Outcomes in ischemic and hemorrhagic stroke patients with cancer: The Japan Stroke Data Bank.

INTRODUCTION: Data on the impact of malignancy on outcomes in patients with stroke, especially hemorrhagic stroke, are limited. We aimed to clarify the association between cancer and outcomes for each stroke type (ischemic/hemorrhagic) using a hospital-based multicenter stroke registration database. PATIENTS AND METHODS: Study participants were adult patients within 7 days of the onset of ischemic stroke (IS) or hemorrhagic stroke (HS) between 2000 and 2020 in the Japan Stroke Data Bank (JSDB). The patients were categorized into two groups according to whether they had a history of cancer. Outcomes included good functional outcomes, representing a modified Rankin Scale score of 0-2 at discharge and in-hospital mortality. RESULTS: Of the 203,983 patients analyzed in this substudy, 152,591 (women, 39.9 %; median age, 75 years) had IS, and 51,392 (48.6 %; 69 years) had HS. Of these, 6409 IS (4.2 %) and 1560 HS (3.0 %) patients had any cancer. IS patients with cancer had a lower frequency of good functional outcomes (47.5 % vs. 56.3 %; adjusted odds ratio [aOR] 0.85, 95 % confidence interval [CI] 0.79-0.91) and a higher incidence of in-hospital mortality (6.7 % vs. 4.5 %; aOR 1.59, 95 % CI 1.41-1.80) than those without cancer. HS patients with cancer showed a lower frequency of good functional outcome (24.9 % vs. 35.7 %; aOR 0.88, 95 % CI 0.78-0.99) and higher incidence of in-hospital mortality (20.1 % vs. 16.0 %; aOR 1.26, 95 % CI 1.04-1.52) than those without cancer. CONCLUSIONS: Both IS and HS patients with cancer had significantly lower good functional outcomes and more in-hospital mortality.

Effect of Edaravone on Neurological Symptoms in Real-World Patients With Acute Ischemic Stroke.

Background and Purpose- In Japan, nearly half of ischemic stroke patients receive edaravone for acute treatment. The purpose of this study was to assess the effect of edaravone on neurological symptoms in patients with ischemic stroke stratified by stroke subtype. Methods- Study subjects were 61 048 patients aged 18 years or older who were hospitalized ≤14 days after onset of an acute ischemic stroke and were registered in the Japan Stroke Data Bank, a hospital-based multicenter stroke registration database, between June 2001 and July 2013. Patients were stratified according to ischemic stroke subtype (large-artery atherosclerosis, cardioembolism, small-vessel occlusion, and cryptogenic/undetermined) and then divided into 2 groups (edaravone-treated and no edaravone). Neurological symptoms were evaluated using the National Institutes of Health Stroke Scale (NIHSS). The primary outcome was changed in neurological symptoms during the hospital stay (ΔNIHSS=NIHSS score at discharge-NIHSS score at admission). Data were analyzed using multivariate linear regression with inverse probability of treatment weighting after adjusting for the following confounding factors: age, gender, and systolic and diastolic blood pressure at the start of treatment, NIHSS score at admission, time from stroke onset to hospital admission, infarct size, comorbidities, concomitant medication, clinical department, history of smoking, alcohol consumption, and history of stroke. Results- After adjusting for potential confounders, the improvement in NIHSS score from admission to discharge was greater in the edaravone-treated group than in the no edaravone group for all ischemic stroke subtypes (mean [95% CI] difference in ΔNIHSS: -0.46 [-0.75 to -0.16] for large-artery atherosclerosis, -0.64 [-1.09 to -0.2] for cardioembolism, and -0.25 [-0.4 to -0.09] for small-vessel occlusion). Conclusions- For any ischemic stroke subtype, edaravone use (compared with no use) was associated with a greater improvement in neurological symptoms, although the difference was small (<1 point NIHSS) and of limited clinical significance.

Transplantation of a bone marrow mesenchymal stem cell line increases neuronal progenitor cell migration in a cerebral ischemia animal model.

