Protective stabilization of mitochondrial permeability transition and mitochondrial oxidation during mitochondrial Ca2+ stress by melatonin's cascade metabolites C3-OHM and AFMK in RBA1 astrocytes.

Cyclic 3-hydroxymelatonin (C3-OHM) and N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) are two major cascade metabolites of melatonin. We previously showed melatonin provides multiple levels of mitochondria-targeted protection beyond as a mitochondrial antioxidant during ionomycin-induced mitochondrial Ca2+ (mCa2+ ) stress in RBA1 astrocytes. Using noninvasive laser scanning fluorescence coupled time-lapse digital imaging microscopy, this study investigated whether C3-OHM and AFMK also provide mitochondrial levels of protection during ionomycin-induced mCa2+ stress in RBA1 astrocytes. Interestingly, precise temporal and spatial dynamic live mitochondrial images revealed that C3-OHM and AFMK prevented specifically mCa2+ -mediated mitochondrial reactive oxygen species (mROS) formation and hence mROS-mediated depolarization of mitochondrial membrane potential (△Ψm ) and permanent lethal opening of the MPT (p-MPT). The antioxidative effects of AFMK, however, were less potent than that of C3-OHM. Whether C3-OHM and AFMK targeted directly the MPT was investigated under a condition of "oxidation free-Ca2+ stress" using a classic antioxidant vitamin E to remove mCa2+ -mediated mROS stress and the potential antioxidative effects of C3-OHM and AFMK. Intriguingly, two compounds still effectively postponed "oxidation free-Ca2+ stress"-mediated depolarization of △Ψm and p-MPT. Measurements using a MPT pore-specific indicator Calcein further identified that C3-OHM and AFMK, rather than inhibiting, stabilized the MPT in its transient protective opening mode (t-MPT), a critical mechanism to reduce overloaded mROS and mCa2+ . These multiple layers of mitochondrial protection provided by C3-OHM and AFMK thus crucially allow melatonin to extend its metabolic cascades of mitochondrial protection during mROS- and mCa2+ -mediated MPT-associated apoptotic stresses and may provide therapeutic benefits against astrocyte-mediated neurodegeneration in the CNS.

Chest width, waist circumference, and thigh circumference are predictors of dementia.

OBJECTIVE: Few studies have investigated the relationship between specific body measures and dementia. METHODS: Three-dimensional anthropometric body surface scanning data containing 38 body measures were collected from 6831 participants from the health examination department of a medical center in Taiwan during 2000 to 2008, and 236 dementia cases were identified during the 10-year follow-up. A multiple Cox regression analysis was performed. RESULTS: Specific body measures, namely chest width (hazard ratio [HR] = 0.90; 95% confidence interval [CI] = 0.83-0.98), and right thigh circumference (HR = 0.93; 95% CI = 0.90-0.96), were protective predictors to dementia occurrence. Waist circumference (HR = 1.03; 95% CI = 1.02-1.05) was a risk factor in dementia occurrence. Among the combinations, dementia risk was higher in participants with a larger waist circumference and a smaller right thigh circumference, with the highest HR of 2.49 (95% CI = 1.54-4.03). CONCLUSION: The body measures provide clues for future applications and scientific merits in both clinical and preventive medicine.

The influence of dehydration on the prognosis of acute ischemic stroke for patients treated with tissue plasminogen activator.

BACKGROUND: Many studies have determined that dehydration is an independent predictor of outcome after ischemic stroke (IS); however, none have determined if the use of thrombolytic therapy modifies the negative impact of poor hydration. To inform the stroke registry established at our institution, we conducted a retrospective study to determine if dehydration remains a negative prognostic factor after IS patients treated with tissue plasminogen activator (tPA). METHODS: Between 2007 and 2012, we recruited 382 subjects; 346 had data available and were divided into 2 groups on the basis of their blood urea nitrogen/creatinine (BUN/Cr) ratio. Dehydrated subjects had a BUN/Cr ratio ≥ 15; hydrated subjects had a BUN/Cr < 15. The primary outcome was impairment at discharge as graded by the Barthel Index (BI) and the modified Rankin Scale (mRS). RESULTS: The dehydration group had a greater mean age; more women; lower mean levels of hemoglobin, triglycerides, and sodium; and higher mean potassium and glucose levels. A favorable outcome as assessed by the mRS (≤2) was significantly less frequent among dehydrated subjects, but a favorable outcome by the BI (≥60) was not. Logistic regression and multivariate models confirmed that dehydration is an independent predictor of poor outcome by both the mRS and the BI; however, it was not predictive when patients were stratified by Trial of Org 10,172 in Acute Stroke Treatment subtype. CONCLUSIONS: Our findings indicate that use of thrombolytic therapy does not eliminate the need to closely monitor hydration status in patients with IS.

