Influence of Left Ventricular Ejection Fraction on the Effects of Supplemental Use of Angiotensin Receptor Blocker Olmesartan in Hypertensive Patients With Heart Failure.

BACKGROUND: There is no robust evidence of pharmacological interventions to improve mortality in heart failure (HF) patients with preserved left ventricular ejection fraction (LVEF) (HFpEF). In this subanalysis study of the SUPPORT Trial, we addressed the influence of LVEF on the effects of olmesartan in HF. METHODS AND RESULTS: Among 1,147 patients enrolled in the SUPPORT Trial, we examined 429 patients with reduced LVEF (HFrEF, LVEF <50%) and 709 with HFpEF (LVEF ≥50%). During a median follow-up of 4.4 years, 21.9% and 12.5% patients died in the HFrEF and HFpEF groups, respectively. In HFrEF patients, the addition of olmesartan to the combination of angiotensin-converting enzyme inhibitor (ACEI) and ß-blocker (BB) was associated with increased incidence of death (hazard ratio (HR) 2.26, P=0.002) and worsening renal function (HR 2.01, P=0.01), whereas its addition to ACEI or BB alone was not. In contrast, in HFpEF patients, the addition of olmesartan to BB alone was significantly associated with reduced mortality (HR 0.32, P=0.03), whereas with ACEIs alone or in combination with BB and ACEI was not. The linear mixed-effect model showed that in HFpEF, the urinary albumin/creatinine ratio was unaltered when BB were combined with olmesartan, but significantly increased when not combined with olmesartan (P=0.01). CONCLUSIONS: LVEF substantially influences the effects of additive use of olmesartan, with beneficial effects noted when combined with BB in hypertensive HFpEF patients. (Circ J 2016; 80: 2155-2164).

Clinical impacts of additive use of olmesartan in hypertensive patients with chronic heart failure: the supplemental benefit of an angiotensin receptor blocker in hypertensive patients with stable heart failure using olmesartan (SUPPORT) trial.

We examined whether an additive treatment with an angiotensin receptor blocker, olmesartan, reduces the mortality and morbidity in hypertensive patients with chronic heart failure (CHF) treated with angiotensin-converting enzyme (ACE) inhibitors, ß-blockers, or both. In this prospective, randomized, open-label, blinded endpoint study, a total of 1147 hypertensive patients with symptomatic CHF (mean age 66 years, 75% male) were randomized to the addition of olmesartan (n = 578) to baseline therapy vs. control (n = 569). The primary endpoint was a composite of all-cause death, non-fatal acute myocardial infarction, non-fatal stroke, and hospitalization for worsening heart failure. During a median follow-up of 4.4 years, the primary endpoint occurred in 192 patients (33.2%) in the olmesartan group and in 166 patients (29.2%) in the control group [hazard ratio (HR) 1.18; 95% confidence interval (CI), 0.96-1.46, P = 0.112], while renal dysfunction developed more frequently in the olmesartan group (16.8 vs. 10.7%, HR 1.64; 95% CI 1.19-2.26, P = 0.003). Subgroup analysis revealed that addition of olmesartan to combination of ACE inhibitors and ß-blockers was associated with increased incidence of the primary endpoint (38.1 vs. 28.2%, HR 1.47; 95% CI 1.11-1.95, P = 0.006), all-cause death (19.4 vs. 13.5%, HR 1.50; 95% CI 1.01-2.23, P = 0.046), and renal dysfunction (21.1 vs. 12.5%, HR 1.85; 95% CI 1.24-2.76, P = 0.003). Additive use of olmesartan did not improve clinical outcomes but worsened renal function in hypertensive CHF patients treated with evidence-based medications. Particularly, the triple combination therapy with olmesartan, ACE inhibitors and ß-blockers was associated with increased adverse cardiac events. This study is registered at clinicaltrials.gov-NCT00417222.

A nonsynonymous SNP in PRKCH (protein kinase C eta) increases the risk of cerebral infarction.

