards, while 3 other indicators (intravenous tissue plasminogen activator, anticoagulation for atrial fibrillation, lipid-lowering medication) and 1 safety indicator fall behind. Preliminary analysis shows that compliance with selected GWTG-Stroke guidelines is associated with better outcomes. Conclusions— Results suggest that GWTG-Stroke performance measures, with modification for ethnic factors, can become global standards across national and economic boundaries for assessing and improving quality of stroke care and outcomes. GWTG-Stroke can be incorporated into ongoing stroke registries across nations.

Hysterectomy is a common procedure for benign pathologies of the uterus. Reduced production of estrogen following hysterectomy has been reported. Yet the association between hysterectomy and coronary artery disease (CAD) risk remains controversial. The aim of this study was to investigate the effect of hysterectomy on the risk of CAD; calculations were adjusted for traditional risk factors. This study used a 1 million patient cohort of the Taiwan National Health Insurance database and included a total of 7331 women who received hysterectomy from 2000 to 2013. We randomly selected a control group composed of 29,324 women without hysterectomy by 1:4 matching the age (exact year) with the hysterectomy group. The mean (standard deviation) age was 43.5 ± 4.0 in the hysterectomy and 43.6 ± 4.0 in the control group. A total of 1986 CAD cases developed in both groups during a median follow-up of 7 years. Significant differences were observed in CAD incidence in the hysterectomy versus control group (9.82 vs. 7.17/1000 person-years, P

Background: EXTEND is an investigator-initiated, randomised, double-blind and placebo-controlled Phase III trial of intravenous alteplase vs placebo in patients with ischemic stroke 4.5-9 hours from stroke onset or wake-up-stroke (WUS). The prevalence of intra-cranial vessel occlusion in WUS patients remains to be determined and can guide the development of optimal therapy for this unique group of stroke patients. Objective: To study the prevalence and characteristics of intra-cranial vessel occlusion in this WUS cohort. Methods: Ischemic stroke patients within 4.5-9 hours from stroke onset or with WUS (time of WUS onset defined as the midpoint between time to sleep and awakening with the stroke symptoms) are eligible for enrollment. Criteria for entry into the trial include perfusion-diffusion mismatch using a perfusion threshold of Tmax>6sec and a perfusion:diffusion lesion volume ratio of >1.2. Diffusion lesion volume must be Results: 97 patients had images with adequate quality, including 63 (65%) in the WUS group with median age of 77.0 yrs (IQR 67.0, 81.0) and NIHSS of 14.0 (9.0, 19.0). 62 of 63 patients (98%) had vessel occlusion with 44.4% involving M1 of the middle cerebral artery, 17.5% M2, 4.8% M3, 25.4% both internal carotid artery (ICA) and M1, 4.8% ICA alone and 3.1% the posterior cerebral artery. The median ischemic core volume was 15.0 ml (6.5, 31.5), Tmax>6 volume 88.5ml (58.0, 122.0), mismatch volume 65.5ml (42.8, 92.0), and ratio of 4.8 (2.5, 8.7). 19 patients (30%) demonstrated recanalization on follow-up imaging. Conclusion: In WUS patients there is a very high rate of intracranial vessel occlusion with relatively large volumes of salvageable penumbral tissue. Intravenous thrombolytic therapy followed by thrombectomy in selected cases may be an appropriate therapeutic option with safety and efficacy remaining to be established in randomized controlled trials.

Stroke incidence and mortality are disproportionately higher among African Americans than among whites.To describe the recurrent stroke characteristics and determine the predictability of known vascular risk factors for stroke recurrence in African Americans.The authors followed 1,809 African Americans in the African-American Antiplatelet Stroke Prevention Study with recent noncardioembolic ischemic stroke for recurrent stroke, recurrent stroke subtype, and disability.Of the subjects, 10.6% experienced a recurrent stroke during follow-up. The mean interval between eligibility and recurrent stroke was 325 days (median 287 days, SD = 224 days). Stroke recurrence resulted in an average 1.5-point increase in the National Institute of Health Stroke Scale (p0.001) and a 3.5-point decrease in modified Barthel Index (p0.001). Of previously nondisabled subjects, 48% became disabled or died after stroke recurrence (p0.0001). Longitudinal analysis resulted in a hazard for recurrent stroke for each 10-mm Hg increase in systolic blood pressure of 1.103 (95% CI: 1.031 to 1.179, p = 0.004), pulse pressure 1.123 (95% CI: 1.041 to 1.213, p = 0.003), and mean arterial pressure 1.123 (95% CI: 1.001 to 1.260, p = 0.048). Multivariate analysis revealed increases in the recurrent stroke hazard for increases in baseline Glasgow Outcome Score (1.449, 95% CI: 1.071 to 1.961, p = 0.016) and increases in longitudinal pulse pressure (1.009, 95% CI: 1.001 to 1.017, p = 0.029).Recurrent stroke leads to disability and disability predicts recurrent stroke. Hypertension is the most predictive modifiable stroke risk factor.