Mesenchymal stem cell (MSC) transplantation is demonstrated to improve functional and pathological recovery in cerebral ischemia. To understand the underlying mechanism, we transplanted a MSC line (B10) in a rat middle cerebral artery occlusion (MCAO) model and checked the proliferation and migration of neuronal progenitor cells (NPCs). B10 transplantation increased NPCs in the subventricular zone and their migration towards the lesion area at an earlier time. Fourteen days after MCAO, some NPCs were differentiated to neurons and astrocytes. Although B10 transplantation increased total number of both astrocytes and neurons, it only increased the differentiation of NPC to astrocyte. The mRNA of polysialylation enzyme ST8SiaIV and a chemokine SDF-1 were persistently increased in B10-transplanted groups. SDF-1-positive cell number was increased in the core and penumbra area, which was expressed in macrophage/microglia and transplanted B10 cells at 3 days after MCAO. Furthermore, SDF-1 mRNA expression in cell culture was high in B10 compared to a microglia (HMO) or a neuronal (A1) cell line. B10 culture supernatant increased in vitro A1 cell migration, which was significantly inhibited by siRNA-mediated SDF-1 silencing in B10. Thus, our results suggested that MSC transplantation increased endogenous NPC migration in cerebral ischemic condition by increasing chemokine and polysialylation enzyme expression, which could be helpful for the restorative management of cerebral ischemia.

A human neural stem cell line provides neuroprotection and improves neurological performance by early intervention of neuroinflammatory system.

A human neural stem cell line, HB1.F3, demonstrated neuroprotective properties in cerebral ischemia animal models. In this study, we have investigated about the mechanisms of such neuroprotection, mainly focusing on the neuroinflammatory system at an earlier time point of the pathology. Cerebral ischemia model was generated by middle cerebral artery occlusion (MCAO) in adult male Wister rats. HB1.F3 cells were transplanted through jugular vein 6h after MCAO. Forty eight hours after MCAO, transplanted rats showed better neurological performance and decreased TUNEL positive apoptotic cell number in the penumbra. However, haematoxylin and eosin staining and immunostaining showed that, HB1.F3 cells did not affect the necrotic cell death. Twenty four hours after MCAO (18h after HB1.F3 transplantation), infiltrated granulocytes and macrophage/microglia number in the core regions were decreased compared to PBS-treated controls. Immunohistochemical analysis further demonstrated that the transplantation decreased inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 expressing cell number in the core and penumbra, respectively. Double immunofluorescence results revealed that iNOS was mainly expressed in granulocytes and macrophage/microglia in the core region, and COX-2 mainly expressed in neurons, endothelial cells and granulocytes in penumbra. Further analysis showed that although the percentage of iNOS expressing granulocytes and macrophage/microglia was not decreased, COX-2 expressing neurons and vessel number was decreased by the transplantation. In vitro mRNA analysis showed that brain-derived neurotrophic factor (BDNF), basic fibroblast growth factor (ßFGF) and bone morphogenic protein (BMP)-4 expression was high in cultured HB1.F3 cells. Thus, our results demonstrated that HB1.F3 cell transplantation provide neuroprotection possibly through the regulation of early inflammatory events in the cerebral ischemia condition.

Influence of Antiplatelet Drugs on the Outcome of Subarachnoid Hemorrhage Differs with Age.