Cerebral infarction is the most common type of stroke and often causes long-term disability. To investigate the genetic contribution to cerebral infarction, we conducted a case-control study using 52,608 gene-based tag SNPs selected from the JSNP database. Here we report that a nonsynonymous SNP in a member of protein kinase C (PKC) family, PRKCH, was significantly associated with lacunar infarction in two independent Japanese samples (P = 5.1 x 10(-7), crude odds ratio of 1.40). This SNP is likely to affect PKC activity. Furthermore, a 14-year follow-up cohort study in Hisayama (Fukuoka, Japan) supported involvement of this SNP in the development of cerebral infarction (P = 0.03, age- and sex-adjusted hazard ratio of 2.83). We also found that PKCeta was expressed mainly in vascular endothelial cells and foamy macrophages in human atherosclerotic lesions, and its expression increased as the lesion type progressed. Our results support a role for PRKCH in the pathogenesis of cerebral infarction.

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.

Functional SNP of ARHGEF10 confers risk of atherothrombotic stroke.

Although stroke is a common cause of death and a major cause of disability all over the world, genetic components of common forms of ischemic stroke are largely unknown. To identify susceptibility genes of atherothrombotic stroke, we performed a large case-control association study and a replication study in a total of 2775 cases with atherothrombotic stroke and 2839 controls. Through the analysis in 860 cases and 860 age- and sex-matched controls, we found that a single-nucleotide polymorphism (SNP), rs2280887, in the ARHGEF10 gene was significantly associated with atherothrombotic stroke even after the adjustment of multiple testing by a permutation test [unadjusted P = 1.2 x 10(-6), odds ratio = 1.80, 95% confidence interval (CI) = 1.42-2.28]. This association was replicated in independent 1915 cases and 1979 controls. Subsequent fine mapping found another three SNPs which showed similar association due to strong linkage disequilibrium to rs2280887 (r(2) > 0.95). In the functional analyses of these four highly associated SNPs, using luciferase assay and electrophoretic mobility shift assay we found that rs4376531 affected ARHGEF10 transcriptional activity due to the different Sp1-binding affinity. In small GTPase activity assay, we found that a gene product of ARHGEF10 specifically activated RhoA. A population-based cohort study revealed the subjects with rs4376531 CC or CG to increase the incidence of ischemic stroke (P = 0.033, hazard ratio = 1.79, 95% CI = 1.05-3.04). Our data suggest that the functional SNP of ARHGEF10 confers the susceptibility to atherothrombotic stroke.

Dabigatran and factor Xa inhibitors for stroke prevention in patients with nonvalvular atrial fibrillation.

Stroke is a major health problem worldwide, and is often fatal or associated with poor long-term outcomes. Atrial fibrillation (AF) is responsible for up to 20% of all strokes; and the risk of stroke in patients with AF increases with age. Although warfarin is well established for the prevention of stroke in patients with AF, it has some limitations, particularly a narrow therapeutic window, variable/unpredictable pharmacokinetic/pharmacodynamic properties, the restriction of vitamin K intake, and the need for regular coagulation monitoring. Therefore, warfarin is underused for stroke prevention in patients with AF. Several anticoagulants that inhibit thrombin or factor Xa have been developed. Dabigatran is a direct thrombin (factor IIa) inhibitor that overcomes many of the limitations associated with warfarin. The recent Randomized Evaluation of Long Term Anticoagulant Therapy study showed the noninferiority of 110 mg and 150 mg dabigatran twice daily, and the superiority of 150 mg dabigatran twice daily versus adjusted-dose warfarin in the prevention of stroke or systemic embolism in patients with nonvalvular AF. In addition, the rate of intracranial hemorrhage was much lower with both doses of dabigatran than with warfarin. Dabigatran was recently approved in Japan for the prevention of ischemic stroke and systemic embolism in patients with nonvalvular AF. Therefore, in this review, we discuss the properties of dabigatran and its clinical efficacy, safety, and positioning in the prevention of stroke. We also discuss precautions for the use of dabigatran and future perspectives with a view to reducing the risk of stroke with new oral anticoagulants, including factor Xa inhibitors in AF patients.