Background and Purpose— Diffusion-weighted imaging (DWI) has been established as a marker of acute ischemic brain injury. We sought to determine the relationship between cerebral blood flow (CBF) and apparent diffusion coefficient (ADC) and to explore whether the elapsed time between MRI acquisition and symptom onset alters this relation in acute stroke patients. Methods— Sixteen acute stroke patients were studied with DWI and perfusion-weighted imaging, from which ADC and CBF were calculated. ADC values were normalized (nADC) to the contralateral, nonischemic hemisphere and then correlated pixel by pixel with CBF within a region of interest defined by abnormal transit time. To explore potential temporal effects on the relationship between CBF and nADC, patients were divided into 2 groups based on the duration between symptom onset and MR imaging for data analysis: group A, 2 to 4 hours (n=8), and group B, 4.5 to 6.5 hours (n=8). Results— nADC was plotted against CBF for each pixel in all 16 subjects, and a composite relationship was derived. After a gradual decline, an abrupt drop in nADC occurred below a CBF threshold value of 21 mL · min −1 · 100 g −1 . When subjects were divided into early and late imaging groups, the group of patients imaged earlier (group A) had a lower threshold (15 mL · min −1 · 100 g −1 ) than the group imaged later (group B, 24 mL · min −1 · 100 g −1 ). Conclusions— Our results demonstrate that a relationship between nADC and CBF exists in the ischemic brain and that ADC values alone may provide useful information in predicting perfusion status. However, this relationship may change with elapsing time between stroke onset and imaging.

No study has investigated the role of pancreatic cancer in the stroke risk using population data. We used claims data obtained from a universal health insurance program of Taiwan to evaluate the stroke risk in pancreatic cancer patients.From the catastrophic disease registry of the insurance, we identified 7479 patients with pancreatic malignancy without stroke history from 2000 to 2009. The comparison cohort consisted of 29,916 individuals identified from 1 million insured people without cancer and stroke history, matching with the cancer cohort by propensity score. We followed each selected individual until stroke was diagnosed or until being censored for death or withdrawal from insurance, or for a maximum of 3 follow-up years, or the end of 2011.The pancreatic cancer cohort had a 2.3-fold greater incident stroke than comparisons had (28.5 vs 12.3 per 1000 person-years), with an adjusted hazard ratio (aHR) of 2.74 (95% confidence interval (CI) = 2.31-3.24) after controlling for covariates, or a subdistribution hazard ratio (SHR) of 2.04 (95% CI = 1.74-2.40) accounting for the competing risk of deaths. During the follow-up period, stroke events occurred constantly in comparisons, but declined rapidly in the cancer cohort. The pancreatic cancer cohort had a stroke incidence of 46.6 per 1000 person-years within 6 months postdiagnosis, with an aHR of 4.37 (95% CI = 3.45-5.54) and a SHR of 3.87 (95% CI = 3.08-4.86), relative to comparisons.Our study suggests that patients with pancreatic cancer are at an elevated risk of stroke, patients deserve sufficient follow-up care, particularly in the first 6 months after the diagnosis of the cancer, and for those with comorbidities.

Objective: To review the risk of MS exacerbations after infectious episodes potentially preventable by vaccination, and the risks and benefits of immunizing patients with MS. Methods: The authors searched MEDLINE (1966 to January 2001; U.S. National Library of Medicine, Bethesda, MD), HealthSTAR, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) database (Cinahl Information Systems, Glendale, CA) for English-language articles. Each study was summarized and rated for quality of evidence. Then feasible data were pooled and analyzed in meta-analysis. Results: The risk of contracting common infectious diseases in patients with MS is not well established. There is strong evidence for an increased risk of MS exacerbations during weeks around an infectious episode. There is strong evidence against an increased risk of MS exacerbation after influenza immunization. There is no evidence that hepatitis B, varicella, tetanus, or Bacille Calmette–Guerin vaccines increase the risk of MS exacerbations. Insufficient evidence was found for other vaccines. Conclusions: Evidence supports 1) strategies to minimize the risk of acquiring infectious diseases that may trigger exacerbations of MS; and 2) the safety of using influenza, hepatitis B, varicella, tetanus, and Bacille Calmette–Guerin (BCG) vaccines in patients with MS.

Background and Purpose— Cells lacking the ATM (ataxia telangectasia mutated) gene are hypersensitive to DNA damage caused by a variety of insults. ATM may regulate oxidative stress–induced signaling cascades involving nuclear factor-κB (NF-κB), a transcription factor that is upstream of a wide variety of stress-responsive genes. We investigated the potential interaction of ATM and NF-κB after oxygen-glucose deprivation (OGD) in cerebral endothelial cells (CECs). Methods— Primary cultures of mouse CECs were subjected to OGD in the absence or presence of ATM antisense oligonucleotides or the NF-κB inhibitor SN50. ATM expression was determined with the use of reverse transcription–polymerase chain reaction and Western blot, and NF-κB activity was assessed by electrophoretic mobility shift assay. Cells were assessed for mitochondrial DNA damage with the use of long polymerase chain reaction and were assessed for caspase-3 and caspase-8 activity with the use of fluorogenic substrates. Cell death was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide and LDH release. Results— OGD stimulated ATM gene expression at the mRNA and protein level in CECs as early as 1 hour after OGD initiation. ATM gene knockdown with the use of an antisense oligonucleotide suppressed OGD-induced ATM protein expression, which was accompanied by an attenuation of NF-κB activation and the subsequent expression of downstream genes, including the antiapoptotic gene c-IAP2. ATM knockdown also accentuated OGD-induced mitochondrial DNA damage and the activation of caspase-3 and caspase-8, leading to enhanced CEC death. The specific NF-κB inhibitor SN50 mimicked the effects of ATM knockdown. Conclusions— We conclude that ATM may play a cytoprotective role in OGD-induced CEC death via a NF-κB–dependent signaling pathway.