BACKGROUND: The aim of this study was to examine the risk factor profiles and functional outcomes of subarachnoid hemorrhage (SAH) in different age groups, focusing on the effect of antiplatelet drugs when used before stroke. METHODS: A total of 5344 patients with SAH were included in a multicenter, hospital-based registration study involving 95 Japanese institutes from 2000 to 2012. Patients' profiles and use of antithrombotic agents were retrospectively reviewed. A modified Rankin Scale score of 4 or more at discharge was defined as poor outcome. RESULTS: The frequency of antithrombotic agent use increased with age; it reached its peak (10.9%) among patients in their 80s and remained constant at 7.5% for those 90 years or older. Poorer outcomes were evident as age increased. The frequency of hypertension increased with age, whereas current smoking and heavy drinking reached its peak among patients in their 40s and 50s, respectively. The use of antiplatelet agents significantly improved outcome in patients younger than 60 years (P = .04). In contrast, in the older group (≥60 years), the use of antiplatelet agents tended to worsen the outcome; patients aged 70-79 years who had used these agents had a significantly worse outcome compared with those who had not (P = .03). CONCLUSIONS: In the present study, the influence of antiplatelet agents was different among age groups. The potential beneficial effects of antiplatelet agents must be weighed against their potential adverse effects in the context of SAH, considering the differences in age-related outcomes.

Subsequent vascular events after ischemic stroke: the Japan Statin Treatment Against Recurrent Stroke-Longitudinal.

BACKGROUND: We undertook a multicenter cohort observational study to investigate the frequency and type of subsequent vascular events after an ischemic stroke and to compare the rates of vascular events between patients with and without hyperlipidemia. METHODS: This nationwide study was conducted in 19 hospitals participating in the Japan Standard Stroke Registry Study. We enrolled ischemic stroke patients, including those with a transient ischemic attack, who had not experienced any vascular events before enrollment after their ischemic stroke events. Each subject was observed prospectively from September 1, 2003, to October 1, 2005, or until a primary end point or death. Primary end points included subsequent fatal or nonfatal vascular events: stroke, angina pectoris, acute myocardial infarction, aortic aneurysm, or arteriosclerosis obliterans. RESULTS: A total of 449 patients (mean age, 67.6 years; 64.8% men) were enrolled in this study. Of the 41 vascular events observed during follow-up, 40 were stroke. The median observation period was 568 days. We found that patients with hyperlipidemia had a significantly higher rate of vascular events compared with those without hyperlipidemia according to the Kaplan-Meier method and the log-rank test (P = .013). Hyperlipidemia significantly increased the risk of vascular events (hazard ratio, 2.169 [1.125-4.312]; P = .021) according to the Cox proportional hazard model after adjusting for confounding factors (age, sex, days from ischemic stroke until enrollment, smoking habits, and daily drinking habits). CONCLUSIONS: This study demonstrated that stroke was the most common subsequent vascular event after ischemic stroke; the study also indicated that hyperlipidemia could be a risk factor for subsequent vascular events after ischemic stroke.

Human mesenchymal stem cell transplantation changes proinflammatory gene expression through a nuclear factor-κB-dependent pathway in a rat focal cerebral ischemic model.

Previous studies have demonstrated the immunomodulatory functions of mesenchymal stem cells (MSCs) in cerebral ischemic rats. However, the underlying mechanisms are unclear. The purpose of this study is to investigate the effects of MSC transplantation on transcriptional regulations of proinflammatory genes in cerebral ischemia. Transient ischemia was induced by middle cerebral artery occlusion (MCAO) in adult male Sprague-Dawley rats. After 24 hr, vehicle (PBS) or a human MSC line (B10) was transplanted intravenously. The neurological deficits, infarct volume, cellular accumulations, and gene expression changes were monitored by means of behavior tests, MRI, immunohistochemistry, Western blotting, laser capture microdissection, and real-time PCR. In the core area of the B10 transplantation group, the number of ED1-positive macrophage/microglia was decreased compared with the PBS group. In the core, nuclear factor-κB (NF-κB) was decreased, although CCAAT/enhancer-binding protein ß was not changed; both were expressed mainly in ED1-positive macrophage/microglia. Likewise, mRNAs of NF-κB-dependent genes including interleukin-1ß, MCP-1, and inducible nitric oxide synthase were decreased in ED1-positive and Iba-1-positive macrophage/microglia in the B10 transplantation group. Moreover, upstream receptors of the NF-κB pathway, including CD40 and Toll-like receptor 2 (TLR2), were decreased. Immunofluorescence results showed that, in the B10 transplantation group, the percentages of NF-κB-positive, CD40-positive, and TLR2-positive cells were decreased in ED1-positive macrophage/microglia. Furthermore, NF-κB-positive cells in the CD40- or TLR2-expressing cell population were decreased in the B10 transplantation group. This study demonstrates that B10 transplantation inhibits NF-κB activation, possibly through inhibition of CD40 and TLR2, which might be responsible for the inhibition of proinflammatory gene expression in macrophage/microglia in the infarct lesion.