[Nutrition support team (NST) intervention for hip fracture in elderly patients over 90 years old - Validation effect using the Functional Independence Measure].

AIM: Malnutrition is common in the hospitalized elderly with hip fractures and has been linked to poorer recovery and increased complications. Hence, the aim of this study is to investigate whether nutrition support team (NST) intervention has a beneficial effect on rehabilitation outcome in the elderly, especially in the oldest-old patients with hip fracture using the Functional Independence Measure (FIM). METHOD: Patients were classified into two groups before and after NST intervention, and we evaluated FIM gain, FIM efficacy, and discharge outcomes. Every item was compared in low-ADL patients with an FIM of 54 or less on admission. RESULTS: The numbers of patients were 18 in the non-NST and 22 in the NST group. Although nutritional indicators on admission showed no significant difference in the groups, FIM gain and FIM efficacy were significantly higher (p<0.01) and walking ability at discharge was better in the NST group (p<0.05). In low-ADL patients, the same results were confirmed. CONCLUSION: Although the malnourished patients often have a poor prognosis, there was a significant improvement in rehabilitation effect and discharge outcome in the NST group. Thus, these results suggest the effectiveness of multidisciplinary NST intervention. Moreover, even in elderly patients with low ADL on admission, significant effect of rehabilitation can be expected by appropriate nutritional management.

Change in intracellular pH causes the toxic Ca2+ entry via NCX1 in neuron- and glia-derived cells.

Brain hypoxia or ischemia causes acidosis and the intracellular accumulation of Ca(2+) in neuron. The aims of the present study were to elucidate the interaction between intracellular pH and Ca(2+) during transient acidosis and its effects on the viability of neuronal and glial cells. Intracellular Ca(2+) and pH were measured using the fluorescence of fura-2 and 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein acetoxymethyl ester in neuroblastoma (IMR-32), glioblastoma (T98G), and astrocytoma (CCF-STTG1) cell lines. The administration of 5 mM propionate caused intracellular acidification in IMR-32 and T98G cells but not in CCF-STTG1 cells. After the removal of propionate, the intracellular pH recovered to the resting level. The intracellular Ca(2+) transiently increased upon the removal of propionate in IMR-32 and T98G cells but not in CCF-STTG1 cells. The transient Ca(2+) increase caused by the withdrawal of intracellular acidification was abolished by the removal of external Ca(2+), diminished by a reduction of external Na(+), and inhibited by benzamil. Transient acidosis caused cell death, whereas the cells were more viable in the absence of external Ca(2+). Benzamil alleviated cell death caused by transient acidosis in IMR-32 and T98G cells but not in CCF-STTG1 cells. These results suggest that recovery from intracellular acidosis causes a transient increase in cytosolic Ca(2+) due to reversal of Ca(2+) transport via Na(+)/Ca(2+) exchanger coactivated with Na(+)/H(+) exchanger, which can cause cell death.

LDL cholesterol and the development of stroke subtypes and coronary heart disease in a general Japanese population: the Hisayama study.

BACKGROUND AND PURPOSE: Although the relation between serum LDL cholesterol level and coronary heart disease (CHD) is well established, its relation with stroke subtypes is less clear. METHODS: A total of 2351 inhabitants age >or=40 years in a Japanese community were followed up for 19 years. RESULTS: During follow-up, 271 subjects developed stroke and 144 developed CHD. Whereas the age- and sex-adjusted incidences of CHD significantly increased with increasing LDL cholesterol levels (P for trend <0.001), the associations between LDL cholesterol level and the incidences of ischemic or hemorrhagic stroke were not significant. The age- and sex-adjusted incidences of atherothrombotic infarctions (ATIs) and lacunar infarctions (LIs) significantly increased with increasing LDL cholesterol level (P for trend=0.03 for ATIs and=0.02 for LIs), but no such association was observed for cardioembolic infarction. After multivariate adjustment, the positive associations of LDL cholesterol level with the risks of ATI and CHD remained significant (P for trend=0.02 for ATIs and=0.03 for CHD), whereas the association with LIs was not significant. The risk of ATI significantly increased in the fourth quartile of LDL cholesterol compared with the first quartile (multivariate-adjusted hazard ratio=2.84; 95% CI, 1.17 to 6.93). The multivariate-adjusted risks for developing nonembolic infarction (ATIs and LIs) and CHD were significantly elevated in the groups with elevated LDL cholesterol values with and without the metabolic syndrome. CONCLUSIONS: Our findings suggest that an elevated LDL cholesterol level is a significant risk factor for developing ATI as well as CHD, and these associations are independent of the metabolic syndrome.