Derivation and Validation of a Scoring System for Intravenous Tissue Plasminogen Activator Use in Asian Patients.

BACKGROUND AND PURPOSE: As Chinese Asian populations have an increased risk of intracerebral hemorrhage (ICH) after intravenous tissue plasminogen activator (IV tPA), we aimed to design a rapid, clinically applicable risk scoring system to predict ICH and functional outcomes after IV tPA treatment in Asian ischemic stroke patients. METHODS: From January 2009 to December 2012, consecutive acute ischemic stroke patients treated with IV tPA recruited from the Stroke Registry in Chang Gung Healthcare System (SRICHS) in Taiwan and the National University Hospital of Singapore (NUHS) acute stroke database were used to create and validate a scoring system. Nomogram was created for ICH and 3-month mortality. RESULTS: In total, 932 patients were included in the study: 386 from SRICHS for the derivation of scoring system and 546 from NUHS to validate it. We used nomograms to assign weightage to the scoring system. The presence of atrial fibrillation, glucose level, and the National Institutes of Health Stroke Scale (NIHSS) score were significantly associated with the risk of ICH. Age, NIHSS score, hyperlipidemia, and the presence of post-tPA ICH were significantly associated with mortality. The areas under the curve of derivation and validation cohorts were .663 and .662 for ICH, and .808 and .790 for mortality, respectively. CONCLUSIONS: The scoring system using nomograms can provide a fast, practical, and user-friendly tool that allows physicians to predict the risk of ICH and functional outcomes with IV tPA treatment in a clinical setting.

Association between Atrial Fibrillation and Three-Year Mortality in Nondiabetic Patients with Acute First-Ever Ischemic Stroke.

BACKGROUND: Diabetes mellitus (DM) is a risk factor for atrial fibrillation (AF) and is known to be an important risk factor for death from stroke. The influence of AF on long-term outcomes in patients with ischemic stroke remains controversial. To clarify the exact influence of AF on stroke outcome and exclude the effect from DM, we investigated the influence of AF on the 3-year outcomes of nondiabetic patients with acute first-ever ischemic stroke. METHODS: Five-hundred seventy-four nondiabetic patients with acute first-ever ischemic stroke were enrolled and had been followed for 3 years. Patients were divided into 2 groups according to whether AF was diagnosed or not. Clinical presentations, risk factors for stroke, laboratory data, comorbidities, and outcomes were recorded. RESULTS: A total of 107 patients (18.6%) had AF. The age was significantly older in patients with AF. Total anterior circulation syndrome occurred more frequently among patients with AF (P < .001). The mean length of stay in the acute ward was significantly higher in patients with AF (P < .001). Furthermore, dependent functional status following discharge was higher in patients with AF (P < .001). Multivariate Cox regression revealed that AF is a significant predictor of 3-year all-cause mortality (hazard ratio = 1.98, 95% confidence interval = 1.07-3.67, P = .022). CONCLUSIONS: AF is associated with increased risk of 3-year mortality in nondiabetic patients with acute first-ever ischemic stroke. Careful cardiac evaluation and treatment are essential in patients with AF and stroke.

Coexisting diseases of moyamoya vasculopathy.