Background and Purpose —The early ischemic lesions demonstrated by diffusion-weighted imaging (DWI) are potentially reversible. The purposes of this study were to determine whether resolution of initial DWI lesions is transient or permanent after different brief periods of focal brain ischemia and to evaluate histological outcomes. Methods —Sixteen rats were subjected to 10 minutes (n=7) or 30 minutes (n=7) of temporary middle cerebral artery occlusion or sham operation (n=2). DWI, perfusion-weighted imaging (PWI), and T 2 -weighted imaging (T 2 WI) were performed during occlusion; immediately after reperfusion; and at 0.5, 1.0, 1.5, 12, 24, 48, and 72 hours after reperfusion. After the last MRI study, the brains were fixed, sectioned, stained with hematoxylin and eosin, and evaluated for neuronal necrosis. Results —No MRI or histological abnormalities were observed in the sham-operated rats. In both the 10-minute and 30-minute groups, the perfusion deficits and DWI hyperintensities that occurred during occlusion disappeared shortly after reperfusion. The DWI, PWI, and T 2 WI results remained normal thereafter in the 10-minute group, whereas secondary DWI hyperintensity and T 2 WI abnormalities developed at the 12-hour observation point in the 30-minute group. Histological examinations demonstrated neuronal necrosis in both groups, but the number of necrotic neurons was significantly higher in the 30-minute group (95±4%) than in the 10-minute group (17±10%, P Conclusions —Transient or permanent resolution of initial DWI lesions depends on the duration of ischemia. Transient resolution of DWI lesions is associated with widespread neuronal necrosis; moreover, permanent resolution of DWI lesions does not necessarily indicate complete salvage of brain tissue from ischemic injury.

Background and Purpose —We sought to determine predictors of acute hospital costs in patients presenting with acute ischemic stroke to an academic center using a stroke management team to coordinate care. Methods —Demographic and clinical data were prospectively collected on 191 patients consecutively admitted with acute ischemic stroke. Patients were classified by insurance status, premorbid modified Rankin scale, stroke location, stroke severity (National Institutes of Health Stroke Scale score), and presence of comorbidities. Detailed hospital charge data were converted to cost by application of department-specific cost-to-charge ratios. Physician’s fees were not included. A stepwise multiple regression analysis was computed to determine the predictors of total hospital cost. Results —Median length of stay was 6 days (range, 1 to 63 days), and mortality was 3%. Median hospital cost per discharge was $4408 (range, $1199 to $59 799). Fifty percent of costs were for room charges, 19% for stroke evaluation, 21% for medical management, and 7% for acute rehabilitation therapies. Sixteen percent were admitted to an intensive care unit. Length of stay accounted for 43% of the variance in total cost. Other independent predictors of cost included stroke severity, heparin treatment, atrial fibrillation, male sex, ischemic cardiac disease, and premorbid functional status. Conclusions —We conclude that the major predictors of acute hospital costs of stroke in this environment are length of stay, stroke severity, cardiac disease, male sex, and use of heparin. Room charges accounted for the majority of costs, and attempts to reduce the cost of stroke evaluation would be of marginal value. Efforts to reduce acute costs should be monitored for potential cost shifting or a negative impact on quality of care.

Background and Purpose— Stroke-prone spontaneous hypertensive rats (SHRsp) fed a high-salt diet develop malignant hypertension, blood–brain barrier breakdown, and spontaneous intracerebral hemorrhage (ICH). The precise spatial and temporal relationship between these events has not been well-delineated. Methods— Ten SHRsp male rats, fed a high-salt diet, were imaged weekly using MRI, starting at 12 weeks of age. T1-weighted (with and without Gd), T2-weighted, and T2* sequences were acquired. Permeability maps were calculated. Results— Seven SHRsp rats had spontaneous ICH develop before death. Five of the 7 rats had focally increased vascular permeability at the site of the ICH; 3 of these rats had vascular permeability 1 to 2 weeks before spontaneous ICH. Conclusions— Salt-loaded SHRsp rats have increased vascular permeability up to 2 weeks before ICH, predicting hemorrhage both in space and time. These results suggest that hypertensive ICH is preceded by focal vasculopathy detectable by Gd leak.