Lack of association between variations of PDE4D and ischemic stroke in the Japanese population.

BACKGROUND AND PURPOSE: After the first genomewide association study of ischemic stroke identified PDE4D as a susceptible gene, many replication studies have been conducted. However, the validity of the association has remained controversial because of the heterogeneity of both genetic markers and phenotypes. METHODS: We investigated the association between variations of PDE4D and ischemic stroke by 3 methods: single-marker, haplotype, and tag-single nucleotide polymorphism (SNP) analyses. In the single-marker analysis, we evaluated the association using 2 large case-control samples (1112 cases and 1112 control subjects in a sample obtained from Kyushu, Japan, and 1711 cases and 1786 control subjects in BioBank Japan) and a prospective cohort with 14 years of follow-up. These samples were analyzed both separately and pooled. Haplotype and tag-SNP analyses were performed using the 2 case-control samples together. RESULTS: In single-marker association tests, we found no significant association in the same direction among the 6 SNP reported in the initial study and ischemic stroke subtypes. Haplotype analysis revealed no significant association between the region around the 5'-end of the gene and combined atherothrombotic and cardioembolic infarction. Rs7730070, a SNP located around the 3'-end of PDE4D, showed the lowest nominal probability value by tag-SNP analysis but was not significant after adjustment for multiple testing (adjusted probability value =0.36). CONCLUSIONS: These results suggest that variations in PDE4D are not associated with ischemic stroke risk in the Japanese population.

Amiloride inhibits hydrogen peroxide-induced Ca2+ responses in human CNS pericytes.

The aims of the present study were to investigate the mechanisms of Ca(2+) signaling caused by hydrogen peroxide in CNS pericytes. In cultured human brain microvascular pericytes, cytosolic Ca(2+) concentration was measured by means of fura-2 fluorescence. Reverse transcription and polymerase chain reaction was performed to examine the expression of mRNA. Knockdown of Na(+)/H(+) exchanger (NHE) was done by transfecting the cells with specific double-strand siRNAs for NHE. Externally applied hydrogen peroxide dose-dependently (100 microM-10 mM) increased cytosolic Ca(2+) in human CNS pericytes. Cytosolic Ca(2+) remained high after wash-out of hydrogen peroxide. However, the addition of dithiothreitol rapidly reversed cytosolic Ca(2+) to the resting level. The hydrogen peroxide-induced Ca(2+) increase was not inhibited by nicardipine, Gd(3+), La(3+), or omission of external Ca(2+). Neither thapsigargin nor carbonyl cyanide 4-trifluoromethoxyphenylhydrazone attenuated the hydrogen peroxide-induced Ca(2+) rise. Amiloride and its derivatives, benzamil and hexamethylene amiloride reversed the hydrogen peroxide-induced Ca(2+) increase. Human CNS pericytes expressed acid sensing ion channel (ASIC) 1a, Na(+)/Ca(2+) exchanger (NCX) 1, Na(+)/H(+) exchanger (NHE) 1, and NHE7. However, the removal of external Na(+), treatment with KB-R 7943 and mibefradil, or knockdown of NHE1 and NHE7 did not affect the hydrogen peroxide-induced Ca(2+) increase. Hydrogen peroxide releases Ca(2+) from intracellular Ca(2+) pool via an amiloride-sensitive protein, which is controlled by oxidation of thiol group in human CNS pericytes.

Alcohol intake and quantitative MRI findings among community dwelling Japanese subjects.