BACKGROUND: Several coexisting diseases have been reported in patients with moyamoya vasculopathy (MMV), but studies of quasi-moyamoya disease (quasi-MMD) are rare. This study aims to investigate the frequency of known coexisting diseases in patients with quasi-MMD and to compare quasi-MMD with moyamoya disease (MMD). METHODS: Between 2000 and 2011, we retrospectively screened patients with International Classification of Diseases, Ninth Revision, code of 4375 (MMD) in the Health Information System of our hospital. The vascular images of each patient were confirmed by 2 neurologists and 1 neuroradiologist based on the diagnostic criteria of Japan Ministry of Health and Welfare. We excluded the patients with missing images and erroneous diagnosis. Demographics, coexisting diseases, laboratory data, treatment, and recurrent strokes were recorded. The eligible patients were divided into quasi-MMD and MMD groups according to the presence or absence of coexisting diseases. RESULTS: MMV was found in 90 patients including 37 (41.1%) quasi-MMD and 53 (58.9%) MMD. Atherosclerosis (32.4%) and thyroid disease (29.7%) were the leading coexisting diseases in quasi-MMD. Patients with MMD became symptomatic in a bimodal age distribution, whereas patients with quasi-MMD became symptomatic in a single-peak distribution. The prognosis of recurrent strokes was similar between quasi-MMD and MMD based on Kaplan-Meier analysis. CONCLUSIONS: A bimodal distribution of onset age was noted in MMD, whereas a single-peak distribution was found in quasi-MMD. Coexisting diseases were usually underevaluated but were more common than expected in patients with MMV. Atherosclerosis and thyroid diseases were the leading coexisting diseases in different preferential age.

Long-term Aß exposure augments mCa2+-independent mROS-mediated depletion of cardiolipin for the shift of a lethal transient mitochondrial permeability transition to its permanent mode in NARP cybrids: a protective targeting of melatonin.

Mitochondrial dysfunction is a hallmark of amyloid ß-peptide (Aß)-induced neurodegeneration of Alzheimer's disease (AD). This study investigated whether mtDNA T8993G mutation-induced complex V inhibition, clinically associated with neurological muscle weakness, ataxia, and retinitis pigmentosa (NARP), is a potential risk factor for AD and the pathological link for long-term exposure of Aß-induced mitochondrial toxicity and apoptosis in NARP cybrids. Using noninvasive fluorescence probe-coupled laser scanning imaging microscopy and NARP cybrids harboring 98% mutant genes along with its parental 143B osteosarcoma cells, we demonstrated that Aß-augmented mitochondrial Ca(2+) (mCa(2+))-independent mitochondrial reactive oxygen species (mROS) formation for a cardiolipin (CL, a major mitochondrial protective phospholipid)-dependent lethal modulation of the mitochondrial permeability transition (MPT). Aß augmented not only the amount but also the propagation rate of mROS-induced mROS formation to significantly depolarize mitochondrial membrane potential (∆Ψ(m)) and reduce mCa(2+) stress. Aß-augmented mROS oxidized and depleted CL, thereby enhances mitochondrial fission and movement retardation, which promoted the NARP-augmented lethal transient-MPT (t-MPT) to switch to its irreversible mode of permanent-MPT (p-MPT). Interestingly, melatonin, a multiple mitochondrial protector, markedly reduced Aß-augmented mROS formation and therefore significantly reduced mROS-mediated depolarization of ∆Ψ(m), fission of mitochondria and retardation of mitochondrial movement to stabilize CL and hence the MPT. In the presence of melatonin, Aß-promoted p-MPT was reversed to a protective t-MPT, which preserved ∆Ψ(m) and lowered elevated mCa(2+) to sublethal levels for an enhanced mCa(2+)-dependent O(2) consumption. Thus, melatonin may potentially rescue AD patients associated with NARP symptoms.

The impact of intracranial carotid artery calcification on the development of thrombolysis-induced intracerebral hemorrhage.