Background and Purpose: Ischemic stroke often co-exists with peripheral arterial disease (PAD). Patients with polyvascular diseases carry higher risks of vascular events and death. We initiated a study to evaluate the safety and efficacy of cilostazol in ischemic Stroke patients with PAD (SPAD) and have been taking aspirin for stroke prevention. Methods: The SPAD study is a prospective, multicenter, national, double-blinded, placebo-controlled, randomized trial. Patients with previous ischemic stroke or TIA who have been taking aspirin (100 mg per day), aged 50 years or older, with PAD in the lower limbs based on ankle-brachial index (ABI) Results: From September, 2010 to July, 2012, a total of 800 patients (male, 59.9%; female, 40.1%; average age, 70.4±9.3 years) were enrolled in the SPAD study, including 722 (90.2%) with ischemic stroke or 78 (9.8%) with TIA. Several atherosclerotic risk factors were commonly seen in this study population, including hypertension (88%), diabetes mellitus (48%), hypercholesterolemia (54%), smoking habit (41%), and carotid stenosis (15%). The distribution of baseline ABI were 0.90-0.99 (n=294), 0.70-0.89 (n=371), and Conclusions: The SPAD trial is the first study to evaluate the safety and efficacy of dual antiplatelets, aspirin plus cilostazol, in ischemic stroke patients with PAD. The trial findings are expected to help in choosing better strategy for prevention of vascular events in this polyvascular disease.

Background and Purpose After spinal cord ischemia, some neurons remain viable after an ischemic insult but may be at risk of dying during reperfusion. We searched for morphological and biochemical features of apoptosis, which is a mechanism of delayed neuronal death, in a rabbit model of spinal cord ischemia. Methods The infrarenal aorta of White New Zealand rabbits (n=24) was occluded for 40 minutes using a loop tourniquet. Rabbits were killed after 12, 24, or 48 hours (n=8 per group). The loop was placed but never tightened in sham-operated rabbits (n=6). The lumbar segment of the spinal cord (L5 to L7) was used for morphological studies, including hematoxylin and eosin staining and a modified terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end-labeling (TUNEL) staining method. Electron microscopy was used to examine ultrastructural morphology. In addition, lumbar tissue was used for biochemical investigation of DNA laddering by agarose gel electrophoresis. Results After ischemia, the affected areas contained neurons with positive TUNEL staining. Positive neurons were located in laminae III to IX, although most were concentrated in the intermediate and ventral areas. Adjacent sections stained with hematoxylin and eosin exhibited ischemic cell changes (red and ghost neurons), while apoptotic bodies were also apparent. In addition, electron microscopy of ischemic tissue samples exhibited ultrastructural characteristics of apoptosis, including nuclear condensation and relatively normal organelle morphology. Finally, isolated DNA revealed a ladder on agarose gel electrophoresis, indicating DNA fragmentation into ≈180 multiples of base pairs. Conclusions Spinal cord ischemia in rabbits induces morphological and biochemical changes suggestive of apoptosis. These data raise the possibility that apoptosis contributes to neuronal cell death after spinal cord ischemia.

Background and Purpose Repeated use of mannitol in the setting of ischemic infarction is a controversial and poorly defined therapeutic intervention. The purpose of this study was to examine the effects of repeated mannitol infusions on brain water content and tissue pressure in a well-defined rat model of focal ischemic stroke. Methods Mannitol infusions (0.5, 1.5, or 2.5 g/kg) were given by intravenous bolus 4 or 24 hours after 90-minute transient cortical ischemia in the territory of the right middle cerebral artery in rats and every 4 hours thereafter for a total of 24 hours. Fluid replacement was limited to 0.5 mL IV isotonic saline administered immediately after each mannitol dose. Control rats received 0.5 mL IV saline at the same intervals and were otherwise under ad libitum conditions. Water contents (percent H 2 O) of whole hemispheres and of cortical biopsies were measured with the wet-dry method, and blood samples were analyzed for plasma osmolality and chemistries. In a subgroup of rats, tissue pressure was also measured within the hemisphere ipsilateral to the infarct. Results Repeated mannitol infusions resulted in a dose-dependent increase in plasma osmolality and a dose-dependent decrease in the percent H 2 O of the ischemic middle cerebral artery cortex and ipsilateral hemisphere. In contrast, percent H 2 O of the contralateral cortex and hemisphere was significantly decreased only in the groups given the highest dose of mannitol (2.5 g/kg). Mannitol infusions at a dose of 1.5 g/kg begun 24 hours after reperfusion were also associated with a significant reduction of tissue pressure. Conclusions In a rat model of ischemic cortical infarction, repeated mannitol infusions resulted primarily in a decrease in the percent H 2 O of the infarct and ipsilateral hemisphere, as well as decreased tissue pressure.

Background and Purpose DNA damage and repair are areas of research with important implications for stroke and cerebral trauma. DNA damage is present in central nervous system (CNS) injury, and defects in repair mechanisms are associated with neurodegenerative disease. Methods A workshop, DNA Damage and Repair in CNS Injury , was organized by the National Institute of Neurological Disorders and Stroke in Bethesda, Md, on September 11, 1995. The objective of this workshop was to promote inquiry and to foster application of research in DNA damage and repair after stroke and trauma. Results The participants discussed the connection between the fields of DNA damage and repair and stroke and trauma and identified gaps in knowledge to be filled to expand research of DNA damage and repair in CNS injury. Specific recommendations were made targeting research opportunities in the areas of DNA repair and damage in stroke and trauma. Conclusions Research in the science of DNA injury and repair will likely provide new and important information on mechanisms of cell damage and provide opportunities for the development of novel and effective therapies to reduce CNS injury in stroke and trauma.