Mesenchymal stem cell transplantation modulates neuroinflammation in focal cerebral ischemia: contribution of fractalkine and IL-5.

Mesenchymal stem cells (MSCs) are reported to possess immunomodulatory properties. Previous reports have demonstrated the beneficial effects of MSC-transplantation in focal cerebral ischemia animal models. In this study, we have investigated the neuroimmunomodulatory functions of human MSCs, transplanted in a rat focal ischemia model of transient middle cerebral artery occlusion (MCAO). Our results revealed that in a human mesenchymal stem cell line, B10 cell transplantation decreased the accumulation of Iba-1(+) microglia and GFAP(+) astrocytes, and inhibited proinflammatory gene expression in the core and ischemic border zone (IBZ). Among the proinflammatory genes iNOS, which was expressed in microglia/macrophage, was persistently inhibited up to 7days after MCAO. In vivo laser capture microdissection and double immunofluorescence staining, and in vitro B10 cell culture experiments showed that, in inflammatory conditions, B10 cells expressed cytokines and growth factors including IL-5, fractalkine, IGF-1, GDNF and VEGF. Fractalkine and IL-5 inhibited cytokine-induced proinflammatory gene expression including iNOS in a human microglia cell line. Thus, our results demonstrate that MSC transplantation suppresses MCAO focal ischemia-induced inflammation, possibly through expression of fractalkine and IL-5.

Blood pressure and hypertension are associated with 7 loci in the Japanese population.

BACKGROUND: Two consortium-based genome-wide association studies have recently identified robust and significant associations of common variants with systolic and diastolic blood pressures in populations of European descent, warranting further investigation in populations of non-European descent. METHODS AND RESULTS: We examined the associations at 27 loci reported by the genome-wide association studies on Europeans in a screening panel of Japanese subjects (n=1526) and chose 11 loci showing association signals (1-tailed test in the screening, P<0.3) for an extensive replication study with a follow-up panel of 3 Japanese general-population cohorts (n < or =24 300). Significant associations were replicated for 7 loci-CASZ1, MTHFR, ITGA9, FGF5, CYP17A1-CNNM2, ATP2B1, and CSK-ULK3-with any or all of these 3 traits: systolic blood pressure (P=1.4x10(-14) to 0.05), diastolic blood pressure (P=1.9x10(-12) to 0.05), and hypertension (P=2.0x10(-14) to 0.006; odds ratio, 1.10 to 1.29). The strongest association was observed for FGF5. In the whole study panel, the variance (R(2)) for blood pressure explained by the 7 single-nucleotide polymorphism loci was calculated to be R(2)=0.003 for male and 0.006 for female participants. Stratified analysis implied the potential presence of a gene-age-sex interaction, although it did not reach a conclusive level of statistical significance after adjustment for multiple testing. CONCLUSIONS: We have confirmed 7 loci associated with blood pressure and/or hypertension in the Japanese. These loci can guide fine-mapping efforts to pinpoint causal variants and causal genes with the integration of multiethnic results.

Transplantation of human mesenchymal stem cells promotes functional improvement and increased expression of neurotrophic factors in a rat focal cerebral ischemia model.