BACKGROUND AND PURPOSE: The relationship between alcohol consumption and subclinical findings on magnetic resonance imaging (MRI) remains uncertain. We examined the relationship between light to moderate alcohol intake and silent brain infarction (SBI), white matter lesions (WMLs), and cerebral atrophy. METHODS: Cranial MRI was performed on subjects>or=40 years residing in a rural community in Japan (n=385; mean age, 67.2). Alcohol intake and type was determined using a detailed questionnaire; subjects were categorized into three groups: non-drinkers, light drinkers (<7 drinks per week), and moderate drinkers (>or=7 drinks per week). Former drinkers were considered non-drinkers. Periventricular WMLs, deep WMLs and cerebral atrophy were measured quantitatively using a computer-assisted processing system (%PVWML, %DWML, and %Brain, respectively). RESULTS: Compared with non-drinkers, the prevalence odds ratios for SBI were significantly higher in light and moderate drinkers, after multivariate adjustment. After adjusting for age, sex, and other related factors, the geometric mean %PVWML volumes in light and moderate drinkers were 1.27% and 1.52%, respectively, significantly larger than those for non-drinkers (0.95%). The geometric mean %DWML volume in light drinkers was 0.10%, which was larger than the value for non-drinkers (0.06%); the value for moderate drinkers (0.13%) was significantly larger than that for non-drinkers. The geometric mean %Brain values for non-, light, and moderate drinkers were 92.1, 91.9 and 90.8%, respectively; a statistically significant difference was found between non-drinkers and moderate drinkers. CONCLUSIONS: The present study indicates that regular drinking, including even low levels of consumption, may be a risk factor for subclinical findings detected on MRI in community-dwelling Japanese people.

Deep venous thrombosis after acute intracerebral hemorrhage.

BACKGROUND: We evaluated the incidence of deep venous thrombosis (DVT) and the characteristics of patients with acute ICH who developed DVT. METHODS: We enrolled 52 patients with acute ICH between June 2005 and September 2006. We recorded their stroke risk factors, neurological deficit, hemorrhage size and laboratory data, and performed ultrasonography to detect DVT within 72 h of onset of ICH and after two weeks. RESULTS: DVT was detected a total of 21 patients (40.4%) after two weeks. Patients with DVT tended to be older, and had significantly more severe disturbance of consciousness (p=0.020) and paralysis (p=0.035) on admission than those without DVT. The National Institutes of Health Stroke Scale (NIHSS) score was significantly higher in patients with DVT than those without (p=0.002). Patients with a larger diameter of ICH were more likely to develop DVT (p=0.021). D-dimer value on admission was significantly higher in patients with DVT than those without (p=0.002). Logistic regression analysis indicated that both NIHSS score and D-dimer value were independent risk factors for the occurrence of DVT. CONCLUSIONS: We need be aware that acute ICH patients with severe neurological deficit and high D-dimer value are at increased risk of developing DVT.

The clinical features of adult unilateral moyamoya disease: does it have the same clinical characteristics as typical moyamoya disease?

BACKGROUND: The cerebral hemodynamics in unilateral moyamoya disease have not been clarified. The present study was done to clarify the clinical characteristics of patients with unilateral moyamoya disease compared to those with typical moyamoya disease or occlusive lesions of the internal carotid artery, terminal portion or middle cerebral artery. METHODS: We retrospectively analyzed patients who had unilateral or bilateral steno-occlusive lesions at the internal carotid artery terminal portion or proximal middle cerebral artery. We divided the patients into 3 groups: typical moyamoya (n = 25), unilateral moyamoya (n = 12) and nonmoyamoya (n = 44). Atherosclerotic risk factors and frequency of ischemic and hemorrhagic stroke were compared among the 3 groups. We also examined the extent of cerebral collateral vessels by angiography and used single-photon emission computed tomography to measure the regional cerebral blood flow (rCBF) at rest and after acetazolamide injection. RESULTS: The data on age, sex, hyperlipidemia and smoking habits in the unilateral moyamoya group fell in between those of the typical moyamoya and nonmoyamoya groups. Stroke was less frequent in the unilateral moyamoya group compared to the typical moyamoya or nonmoyamoya groups (p < 0.05). The rCBF at rest and after acetazolamide injection were significantly higher in the unilateral moyamoya group than in the typical moyamoya and nonmoyamoya groups (p < 0.05). CONCLUSIONS: Patients with unilateral moyamoya disease appear to have the lowest frequency of stroke and a reduced rCBF, despite the fact that they have more atherosclerotic risk factors than patients with bilateral lesions.