Dermatologic diseases are not traditional risk factors of stroke, but recent studies show atopic dermatitis, psoriasis, and bullous skin disease may increase the risk of stroke and other cardiovascular diseases. No previous studies have focused on the association between contact dermatitis and stroke.We established a cohort comprised of 48,169 contact dermatitis patients newly diagnosed in 2000-2003 and 96,338 randomly selected subjects without the disorder, frequency matched by sex, age, and diagnosis year, as the comparison cohort. None of them had a history of stroke. Stroke incidence was assessed by the end of 2011 for both cohorts.The incidence stroke was 1.1-fold higher in the contact dermatitis cohort than in the comparison cohort (5.93 vs 5.37 per 1000 person-years, P < 0.01). The multivariable Cox method analyzed adjusted hazard ratios (aHRs) were 1.12 (95% confidence interval [CI], 1.05-1.19) for all stroke types and 1.12 (95% CI, 1.05-1.20) for ischemic stroke and 1.11 (95% CI, 0.94-1.30) for hemorrhagic stroke. The age-specific aHR of stroke for contact dermatitis cohort increased with age, from 1.14 (95% CI, 1.03-1.27) for 65 to 74 years; to 1.27 (95% CI, 1.15-1.42) for 75 years and older. The aHR of stroke were 1.16 (95% CI, 1.07-1.27) and 1.09 (95% CI, 1.00-1.18) for men and women, respectively.This study suggests that patients with contact dermatitis were at a modestly increased risk of stroke, significant for ischemic stroke but not for hemorrhagic stroke. Comorbidity, particularly hypertension, increased the hazard of stroke further.

Vagus nerve may play a role in serum glucose modulation. The complicated peptic ulcer patients (with perforation or/and bleeding) who received surgical procedures with or without vagotomy provided 2 patient populations for studying the impact of vagus nerve integrity. We assessed the risk of developing type 2 diabetes in peptic ulcer patients without and with complications by surgical treatment received in a retrospective population study using the National Health Insurance database in Taiwan.A cohort of 163,385 patients with peptic ulcer and without Helicobacter pylori infection in 2000 to 2003 was established. A randomly selected cohort of 163,385 persons without peptic ulcer matched by age, sex, hypertension, hyperlipidemia, Charlson comorbidity index score, and index year was utilized for comparison. The risks of developing diabetes in both cohorts and in the complicated peptic ulcer patients who received truncal vagotomy or simple suture/hemostasis (SSH) were assessed at the end of 2011.The overall diabetes incidence was higher in patients with peptic ulcer than those without peptic ulcer (15.87 vs 12.60 per 1000 person-years) by an adjusted hazard ratio (aHR) of 1.43 (95% confidence interval [CI] = 1.40-1.47) based on the multivariable Cox proportional hazards regression analysis (competing risk). Comparing ulcer patients with truncal vagotomy and SSH or those without surgical treatment, the aHR was the lowest in the vagotomy group (0.48, 95% CI = 0.41-0.56).Peptic ulcer patients have an elevated risk of developing type 2 diabetes. Moreover, there were associations of vagus nerve severance and decreased risk of subsequent type 2 diabetes in complicated peptic ulcer patients.

The results of large-scale clinical trials of hemodilution therapy and vasodilators for acute stroke have been disappointing. However, interventions involving the manipulation of whole blood viscosity, blood oxygen-carrying capacity, cardiac output, and the resistance properties of cerebral vessels are viable therapeutic modalities currently being investigated. The central aim of all of these therapies is the timely improvement of perfusion and substrate delivery to ischemic brain regions. Better understanding of cerebrovascular flow regulation and the physiology of microvessels may give rise to more effective therapies. In the past, overemphasis on hematocrit reduction and cerebral vasodilators has obscured the potential risks of reducing blood oxygen content and vascular resistance during acute stroke and the importance of optimizing oxygen delivery by other means, in particular by cardiac output augmentation and manipulation of plasma properties. A broader approach to therapeutic strategies for acute stroke includes not only increasing cerebral blood flow, but also interventions that will create favorable changes in the humoral microenvironment and promote overall substrate delivery to the brain.

Infarct volume is one of the common indexes for assessing the extent of ischemic brain injury following focal cerebral ischemia. Accuracy in the measurement of infarct volume is compounded by postischemic brain edema that may increase brain volume in the infarcted region. We evaluated the effect of brain edema on infarct volume determined by triphenyltetrazolium chloride and hematoxylin and eosin stains in a focal cerebral ischemia model in rats. In a middle cerebral artery occlusion model in rats, infarction is confined to the cerebral cortex. The infarct was delineated by triphenyltetrazolium chloride stain and, in selected samples, by hematoxylin and eosin stain. We determined infarct size at different times after the ischemic insult (6 hours to 7 days) in relation to the evolution of brain edema by the direct measurement of infarct volume. Indirect measurement to reduce the effect of edema on infarct volume was also conducted in the same brain samples. Direct measurement showed that infarct volume fluctuated with the evolution of brain edema (one-way analysis of variance, p < 0.0001). Infarct volume determined by indirect measurement was independent of the extent of brain edema and remained stable from 6 hours to 3 days after ischemia. There was a good correlation between triphenyltetrazolium chloride and hematoxylin and eosin stains in delineating infarct volume with both direct and indirect measurement. Traditional direct measurement of infarct volume is associated with an overestimation of infarct volume during the development of brain edema in the first 3 days after ischemia. This artifact can be reduced with indirect measurement, which is based on noninfarcted cortex volume.