BACKGROUND: We aimed to assess whether intracranial carotid artery calcification (ICAC) evident on head computed tomography is a risk factor for symptomatic intracerebral hemorrhage (sICH) following tissue plasminogen activator (tPA) treatment for acute stroke. METHODS: We classified 297 consecutive patients into 2 groups (no to mild ICAC and moderate to severe ICAC) according to ICAC severity. Outcome measures included detection of intracerebral hemorrhage and assessment using a modified Rankin scale (mRS) at 1 month and 1 year after stroke. RESULTS: ICH (any type) was significantly more common in patients with moderate to severe ICAC than in patients with no to mild ICAC (22.5% versus 12%; relative risk [RR], 1.67; 95% confidence interval [CI], 1.1-2.5; P<.05). The moderate to severe ICAC group tended to have a higher percentage of sICH, but this association was not statistically significant (RR, 1.57; 95% CI, .75-3.3, P>.05). Multivariate adjusted regression analysis revealed that moderate to severe ICAC was an independent risk factor for ICH following tPA treatment (odds ratio, 2.52; 95% CI, 1.07-5.94; P=.04). Dependent functional outcome (mRS score 3-6) at 1-month and 1-year follow-up was significantly associated with moderate to severe ICAC (RR, 1.56; 95% CI, 1.06-2.27; and RR, 1.56; 95% CI, 1.06-2.33; P<.05). However, ICAC was not an independent factor of functional dependency at 1-month and 1-year follow-up in the final multivariate regression model. CONCLUSION: A significantly higher percentage of patients with moderate to severe ICAC developed ICH following tPA administration for stroke. ICAC severity is an independent risk factor for ICH events. ICAC severity can help predict short-term and long-term functional dependency in tPA-treated patients, although this can be confounded by other cardiovascular risk factors and stroke severity.

Association of hyponatremia in acute stroke stage with three-year mortality in patients with first-ever ischemic stroke.

BACKGROUND: Hyponatremia is the most common electrolyte disorder in hospitalized patients, and is frequently a marker of a significant underlying disease. The prognostic value of hyponatremia in patients with acute first-ever ischemic stroke is not known. We aimed to analyze whether hyponatremia in the acute stroke stage contributed to the risk of mortality or recurrent stroke in these patients. METHODS: We studied 925 patients presenting with acute first-ever ischemic stroke between 2002 and 2004. Sodium levels were obtained on arrival at the emergency room within 3 days of acute stroke onset. Hyponatremia was defined as a serum sodium concentration of 134 mmol/l or less. Clinical presentation, stroke risk factors, associated medical disease, and outcome were recorded. All patients were followed for 3 years for survival analysis. A multivariate Cox proportional hazards model was used to identify risk factors for 3-year mortality in these patients. We also constructed Kaplan-Meier survival curves, and compared groups with hyponatremia and normonatremia by means of log rank tests for significant differences. RESULTS: Among the patients with acute first-ever ischemic stroke, 107 (11.6%) were hyponatremic. Among stroke risk factors, the prevalence of diabetes mellitus was significantly higher among hyponatremic patients (p < 0.001). Prevalence of chronic renal insufficiency was also higher in the hyponatremic group (p = 0.002). Clinical presentations, such as the length of acute ward stay, initial impaired consciousness, and clinical course in acute stroke were similar among normo- and hyponatremic patients. Among the complications, pneumonia and urinary tract infection were significantly higher in hyponatremic than in normonatremic patients. After multivariate logistic regression analysis, diabetes mellitus and chronic renal insufficiency were associated with hyponatremia in these patients. Kaplan-Meier analysis indicated that the survival rate was significantly lower in hyponatremic patients than in normonatremic patients (log rank test; p value <0.001). After multivariate Cox proportional hazards model analysis, hyponatremia was a significant predictor of 3-year mortality in these patients after adjustment for related variables (p value = 0.003, hazard ratio = 2.23, 95% confidence interval: 1.30-3.82). CONCLUSION: Hyponatremia in the acute stroke stage is a predictor of 3-year mortality in patients with acute first-ever ischemic stroke that is independent of other clinical predictors of adverse outcome.

mtDNA T8993G mutation-induced mitochondrial complex V inhibition augments cardiolipin-dependent alterations in mitochondrial dynamics during oxidative, Ca(2+), and lipid insults in NARP cybrids: a potential therapeutic target for melatonin.