Previous studies have suggested that intravenous transplantation of mesenchymal stem cells (MSCs) in rat ischemia models reduces ischemia-induced brain damage. Here, we analyzed the expression of neurotrophic factors in transplanted human MSCs and host brain tissue in rat middle cerebral artery occlusion (MCAO) ischemia model. At 1 day after transient MCAO, 3 x 10(6) immortalized human MSC line (B10) cells or PBS was intravenously transplanted. Behavioral tests, infarction volume, and B10 cell migration were investigated at 1, 3, 7, and 14 days after MCAO. The expression of endogenous (rat origin) and exogenous (human origin) neurotrophic factors and cytokines was evaluated by quantitative real-time RT-PCR and Western blot analysis. Compared with PBS controls, rats receiving MSC transplantation showed improved functional recovery and reduced brain infarction volume at 7 and 14 days after MCAO. In MSC-transplanted brain, among many neurotrophic factors, only human insulin-like growth factor 1 (IGF-1) was detected in the core and ischemic border zone at 3 days after MCAO, whereas host cells expressed markedly higher neurotrophic factors (rat origin) than control rats, especially vascular endothelial growth factor (VEGF) at 3 days and epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) at 7 days after MCAO. Intravenously transplanted human MSCs induced functional improvement, reduced infarct volume, and neuroprotection in ischemic rats, possibly by providing IGF-1 and inducing VEGF, EGF, and bFGF neurotrophic factors in host brain.

Microglia transplantation attenuates white matter injury in rat chronic ischemia model via matrix metalloproteinase-2 inhibition.

Chronic cerebral ischemia is thought to induce white matter lesions (WMLs), which contribute to subcortical vascular dementia. Although glial activation and protease upregulation are believed to modify WML pathology, effective therapy remains elusive. Here, we compare the efficacy of microglial cell transplantation and mesenchymal stem cell (MSC) transplantation in protecting against WML development in a chronic cerebral hypoperfusion rat model. A microglial cell line (HMO6), MSC cell line (B10) or vehicle (phosphate-buffered saline; PBS) was intravenously injected, and the appearance and severity of WMLs were evaluated. Transplanted HMO6 and B10 cells migrated to sites of WMLs, including the corpus callosum (CC) and caudoputamen (CP), reduced the severity of WMLs, and inhibited the accumulation and activation of microglia and astrocytes. Transplantation of both cell types reduced the level of matrix metalloproteinase (MMP)-2 mRNA in microglia of the CC. MMP-2 protein level and activity were also both greatly reduced in the same region. Our results indicate that transplantation of either microglial cells or mesenchymal stem cells could inhibit chronic cerebral ischemia-induced WML formation by decreasing MMP-2 expression in microglia and decreasing MMP-2 activity in the CC region.

Roles of proinflammatory cytokines and the Fas/Fas ligand interaction in the pathogenesis of inflammatory myopathies.

Within the lesions of inflammatory myopathies, muscle fibres and invading mononuclear cells express Fas and Fas ligand (FasL), respectively. However, the roles of the Fas/FasL interaction in the pathogenesis of inflammatory myopathies are not fully understood. In the present study, we investigated the roles of proinflammatory cytokines and the Fas/FasL system in the pathogenesis of inflammatory myopathies. In vitro culturing of muscle cells with the proinflammatory cytokines interferon-gamma, tumour necrosis factor-alpha, and interleukin (IL)-1beta synergistically increased Fas expression, susceptibility to Fas-mediated apoptosis, and the expression of cytoplasmic caspases 8 and 3. In addition, culturing of muscle cells with activated CD4(+) T cells induced muscle cell apoptosis, which was partially inhibited by anti-FasL antibody. We also tested the possibility that T helper (Th) 17, which is an IL-17-producing helper T-cell subset that plays crucial roles in autoimmune and inflammatory responses, participates in the pathogenesis of inflammatory myopathies. Interestingly, in vitro culturing of dendritic cells with anti-Fas immunoglobulin M (IgM) or activated CD4(+) T cells induced the expression of mRNA for IL-23p19, but not for IL-12p35, in addition to proinflammatory cytokines. Furthermore, IL-23p19 and IL-17 mRNAs were detected in the majority of biopsy samples from patients with inflammatory myopathies. Taken together, these results suggest that proinflammatory cytokines enhance Fas-mediated apoptosis of muscle cells, and that the Fas/FasL interaction between invading dendritic cells and CD4(+) T cells induces local production of IL-23 and proinflammatory cytokines, which can promote the proliferation of Th17 cells and enhance Fas-mediated apoptosis of muscle cells, respectively.