Using a rat model of stroke, we examined the effects of focal cerebral ischemia on the metabolism of polyphosphoinositides by injecting 32Pi into both the left and right cortices. After equilibration of the label for 2-3 hours, ischemia induced a significant decrease (p less than 0.001) in the concentrations of labeled phosphatidyl 4,5-bisphosphates (66-78%) and phosphatidylinositol 4-phosphate (64-67%) in the right middle cerebral artery cortex of four rats. The phospholipid labeling pattern in the left middle cerebral artery cortex, which sustained only mild ischemia and no permanent tissue damage, was not different from that of two sham-operated controls. However, when 32Pi was injected 1 hour after the ischemic insult, there was a significant decrease (p less than 0.01) in the incorporation of label into the phospholipids in both cortices of four ischemic rats compared with four sham-operated controls. Furthermore, differences in the phospholipid labeling pattern were observed in the left cortex compared with the sham-operated controls. The change in labeling pattern was attributed to the partial reduction in blood flow following ligation of the common carotid arteries. We provide a sensitive procedure for probing the effects of focal cerebral ischemia on the polyphosphoinositide signaling pathway in the brain, which may play an important role in the pathogenesis of tissue injury.

Rheumatoid arthritis (RA), a chronic, systemic inflammatory disorder, primarily affects joints. Several studies have indicated that early inflammation, cardiovascular disease, and depression in patients were associated with a considerably increased risk of dementia. Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used for treating RA. NSAIDs facilitate alleviating RA-associated chronic pain, inflammation, and swelling. Therefore, we conducted this nationwide study for evaluating the association between the dementia risk and NSAID treatment in patients with RA. The RA cohort comprised patients aged 20 years and older who were newly diagnosed with RA between 2000 and 2011, with data obtained from the Registry of Catastrophic Illnesses Patient Database (RCIPD). Patients without RA were frequency matched with the RA cohort at a 1:4 ratio according to age, sex, and year of RA diagnosis. The relative risks of dementia were estimated using Cox proportional hazard models. The risk of dementia in the RA cohort was not significantly higher than that in the non-RA cohort (adjusted HR [hazard ratio] = 0.95, 95% confidence interval [CI] = 0.87–1.02). Regarding the duration of NSAID treatment, the risk of dementia was significantly lower when the RA cohort used NSAIDs for >2191 days (HR = 0.56, 95% CI = 0.45–0.68). A longer duration of NSAID treatment possibly reduces the risk of dementia. Additional studies are warranted for verifying the association of dementia risk with NSAID treatment in patients with RA.

Whether patients with diverticular diseases exhibit a higher risk of developing pyogenic liver abscess (PLA) remains inconclusive.From the inpatient claims in Taiwan's National Health Insurance Research Database, we identified 54,147 patients diagnosed with diverticulosis in the 1998 to 2010 period and 216,588 controls without the disorder. The 2 cohorts were matched by age, sex, and admission year, and were followed up until the end of 2010 to estimate the risk of PLA.Overall, the incidence of PLA was 2.44-fold higher in the diverticular-disease group than in the controls (11.5 vs 4.65 per 10,000 person-year). The adjusted hazard ratio (aHR) of PLA was 2.11 (95% confidence interval [CI], 1.81-2.44) for the diverticular-disease group, according to a multivariate Cox proportional hazards regression model. The age-specific data showed that the aHR for the diverticular-disease group, compared with the controls, was the highest inpatients younger than 50 years old (aHR, 4.03; 95% CI, 2.77-5.85). Further analysis showed that the diverticular-disease group exhibited an elevated risk of PLA regardless of whether patients had diverticulitis.The patients with diverticular diseases exhibited a higher risk of PLA.

Previous studies indicated that gout is a risk factor of cardiovascular diseases. This study aimed to determine if patients with gout have an increased risk of deep vein thrombosis (DVT) or pulmonary embolism (PE).We used the Longitudinal Health Insurance Database, a subset of the national insurance claim dataset, which enrolled 1 million Taiwanese to identify 57,981 patients with gout and 115,961 reference subjects matched by sex, age, and entry date of diagnosis. The risk of DVT and PE was analyzed using the Cox proportional hazards model.In this Taiwanese dataset observed from 2000 to 2010, we found the incidence of DVT was 5.26 per 10 person-years in the gout cohort, which was twofold higher than the incidence of 2.63 per 10 person-years in the reference cohort. After adjusting for age, sex, and 9 comorbidities, the hazard ratio (HR) of developing DVT was 1.66 (95% confidence interval [CI] = 1.37-2.01). Among patients with gout, the youngest age group had the highest increase in the risk of developing DVT (HR [95% CI] = 2.04 [1.24-3.37] for ages 20 to 49 years, 1.80 [1.28-2.51] for ages 50 to 64 years, and 1.45 [1.11-1.91] for ages ≥65 years). The incidence of PE was about one-fifth that of DVT in gout patients, but the effect of gout on the risk was similar (HR [95% CI] = 1.53 [1.01-2.29]).Our analysis confirmed that gout increased the risk of DVT and PE. Further exploration is needed in the future.