Mitochondrial dynamics including morphological fission and mitochondrial movement are essential to normal mitochondrial and cellular physiology. This study investigated how mtDNA T8993G (NARP)-induced inhibition of mitochondrial complex V altered mitochondrial dynamics in association with a protective mitochondrial phospholipid, cardiolipin (CL), as a potential therapeutic target. NARP cybrids harboring 98% of mtDNA T8993G genes and its parental osteosarcoma 143B cells were studied for comparison, and protection provided by melatonin, a potent mitochondrial protector, was explored. We demonstrate for the first time that NARP mutation significantly enhances apoptotic death as a result of three distinct lethal mitochondrial apoptotic insults including oxidative, Ca(2+), and lipid stress. In addition, NARP significantly augmented pathological depletion of CL. NARP-augmented depletion of CL results in enhanced retardation of mitochondrial movement and fission and later swelling of mitochondria during all insults. These results suggest that CL is a common and crucial pathological target for mitochondrial apoptotic insults. Furthermore, CL possibly plays a central role in regulating mitochondrial dynamics that are associated with NARP-augmented mitochondrial pathologies. Intriguingly, melatonin, by differentially preserving CL during various stresses (oxidation > Ca(2+) > lipid), rescues differentially CL-altered mitochondrial dynamics and cell death (oxidation > Ca(2+) > lipid). Thus, melatonin, in addition to being a mitochondrial antioxidant to antagonize mitochondrial oxidative stress, a mitochondrial permeability transition modulator to antagonize mitochondrial Ca(2+) stress, may stabilize directly CL to prevent its oxidization and/or depletion and, therefore, exerts great potential in rescuing CL-dependent mitochondrial dynamics-associated mitochondrial pathologies for treatment of NARP-induced pathologies and diseases.

Cervicocranial fibromuscular dysplasia in Taiwanese ischemic stroke patients.

INTRODUCTION: Clinical research of cervicocranial fibromuscular dysplasia (FMD) is rare in Asian populations. Our study reviewed Taiwanese ischemic stroke patients with cervicocranial FMD and compared them with previous reports. METHODS: Between 2000 and 2011, we collected 19 consecutive cervicocranial FMD patients who received demographic registration, a blood test for excluding vasculitis, and comprehensive angiography. Cerebral ultrasound, vascular images and clinical outcomes (Barthel index, modified Rankin scale, recurrent stroke, or death) were monitored during follow-up. RESULTS: Of the 19 patients, 16 (84%) had carotid FMD, while 7 (37%) had vertebral FMD. Only 2 investigated patients (13%) had renal FMD and 1 (5%) had cerebral aneurysm. 14 (74%) presented acute arterial dissection. All patients received medical treatment and had neither recurrent stroke nor dissection during follow-up. In the literature review of 225 FMD patients, 3.6% had recurrent stroke during follow-up, and some reported surgical procedure or angioplasty could give a good clinical outcome in progressing ischemia irrelevant to the cause of stenosis. CONCLUSION: In Taiwanese cervicocranial FMD patients, arterial dissection was one of the most common clinical presentations. Most of our patients had isolated involvement of the cervicocranial artery and carried a favorable outcome under medical treatment.

Clinical characteristics of adult tetanus in a Taiwan medical center.

BACKGROUND/PURPOSE: Despite effective vaccine programs, tetanus is occasionally observed in adults. We reviewed clinical presentation data for adult patients with tetanus in the post-vaccine era in Taiwan. METHODS: We retrospectively reviewed the medical records of all adult patients (age >18 years) discharged from Chang-Gung Memorial Hospital at Lin-Ko (CGMHLK) after treatment for tetanus between January 1996 and July 2005. Data regarding demographic characteristics, clinical manifestation, treatment, and outcome were collected. To assess the features for different age groups, patients were divided into those aged ≥65 years and those aged <65 years. To identify risk factors for respiratory failure, the patients were classified as those with and without respiratory failure. RESULTS: Twenty-three patients with tetanus, 11 (48%) women and 12 (52%) men, were included in the study. The average age was 57 ± 18 years (range 18-84 years). Eighteen (78%) patients had a history of acute injury. The average incubation period was 8 ± 5 days. The most common clinical presentation at onset was trismus (78%). Thirteen (57%) patients developed respiratory failure and underwent endotracheal intubation. The most common complication was pneumonia (30%). All the patients survived and recovered. Age ≥65 years was significantly associated with trismus, dysphagia, dysarthria, and pneumonia. Generalized tetanus subtype and pneumonia were significant risk factors for respiratory failure. CONCLUSION: This study revealed several characteristics of adult tetanus cases in the post-vaccine era in Taiwan. Further serological studies and improved tetanus vaccinations may be needed to ensure better protection, especially for high-risk populations. The exceptionally good prognosis for our patients confirms that appropriate treatment, including wound care, early diagnosis, proper medication, and prevention of complications, is essential in managing this traditional curable disease.

A disease-specific language representation model for cerebrovascular disease research.