Polymorphisms in the lymphotoxin alpha gene and the risk of ischemic stroke in the Japanese population. The Fukuoka Stroke Registry and the Hisayama Study.

BACKGROUND AND PURPOSE: Lymphotoxin alpha (LTA), one of the tumor necrosis factor family proteins, is an important proinflammatory cytokine and appears to play a putative role in the inflammatory process of atherosclerosis. Recent genetic studies have suggested that variations in the gene encoding LTA, which affect its expression and biological function, may contribute to the development of vascular diseases. We conducted a case-control study to clarify the association of LTA gene polymorphisms with ischemic stroke in a large Japanese population. METHODS: Genotyping for LTA A252G and C804A polymorphisms was achieved by a rapid-cycle polymerase chain reaction and melting curve analysis using fluorescent probes in 1,044 incident cases of ischemic stroke recruited from the Fukuoka Stroke Registry and 1,044 age- and sex-matched control subjects recruited from the Hisayama Study. RESULTS: The overall distribution of allele and genotype for each polymorphism was similar between stroke patients and control subjects. The allele frequencies of 252G and 804A were slightly lower in stroke patients than in control subjects; however, conditional logistic regression analysis adjusted for potential risk factors found no association between the risk of ischemic stroke and either polymorphism. In terms of stroke subtype, we also found no association of these polymorphisms with any subtypes of ischemic stroke. CONCLUSIONS: Neither the A252G nor C804A polymorphism of the LTA gene was associated with stroke overall and any subtypes of ischemic stroke in the Japanese population.

Characteristic sonographic findings of early restenosis after carotid endarterectomy.

OBJECTIVE: Restenosis of the carotid artery after carotid endarterectomy (CEA) is a major complication. The frequency, time of occurrence, and tissue characteristics of carotid restenosis were assessed with sonography. METHODS: Two hundred sixteen patients who had CEA for carotid stenosis were studied; follow-up sonography and magnetic resonance angiography were done 2 weeks, 3 months, and then every year after CEA. On sonography, restenosis was defined as an internal carotid artery (ICA) with a peak systolic velocity of 170 cm/s or greater or a maximum area of stenosis of 90% or greater. RESULTS: During 605 artery-years of follow-up, 18 patients (7.5%) were found to have restenosis on sonography: 4 at 3 months, 11 at 1 year, and 3 at 2 years after CEA. At the time that restenosis was detected, in all 18 ICAs the peak systolic velocity exceeded 200 cm/s and had more than doubled since the last measurement (mean +/- SD, 103 +/- 27 to 321 +/-107 cm/s), whereas the area of stenosis exceeded 90% in 6 patients, and magnetic resonance angiography revealed stenosis of 60% or greater in 8 patients. On sonography, all of the restenotic plaques were isoechoic and concentric. The restenosis was asymptomatic in 17 patients. Vascular risk factors or the severity of initial carotid stenosis before CEA were not associated with development of restenosis. Eleven patients had successful endovascular therapy, and the others received medical treatment. CONCLUSIONS: A marked increase in the flow velocity through an operated ICA is a good indication of restenosis. The isoechogenicity and concentricity of the restenotic plaques suggest that the restenosis is primarily the result of intimal hyperplasia.

Cerebral venous thrombosis associated with iron deficiency anemia.