The aim of this study was to elucidate the relationship between spinal cord injury (SCI) and the risk of peripheral arterial disease (PAD) in a cohort study with a large representative sample. The National Health Insurance Database was used to select patients who were diagnosed from 2000 to 2010. Patients with a history of PAD were excluded. The SCI group comprised 42,673 patients diagnosed with SCI, and we enrolled 170,389 matched controls (non-SCI group). We used a Cox proportional hazards regression model to analyze the adjusted risk of PAD between the case and control patients. Patients with SCI exhibited a significantly higher risk (hazard ratio [HR] = 1.37; 95% confidence interval [CI] = 1.22–1.53) of PAD than patients without SCI. Patients with diabetes were at the highest risk of developing PAD (adjusted HR = 3.11, 95% CI = 2.80–3.44). Among patients without comorbidity, SCI patients exhibited a significantly higher risk of PAD than non-SCI patients. Furthermore, lumbar, sacral, or coccygeal spine, and multiple spine SCI were significantly associated with an increased risk of PAD (HR = 1.56, 95% CI = 1.33–1.84, HR = 2.11, 95% CI = 1.59–2.79, respectively). SCI is associated with an increased risk of PAD. Future studies should focus on modifying risk factors to reduce PAD risk among patients with SCI.

Little was known about the effects of acupuncture on stroke recurrence. The aim of this study is to investigate whether ischemic stroke patients receiving acupuncture treatment have a decreased risk of stroke recurrence. A retrospective cohort study of 30,058 newly diagnosed cases of ischemic stroke in 2000 to 2004 was conducted based on the claims of Taiwan National Health Insurance Research Database. The use of acupuncture treatment and stroke recurrence were identified during the follow-up period from 2000 to 2009. This study compared the risk of stroke recurrence between ischemic stroke cohorts with and without acupuncture treatment by calculating adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of acupuncture associated with stroke recurrence in the Cox proportional hazard model. The stroke recurrence rate per 1000 person-years decreased from 71.4 without to 69.9 with acupuncture treatment (P

P16 It has been suggested that the relationship between oxygen delivery and oxygen demand defines brain tissue at risk during cerebral ischemia. We have recently demonstrated that a quantitative estimate of cerebral blood oxygen saturation (and thereby oxygen extraction fraction, OEF) can be obtained using MRI in vivo. When combined with MR estimated cerebral blood flow (CBF), a quantitative measure of MR-CMRO2 can be calculated. In this study, we sought to explore the potential clinical utility of MR-CMRO2 in determining brain tissue at risk during cerebral ischemia. Seven patients with acute ischemic strokes were imaged at 4.5±.9 hrs (tp1) and 6 of the patients were imaged 3–5 days after stroke onset (tp2) with diffusion-weighted imaging (DWI) and perfusion-weighted imaging (PWI). In addition, a 2D multiecho gradient/spin echo sequence was employed to acquire images which were subsequently used to estimate MR-OEF. Singular value decomposition was used to obtain a quantitative estimate of CBF to calculate MR-CMRO2 (= MR-OEF x MR-CBF). At tp1, 5/7 patients showed a DWI-PWI mismatch (PWI>DWI) while 2/7 patients exhibited match. At tp2, only 1 patient showed PWI

P85 Stroke is a vascular disease in which brain cell death is initiated by a great reduction in blood flow. Only a few minutes of markedly lowered local blood flow (focal ischemia) may injure neurons and non-neuronal cells (e.g., endothelial cells and astrocytes) and lead to their death. The size and type of lesion depend on the duration and extent of flow reduction plus other local, mainly intrinsic variables. To understand the interplay between flow reduction and intrinsic factors in short-term, focal ischemic damage, blood flow and cell injury were assessed in three strains of mice. Method: The middle cerebral artery (MCA) was unilaterally occluded for 15 min in SV129, C57Bl/6, and Balb/C mice. Local cerebral blood flow (LCBF) was measured at the end of MCA occlusion by quantitative autoradiography (N=6 per strain). In other mice, cell damage and infarct size were assayed after 1–7days of reperfusion. Results: LCBF in the ischemic core region during MCA occlusion was greatly and similarly reduced in all three strains (range=3–20 ml/100g/min); LCBF in the penumbra, however, differed among the strains (LCBF in descending order: SV129>C57Bl/6>Balb/c mice). In addition, the penumbral zone was strikingly narrow in Balb/C mice. After 24 hr of reperfusion, the frequency of TUNEL positive cells in the ischemic core was highest (and most widespread) in Balb/C mice, much less in C57B1/6 mice, and nil in SV129 mice. Consistently, infarcts were seen after 3-day reperfusion in Balb/C and C57B1/6 mice but not in SV129 mice; increasing MCA occlusion to 30 min, however, caused infarction in the cerebral cortex of SV129 mice. Conclusion: These results indicate considerable dependence of brain cell damage on LCBF reduction with transient focal ischemia and suggest that there are intrinsic differences in cerebrovascular structure and/or function among these three mouse strains. Other differences in genetic background may, however, contribute to this interstrain variation in vulnerability to transient focal ischemic. Supported by NIH grants NS37372 and NS25545.