BACKGROUND: Effectively utilizing disease-relevant text information from unstructured clinical notes for medical research presents many challenges. BERT (Bidirectional Encoder Representation from Transformers) related models such as BioBERT and ClinicalBERT, pre-trained on biomedical corpora and general clinical information, have shown promising performance in various biomedical language processing tasks. OBJECTIVES: This study aims to explore whether a BERT-based model pre-trained on disease-related clinical information can be more effective for cerebrovascular disease-relevant research. METHODS: This study proposed the StrokeBERT which was initialized from BioBERT and pre-trained on large-scale cerebrovascular disease related clinical text information. The pre-trained corpora contained 113,590 discharge notes, 105,743 radiology reports, and 38,199 neurological reports. Two real-world empirical clinical tasks were conducted to validate StrokeBERT's performance. The first task identified extracranial and intracranial artery stenosis from two independent sets of radiology angiography reports. The second task predicted the risk of recurrent ischemic stroke based on patients' first discharge information. RESULTS: In stenosis detection, StrokeBERT showed improved performance on targeted carotid arteries, with an average AUC compared to that of ClinicalBERT of 0.968 ± 0.021 and 0.956 ± 0.018, respectively. In recurrent ischemic stroke prediction, after 10-fold cross-validation on 1,700 discharge information, StrokeBERT presented better prediction ability (AUC±SD = 0.838 ± 0.017) than ClinicalBERT (AUC±SD = 0.808 ± 0.045). The attention scores of StrokeBERT showed better ability to detect and associate cerebrovascular disease related terms than current BERT based models. CONCLUSIONS: This study shows that a disease-specific BERT model improved the performance and accuracy of various disease-specific language processing tasks and can readily be fine-tuned to advance cerebrovascular disease research and further developed for clinical applications.

Visualization of melatonin's multiple mitochondrial levels of protection against mitochondrial Ca(2+)-mediated permeability transition and beyond in rat brain astrocytes.

Melatonin protects cells against various types of oxidative stress-induced apoptosis due primarily to its ability to effectively scavenge pathological and disease condition-augmented generation of mitochondrial reactive oxygen species (mROS). Once produced, mROS indiscriminately damage mitochondrial components and more importantly they crucially activate directly the mitochondrial permeability transition (MPT), one of the critical mechanisms for initiating post mitochondrial apoptotic signaling. Whether or not melatonin targets directly the MPT, however, remains inconclusive, particularly during oxidative stress. This study, thus, investigated this possibility of an 'oxidation free Ca(2+) stress' in the presence of vitamin E after ionomycin exposure as a sole Ca(2+)-mediated MPT in order to exclude melatonin's primary antioxidative effects as well as Ca(2+)-mediated oxidative stress. The studies were carried out using cultured rat brain astrocytes RBA-1. With the application of laser scanning multiple fluorescence imaging microscopy, we visualized for the first time multiple mitochondrial protective effects provided by melatonin during Ca(2+) stress. First, melatonin, due to its primary antioxidative actions, completely prevented mCa(2+)-induced mROS formation during ionomycin exposure. Secondly, when melatonin(')s antioxidative effects were prevented due to the addition of vitamin E, melatonin significantly prevented mCa(2+)-mediated MPT and apoptosis suggesting its direct targeting of the MPT. Surprisingly, in the presence of cyclosporin A, a MPT inhibitor, melatonin reduced further mCa(2+)-mediated apoptosis during ionomycin exposure also suggesting its targeting beyond the MPT. As astrocytes are actively involve in regulating synaptic transmission and neurovascular coupling in the CNS, these multiple mitochondrial layers of protection provided by melatonin against mCa(2+)-and/or mROS-mediated apoptosis in astrocytes may be crucial for future therapeutic prevention and treatment of astrocyte-mediated neurodegenerative diseases in the CNS.

Comparison of long-term efficacy and safety between cilostazol and clopidogrel in chronic ischemic stroke: a nationwide cohort study.