Involvement of cystatin C in pathophysiology of CNS diseases.

Cystatin C Leu68Gln variant is known to induce amyloid deposition in cerebral arterioles, resulting in Icelandic type cerebral amyloid angiopathy (CAA). Wild-type cystatin C is also observed in solitary CAA involving amyloid beta protein (Abeta), and accelerates the amyloidogenicity of Abeta in vitro. In neurological inflammatory diseases and leptomeningeal metastasis, low cystatin C levels are accompanied with high activities of cathepsins in the cerebrospinal fluid. Among the cells in CNS, astrocytes appear to secrete cystatin C in response to various proteases and cytokines. Co-localization of Abeta and cystatin C in the brains of Alzheimer's disease (AD) led to the hypothesis that cystatin C is involved in the disease process. We demonstrated that cystatin C microinjection into rat hippocampus induced neuronal cell death in dentate gyrus. Furthermore, apoptotic cell death was observed in neuronal cells treated with cystatin C in vitro. Up-regulation of cystatin C was observed in glial cells with neuronal cell death in vivo. These findings indicate the involvement of cystatin C in the process of neuronal cell death.

Metabolic syndrome increases the risk of ischemic stroke in women.

BACKGROUND: Metabolic syndrome is a characterized by a cluster of cardiovascular risk factors, including visceral obesity, insulin resistance, dyslipidemia, and hypertension. The criteria for diagnosing metabolic syndrome differ among ethnic groups, due in part to differences in eating habits and body build. Little is known about the relationship between metabolic syndrome and ischemic stroke in Asian countries. The aim of this study was to investigate the relationship between metabolic syndrome and first-time ischemic strokes. SUBJECTS & METHODS: Study subjects were 1,493 Japanese adults aged 55 years-old or older with no diabetes mellitus, no history of stroke and no neurological abnormalities, who participated in a voluntary neurological health screening at the Institute of Shimane Health Science, Japan (767 men, 62.0 +/- 5.9 years old at entry and 726 women, 61.8 +/- 5.1 years old at entry). All subjects were given an annual clinical stroke questionnaire. Clinical details of patients who reported strokes were confirmed with the attending physicians. Each subject was evaluated for an average of 6.4 +/- 3.8 years. Metabolic syndrome was defined using the modified criteria for Japanese population published in April 2005. RESULTS: Metabolic syndrome was diagnosed in 11.0% of men and 1.1% of women. Adjusting for age and smoking, female subjects with metabolic syndrome had a 23.1-fold increased risk of suffering ischemic strokes [95% confidence interval (CI), 2.7-196], whereas metabolic syndrome did not increase the risk of ischemic stroke in men. CONCLUSIONS: Metabolic syndrome is more likely to influence a risk for ischemic stroke in women than in men.

Upregulation of protease-activated receptor-1 in astrocytes in Parkinson disease: astrocyte-mediated neuroprotection through increased levels of glutathione peroxidase.