A 55-year-old man presented with generalized seizures and postictal left hemiparesis. Computed tomography scanning of his head showed a low density area in the right frontal lobe. Cerebral angiography demonstrated a partial defect in the superior sagittal sinus and cortical veins, indicating the presence of cerebral venous thrombosis. He had bleeding from a peptic ulcer and the laboratory data revealed iron deficiency anemia concomitant with an elevation of D-dimer and thrombin-antithrombin III complex (TAT). After the anemia resolved with the treatment of the peptic ulcer and iron supplementation, the TAT and D-dimer levels were normalized, and the occluded veins were recanalized. In a cerebral venous thrombosis associated with iron deficiency anemia, treatment for the anemia may improve hypercoagulable state without antithrombotic therapy, although the long-term monitoring of TAT and D-dimer levels is required.

Apathy and functional recovery following first-ever stroke.

Apathy is defined as lack of feeling, emotion, or concern. The objective of this study was to examine the frequency of apathy after a first-ever stroke and to prospectively study the impact of apathy on functional recovery. The patients enrolled in this study had the following characteristics: (i) they had experienced a first ischemic or hemorrhagic stroke; (ii) they ranged from 45 to 90 years of age; (iii) the interval from onset to admission ranged from 21 to 90 days; and (iv) they did not demonstrate either marked dementia or aphasia. The functional status was assessed by the Barthel index and the functional independence measures on admission and after a 3-month rehabilitation period. On the basis of the apathy scale, the patients were grouped into those experiencing apathy and those who did not. Next, the scores of the functional measures in the two groups were compared. A total of 67 patients--38 males and 29 females--were analyzed. Fourteen patients (21%) were diagnosed as being apathetic. The apathetic patients tended to be older and more cognitively impaired than the nonapathetic patients. The severity of neurological deficits, the frequency of depression, and the functional status on admission did not differ substantially in the patients with or without apathy. Although the difference was marginal, apathetic patients showed less improvement in the Barthel index or the subscore of functional independence measures than nonapathetic patients after rehabilitation. Thus, we concluded that apathy is not a rare condition after first-ever stroke and it may impair stroke recovery.

[Molecular epidemiology of cerebrovascular diseases; the Hisayama study and the Fukuoka Stroke Registry (FSR)].

The underlying pathogenesis of stroke is mediated by a variety of environmental risk factors as well as genetic ones. Thus, we have to evaluate the environmental factors precisely to identify the stroke-related gene polymorphisms. The Hisayama study, an epidemiological study of cardiovascular diseases, was established in 1961 in Hisayama, Japan. In 2002, a screening survey for the genetic study was performed in Hisayama. The Fukuoka Stroke Registry (FSR) is a hospital-based registration of stroke patients. Stroke specialists from eight medical centers in southern Japan have participated in FSR. In the present study, control and case subjects were recruited from the Hisayama study and FSR, respectively. We performed a genome-wide case-control study and found that a nonsynonymous SNP in PRKCH encoding a member of protein kinase C (PKCC eta) was significantly associated with brain infarction. As a candidate gene analysis, we investigated the role of NAD (P) H oxidase C242T polymorphism in the development of brain infarction. The C242T polymorphism was not associated with lacunar and atherothrombotic infarction; however, the presence of T-allele may have a protective role in the occurrence of atrial fibrillation and cardioembolic brain infarction. These studies may provide important information for the development of the therapeutic strategies against stroke.

[Blood pressure lowering therapy for mild hypertensive patients with a history of stroke].

Hypertension is the primary and one of the major risk factors for stroke. Many hypertensive patients with a history of stroke might have mild to moderate hypertension at the same time. In order to prevent recurrence of cardiovascular diseases including stroke, we should lower their blood pressure levels, carefully and slowly below less than 140/90 mmHg or much lower. Additionally, the patients having any occlusion or stenoses in their carotid and/or intracranial arteries, or even in old-old patients with atherosclerosis, might need further consideration for the cerebral blood flow insufficiency in the course of blood pressure lowering therapy. Although the advantages of inhibitors of renin-angiotensin system are lionized these days (advertisement based medicine: ABM), we should never forget to select more favorable antihypertensive drugs for each patient in case by case (individual based medicine: IBM), to get the definite blood pressure lowering effects without worsening any complications. We also need further gathering of many evidences in a net-work-meta-analysis way, on blood pressure lowering therapy in those hypertensive patients with a history of stroke (evidence based medicine: EBM).