BACKGROUND: Previous clinical trials showed a significant difference in efficacy and safety among antiplatelets in acute ischemic stroke (IS). The present study wished to compare the efficacy and safety head-to-head between cilostazol and clopidogrel in chronic IS. METHODS: This open prospective cohort study recruited chronic IS patients with an index hospitalization between 2001 and 2013 from Taiwan National Health Insurance Research Database. In the 504,191 hospitalized patients, patients who had missing information and history of atrial fibrillation or rheumatic heart disease, received mechanical valve replacement or anticoagulants, expired during the index hospitalization, received follow-up ⩽6 months, or had recurrent stroke within 6 months after index stroke were excluded. RESULTS: Among the 15,968 eligible patients, 502 patients who consistently received either cilostazol or clopidogrel from the 7th month after the index stroke were included for analysis after propensity score matching. The 3-year primary outcomes showed similar frequency of recurrent IS, all-cause mortality, and acute myocardial infarction (AMI), and similar frequency of intracerebral hemorrhage, gastrointestinal bleeding, and major bleeding between the cilostazol and clopidogrel groups. Subgroup analysis revealed that patients with a history of hypertension or gastrointestinal bleeding had a trend of having lower frequency of recurrent IS or major bleeding, respectively, in the cilostazol group. CONCLUSION: The present real-world study demonstrated no significant difference in efficacy and safety between cilostazol and clopidogrel in chronic IS. However, cilostazol might be better than clopidogrel in patients with a history of hypertension or gastrointestinal bleeding.

Impact of chronic kidney disease severity on causes of death after first-ever stroke: A population-based study using nationwide data linkage.

BACKGROUND: Stroke is prevalent in patients with chronic kidney disease (CKD) and is associated with high mortality, but the causes of death after stroke among different CKD stages are not well known. AIMS: We aimed to investigate whether the severity of CKD would impact on the causes of death after first-ever stroke. METHODS: This retrospective multicenter cohort study included stoke patients with CKD between 2007 and 2012. The cause of death and date of death were ascertained by linking the National Death Registry Database of Taiwan. Clinical outcomes, 1-month, and 1-year mortality rates, and major causes of death were compared according to five CKD stages (G1 to G5) in the ischemic and hemorrhagic stroke separately. RESULTS: Of these patients, 9,878 were first-ever ischemic stroke (IS) patients, and 1,387 were first-ever hemorrhagic stroke (HS) patients. Patients with CKD G5 had the highest one-year mortality rate with hazard ratio 5.28 [95%CI, 3.94-7.08] in IS and 3.03 [95%CI, 2.03-4.54] in HS when compared to G1 patients. Leading causes of one-year death after IS were stroke, cancer, and pneumonia in early (G1-3) CKD patients, while diabetes mellitus, CKD, and stroke itself contributed to the major mortality in CKD G5 patients. An inverse association between eGFR decrement and the proportion of deaths caused by stroke itself was observed in CKD G2-5 patients after IS. Stroke was the leading cause of one-year death among all CKD patients after HS. CONCLUSIONS: Asides from high mortality, late-stage CKD patients had different causes of death from early CKD patients after stroke. This study highlights the need to imply different treatment strategies in late-stage CKD post-stroke patients to improve their prognosis.

Risk Factors Associated with Outcomes of Recombinant Tissue Plasminogen Activator Therapy in Patients with Acute Ischemic Stroke.

Ischemic stroke is the most common type of stroke, and early interventional treatment is associated with favorable outcomes. In the guidelines, thrombolytic therapy using recombinant tissue-type plasminogen activator (rt-PA) is recommended for eligible patients with acute ischemic stroke. However, the risk of hemorrhagic complications limits the use of rt-PA, and the risk factors for poor treatment outcomes need to be identified. To identify the risk factors associated with in-hospital poor outcomes in patients treated with rt-PA, we analyzed the electronic medical records of patients who were diagnosed with acute ischemic stroke and treated for rt-PA at Chang Gung Memorial Hospitals from 2006 to 2016. In-hospital death, intensive care unit (ICU) stay, or prolonged hospitalization were defined as unfavorable treatment outcomes. Medical history variables and laboratory test results were considered variables of interest to determine risk factors. Among 643 eligible patients, 537 (83.5%) and 106 (16.5%) patients had favorable and poor outcomes, respectively. In the multivariable analysis, risk factors associated with poor outcomes were female gender, higher stroke severity index (SSI), higher serum glucose levels, lower mean corpuscular hemoglobin concentration (MCHC), lower platelet counts, and anemia. The risk factors found in this research could help us study the treatment strategy for ischemic stroke.