In the present study, we investigated the expression of protease-activated receptors (PARs), receptors for thrombin, in substantia nigra pars compacta (SNpc) of Parkinson disease (PD) brains and cultures of human neurons, astrocytes, oligodendrocytes, and microglia as determined by immunocytochemistry and reverse transcriptase-polymerase chain reaction (RT-PCR). Expression of PAR-1 was demonstrated only in glial fibrillary acidic protein-positive astrocytes in SNpc, and the number of astrocytes expressing PAR-1 increased in SNpc of PD as compared with nonneurologic control brain. Immunoreactivity for thrombin and prothrombin was stronger in astrocytes and the vessel walls in SNpc of PD brains. PAR-1 was expressed in human astrocytes and neurons, but not in oligodendrocytes or microglia as determined by RT-PCR. We investigated thrombin-mediated activation of human astrocytes. Thrombin treatment activates human astrocytes and induces morphologic change and a marked increase in proliferation of astrocytes. Increased expression of glial cell line-derived growth factor and glutathione peroxidase (GPx) but no change in the expression of nerve growth factor and inflammatory cytokines/chemokine (IL-1beta, IL-6, IL-8, MCP-1) was found in thrombin/PAR-activated astrocytes. Next, we studied the neuroprotective effect exerted by thrombin-activated astrocytes in human cerebral neuron x human neuroblastoma hybrid neurons. Although thrombin showed neurotoxicity against human hybrid neurons in a dose-dependent manner, the conditioned media derived from thrombin-pretreated astrocyte cultures promoted the survival of human hybrid neurons. The protective effect was completely inhibited with a GPx inhibitor, mercaptosuccinic acid, indicating that GPx released from thrombin/PAR-activated astrocytes is responsible for neuroprotection of hybrid neurons against thrombin cytotoxicity. The present study suggests that the increased expression of PAR-1 in astrocytes in SNpc of PD brain is the restorative move taken by the brain to provide neuroprotection against neuronal degeneration and cell death of dopaminergic neurons caused by noxious insults during the progression of PD pathology.

Surgery for spontaneous intracerebral hemorrhage has greater remedial value than conservative therapy.

BACKGROUND: The aim of this study was to compare the efficacy of surgery for spontaneous intracerebral hemorrhage with that of medical treatment, based on data from the Japan Stroke Registry Study. METHODS: From 1999 to 2001, 1010 patients with spontaneous intracerebral hemorrhage were registered in the Japan Standard Stroke Registry Study from 45 stroke center hospitals in Japan. The National Institutes of Health Stroke Scale (NIHSS), Japan Stroke Scale (JSS), and modified Rankin Scale scores were used to compare severity and improvement in patients given surgical and medical treatment. CONCLUSIONS: Surgically treated patients, especially those with cerebellar hemorrhage, had significantly greater improvement in NIHSS or JSS score compared with medically treated patients. Our findings indicated that the patients who underwent surgery appeared to have better outcomes. But, because the study was not randomized, this observation cannot be interpreted as indicating that surgery is advantageous.

Neuronal cell death induced by cystatin C in vivo and in cultured human CNS neurons is inhibited with cathepsin B.

Cystatin C, a cysteine protease inhibitor, is implicated in pathogenesis of late-onset Alzheimer's disease and other neurological disorders. Our recent study showed that cystatin C injection into rat hippocampus induced neuronal cell death in granule cell layer of dentate gyrus in vivo. We further confirmed that cystatin C neurotoxicity was inhibited by simultaneous coapplication of cathepsin B, a cysteine protease. In vitro cytotoxicity was also studied in cultures of human CNS neurons, mixed cultures with astrocytes and A1 human hybrid neurons. Cystatin C induced neuronal cell death in a dose-dependent manner, which accompanied increased number of TUNEL (+) cells, up-regulation of active caspase-3 and DNA ladder. The results of the present study indicate that cystatin C participates in the process of apoptotic neuronal cell death in experimental conditions by means of inhibitory activity of cysteine proteases, and that cystatin C might be involved in the pathogenesis in human neurological disorders including Alzheimer's disease.

Autoimmune-associated hemophagocytic syndrome.

Hemophagocytic syndrome (HPS) is a clinicopathological condition characterized by the activation of histiocytes with prominent hemophagocytosis in bone marrow and other reticuloendothelial systems. The occurrence of HPS is usually associated with underlying disorders such as infection and lymphoma. Recently, we described patients with autoimmune disease who developed HPS. In these cases there was no evidence of underlying infection and malignancy, and the occurrences of HPS were associated with active autoimmune disease. Based on these observations, we described autoimmune-associated hemophagocytic syndrome (AAHS). This disease entity is becoming better known, and case reports presenting features compatible with clinical AAHS are increasing. Here, we review the clinical aspects, mechanisms, diagnosis, and treatment of AAHS according to our data and that in the literature.