P52 With PET, elevated OEF in ischemic tissue is normally observed immediately after the onset of ischemia, followed by decreased OEF when ischemic tissue becomes irreversible damaged. This temporal alteration of OEF can potentially be reflected in the small cerebral veins within and/or adjacent to the ischemic tissue as an alteration in the level of blood oxygen saturation. A MR imaging method, referred to as HRBV, was employed to elucidate the temporal alteration of small cerebral veins adjacent to the ischemic tissue. Ten patients with hemispheric strokes were prospectively imaged using a high resolution 3D T2*-weighted sequence (TE=47ms). Both magnitude and phase images were obtained. A mask which highlights pixels with the presence of local susceptibility was generated for each slice via the phase images. Finally, HRBV maps were obtained by multiplying the mask with the corresponding magnitude image. In addition, conventional MR techniques including DWI and PWI were obtained. All patients were studied within 6 hrs after onset of stroke (4.2 +1.4 hrs, t1). Follow-up MR images were obtained at 48 hrs (t2) and 3 months (t3). Diffusion-Perfusion mismatch (DPMM) was expressed as a percentage with DPMM=(PWI-DWI)/PWI. The prominence of enlarged veins in the ischemic territory on HRBV images was rated from 0 (absence of prominent veins) to 3 (numerous prominent veins). At t1, 8 patients with marked DPMM (78.6 +4.5 %) had numerous prominent (grade 3) veins in the ischemic region on HRBV images. At t2, a substantial decrease in DPMM (26.3 +10%) was associated with far fewer prominent veins (grade 0–1). One patient with persistent DPMM (69% at t1 and 62% at t2) had grade 3 veins on HRBV at both time points. Another patient with very little DPMM (5%) had very few prominent veins (grade 1) at t1 and absence of veins (grade 0) with no DPMM at t2. At t3, all patients either had an absence or decreased number of veins in the regions of infarction. Our results are in good agreement with the postulated hypothesis that DPMM may indicate the presence of salvageable tissue where HRBV exhibited numerous prominent veins with low blood oxygen saturation while these veins deminished when no DPMM and/or irreversible tissue damage occurred.

The efficacy and safety of pentoxifylline were assessed in 297 adult patients with ischemic stroke in a multicenter, double-blind, randomized and placebo-controlled trial. Treatment was started within 12 hours after the stroke onset. Study medication was administered intravenously continuously (16 mg/kg/day, maximum 1,200 mg/day) for 3 days and per os (400 mg t.i.d.) for the remainder of 28 days. Demographic data were comparable, and functional impairment and mortality (pentoxifylline 12%, placebo 10%) were not different between the two groups. Neurologic deficit scores improved from baseline admission scores during the 4-week study in both groups but did not differ between groups at admission or throughout the study except during the first few days when the consciousness level (Days 1 and 2), motor function (Days 1 and 2), cranial nerve function (Days 1-4), and total neurologic deficit scores (Days 1 and 2) were better in the pentoxifylline group than in the placebo group, especially in a subset of patients with severe deficits at admission. Laboratory values and side effects were also comparable between groups. Our study indicates that pentoxifylline can be given safely in patients with acute ischemic stroke. Although pharmacologic effects were present during the first few days, the clinical benefits were small and not sustained.

Our understanding of the biochemistry and biologic actions of AA metabolites has been greatly expanded in recent years. The discoveries of TXA2, PGI2, and LTs have fostered new concepts of the pathophysiology of cerebral ischemia. New approaches to treatment of ischemia include seeking an optimal dose of aspirin, developing drugs that selectively inhibit or antagonize TXA2 or LTs, and administering PGI2 or its analogues. Altering the dietary content of essential fatty acids for prophylaxis is also being studied. Though the results of this thrust are still preliminary, the exploration of these therapeutic strategies in cerebrovascular disorders based on further understanding of the pathophysiologic roles of TXA2, PGI2, LTs and probably other AA metabolites is anticipated with some optimism.

Hypertensive intracerebral hemorrhage (HICH) is generally considered to be a monophasic event. Enlargement of the initial hematoma after several hours or days has rarely been documented. We describe the clinical and CT findings in 8 patients (5 men, 3 women, aged 39 to 68 years) with continued bleeding or rebleeding during the acute phase of HICH. The thalamus was the most frequent site of hemorrhage (6/8). The neurologic status deteriorated in all: 6 within 24 hours, and 2 after 5 and 7 days. Persistent hypertension was common (6/8) prior to extension of the hemorrhage. The 2nd CT revealed an obvious increase in hematoma size in all cases. Four patients died and 4 survived with severe neurologic disability. These serial studies indicate that active bleeding or rebleeding can occur in HICH and suggests that the risk is particularly high with thalamic hemorrhage. We conclude that meticulous control of hypertension after HICH may be justified in selected patients.

Three degrees of focal ischemic infarction in the rat were created in the cerebral cortex supplied by the right middle cerebral artery, by ligation of the right middle cerebral artery and the right common carotid artery and temporary clip compression of the left common carotid artery, in succession. The postischemic accumulation of calcium in cerebral cortex of the right middle cerebral artery territory, determined by atomic absorption spectrometry, correlated with the infarct volume. The results are consistent with the hypothesis that calcium has role as a mediator in the pathogenesis of cerebral infarction.