Pituitary adenoma apoplexy with initial presentation mimicking bacterial meningoencephalitis: a case report.

Pituitary apoplexy is a rare but life-threatening disorder. Clinical presentation of this condition includes severe headache, impaired consciousness, fever, visual disturbance, and variable ocular paresis. Signs of meningeal irritation are very rare. However, if present and associated with headache, fever, and pleocytosis, meningeal irritation may lead to misinterpretation as infectious meningoencephalitis. To the best of our knowledge, pituitary apoplexy with an initial presentation mimicking infectious meningoencephalitis had rarely been reported in the literature. Here, we report a 57-year-old man who had acute severe headache, high fever, neck stiffness, disturbance in consciousness, and left ocular paresis. Laboratory data showed leukocytosis, an elevated C-reactive protein level, and neutrophilic pleocytosis in the cerebrospinal fluid. Because bacterial meningoencephalitis was suspected, empiric antibiotic therapy was administered but in vain. Further examinations indicated a diagnosis of pituitary adenoma with apoplexy. After the immediate administration of intravenous corticosteroid supplement and surgical decompression, the patient recovered.

The influence of anemia on clinical presentation and outcome of patients with first-ever atherosclerosis-related ischemic stroke.

There is considerable debate regarding whether anemia qualifies as a prognostic factor for stroke. The purpose of this study was twofold: first, to assess the influence of anemia on vascular risk factors and clinical presentations in patients with first-ever atherosclerosis-related ischemic stroke and, second, to evaluate whether anemia may be of prognostic importance. A total of 774 consecutive patients with first-ever atherosclerosis-related ischemic stroke were prospectively investigated. Vascular risk factors, clinical presentations and outcomes were recorded and compared between those patients with and without anemia. Stroke recurrence and mortality were recorded at the 3-year follow-up. Of the study population, 168 (21.7%) were anemic. Multivariate analysis revealed that patients with anemia were more likely to be older than 70 years (p<0.001) and have chronic renal insufficiency (p<0.001). After a mean follow-up period of 958 days, 21 (12.5%) and 24 (4.0%) of the patients in the anemic and control groups, respectively, died. Within 3 years of initial onset, the mortality rate was significantly higher in patients with anemia (p=0.021). The Kaplan-Meier analysis for patients with and without anemia showed different survival curves (Log-rank test p<0.001). Within 3 years of the onset of first-ever atherosclerosis-related ischemic stroke, patients who had anemia at the time of the initial admission had an associated higher mortality rate. The stroke risk factors of being older than 70 years and having chronic renal insufficiency were more frequently observed in those patients with anemia.

Low-dose versus standard-dose alteplase in acute ischemic stroke in Asian stroke registries: an individual patient data pooling study.

OBJECTIVE: To investigate the comparative efficacy and safety of the low-dose versus standard-dose alteplase using real-world acute stroke registry data from Asian countries. METHODS: Individual participant data were obtained from nine acute stroke registries from China, Japan, Philippines, Singapore, South Korea, and Taiwan between 2005 and 2018. Inverse probability of treatment weight was used to remove baseline imbalances between those receiving low-dose versus standard-dose alteplase. The primary outcome was death or disability defined by modified Rankin Scale scores of 2 to 6 at 90 days. Secondary outcomes were symptomatic intracerebral hemorrhage and death. Generalized linear mixed models with the individual registry as a random intercept were performed to determine associations of treatment with low-dose alteplase and outcomes. RESULTS: Of the 6250 patients (mean age 66 years, 36% women) included in these analyses, 1610 (24%) were treated with low-dose intravenous alteplase. Clinical outcomes for low-dose alteplase were not significantly different to those for standard-dose alteplase, adjusted odds ratios for death or disability: 1.00 (0.85-1.19) and symptomatic intracerebral hemorrhage 0.87 (0.63-1.19), except for lower death with borderline significance, 0.77 (0.59-1.01). CONCLUSIONS: The present analyses of real-world Asian acute stroke registry data suggest that low-dose intravenous alteplase has overall comparable efficacy for functional recovery and greater potential safety in terms of reduced mortality, to standard-dose alteplase for the treatment of acute ischemic stroke.