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1.
Clin Interv Aging ; 13: 211-220, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29440881

RESUMO

PURPOSE: The synergistic effects of a trunk orthosis and an ankle-foot orthosis (AFO) in stroke patients with a hemiplegic gait are unclear. We previously developed a trunk orthosis with joints providing resistive force (TORF) to modify malalignment of the trunk and pelvis and confirmed its positive effects in stroke patients during level walking without an AFO. The aim of the present study was to determine if this trunk orthosis and an AFO have synergistic effects during level walking in community-dwelling patients with chronic stroke. METHODS: Twenty-eight community-dwelling stroke patients performed level walking at a self-selected speed with an AFO and again while wearing a TORF (TORF group) or a corset (control group). Spatiotemporal, kinematic, and kinetic data were recorded using a three-dimensional motion analysis system. RESULTS: When compared with the control group, the TORF group showed significant increases in walking speed, number of steps on the paretic leg per minute, and peak ankle plantar flexion moment during the single stance phase. CONCLUSION: The TORF increased the ankle joint plantar flexion moment at the end of the single stance phase during level walking in stroke patients, leading to an increase in their gait speed because of the modified trunk and pelvis alignment.


Assuntos
Articulação do Tornozelo/fisiopatologia , Órtoses do Pé , Transtornos Neurológicos da Marcha , Aparelhos Ortopédicos , Reabilitação do Acidente Vascular Cerebral/métodos , Acidente Vascular Cerebral/complicações , Velocidade de Caminhada/fisiologia , Idoso , Fenômenos Biomecânicos , Feminino , Transtornos Neurológicos da Marcha/etiologia , Transtornos Neurológicos da Marcha/fisiopatologia , Transtornos Neurológicos da Marcha/reabilitação , Humanos , Imageamento Tridimensional , Vida Independente , Japão , Masculino , Pessoa de Meia-Idade , Amplitude de Movimento Articular , Análise Espaço-Temporal
2.
Circ J ; 80(10): 2155-64, 2016 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-27628221

RESUMO

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).


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Insuficiência Cardíaca , Hipertensão , Imidazóis/administração & dosagem , Volume Sistólico/efeitos dos fármacos , Tetrazóis/administração & dosagem , Adulto , Idoso , Intervalo Livre de Doença , Feminino , Seguimentos , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/fisiopatologia , Humanos , Hipertensão/complicações , Hipertensão/dietoterapia , Hipertensão/mortalidade , Hipertensão/fisiopatologia , Rim/fisiopatologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Taxa de Sobrevida
3.
EBioMedicine ; 2(9): 1071-8, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26501105

RESUMO

BACKGROUND: Although statin therapy is beneficial for the prevention of initial stroke, the benefit for recurrent stroke and its subtypes remains to be determined in Asian, in whom stroke profiles are different from Caucasian. This study examined whether treatment with low-dose pravastatin prevents stroke recurrence in ischemic stroke patients. METHODS: This is a multicenter, randomized, open-label, blinded-endpoint, parallel-group study of patients who experienced non-cardioembolic ischemic stroke. All patients had a total cholesterol level between 4.65 and 6.21 mmol/L at enrollment, without the use of statins. The pravastatin group patients received 10 mg of pravastatin/day; the control group patients received no statins. The primary endpoint was the occurrence of stroke and transient ischemic attack (TIA), with the onset of each stroke subtype set to be one of the secondary endpoints. FINDING: Although 3000 patients were targeted, 1578 patients (491 female, age 66.2 years) were recruited and randomly assigned to pravastatin group or control group. During the follow-up of 4.9 ± 1.4 years, although total stroke and TIA similarly occurred in both groups (2.56 vs. 2.65%/year), onset of atherothrombotic infarction was less frequent in pravastatin group (0.21 vs. 0.64%/year, p = 0.0047, adjusted hazard ratio 0.33 [95%CI 0.15 to 0.74]). No significant intergroup difference was found for the onset of other stroke subtypes, and for the occurrence of adverse events. INTERPRETATION: Although whether low-dose pravastatin prevents recurrence of total stroke or TIA still needs to be examined in Asian, this study has generated a hypothesis that it may reduce occurrence of stroke due to larger artery atherosclerosis. FUNDING: This study was initially supported by a grant from the Ministry of Health, Labour and Welfare, Japan. After the governmental support expired, it was conducted in collaboration between Hiroshima University and the Foundation for Biomedical Research and Innovation.


Assuntos
Povo Asiático , Pravastatina/uso terapêutico , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/etnologia , Idoso , Isquemia Encefálica/complicações , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Japão , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde/métodos , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , Modelos de Riscos Proporcionais , Recidiva , Acidente Vascular Cerebral/etiologia
4.
Intern Med ; 54(6): 573-7, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25790807

RESUMO

OBJECTIVE: Thiazide diuretics are reported to have antioxidant effects and reduce pulse pressure (PP). The aim of this study was to elucidate whether hydrochlorothiazide additionally exerts such effects in stroke patients under treatment with losartan. METHODS: This study was an open-label, randomized, multicenter study. Patients with a history of chronic stroke and treatment with angiotensin receptor blockers or angiotensin-converting enzyme inhibitors for essential hypertension were enrolled. Fifty-five hypertensive patients were randomly assigned to two groups: those further treated with hydrochlorothiazide and those further treated with non-diuretic antihypertensive drugs. RESULTS: Both groups showed a significant decrease in PP over six months (hydrochlorothiazide group: 67±12 mmHg to 58±12, p<0.001; non-diuretic group: 72±12 to 61±12, p<0.001), although no significant differences were observed between the two groups. The malondialdehyde-modified low-density lipoprotein levels did not change significantly after treatment in either group. CONCLUSION: In this study, hydrochlorothiazide treatment did not provide any additional benefits over non-diuretic antihypertensive drugs in terms of antioxidant effects or reducing PP.


Assuntos
Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Hidroclorotiazida/farmacologia , Hipertensão/epidemiologia , Estresse Oxidativo/efeitos dos fármacos , Acidente Vascular Cerebral/epidemiologia , Idoso , Antagonistas de Receptores de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Anti-Hipertensivos/uso terapêutico , Doença Crônica , Feminino , Hemoglobinas Glicadas , Humanos , Hidroclorotiazida/uso terapêutico , Hipertensão/tratamento farmacológico , Lipoproteínas LDL/efeitos dos fármacos , Losartan/farmacologia , Masculino , Pessoa de Meia-Idade
5.
Eur Heart J ; 36(15): 915-23, 2015 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-25637937

RESUMO

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.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Insuficiência Cardíaca/complicações , Hipertensão/tratamento farmacológico , Imidazóis/uso terapêutico , Tetrazóis/uso terapêutico , Antagonistas Adrenérgicos beta/uso terapêutico , Idoso , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Doença Crônica , Quimioterapia Combinada , Feminino , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/fisiopatologia , Humanos , Hipertensão/complicações , Hipertensão/fisiopatologia , Estimativa de Kaplan-Meier , Masculino , Adesão à Medicação , Estudos Prospectivos , Resultado do Tratamento
6.
J Stroke Cerebrovasc Dis ; 24(2): 473-9, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25447211

RESUMO

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.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipidemias/tratamento farmacológico , Ataque Isquêmico Transitório/prevenção & controle , Acidente Vascular Cerebral/prevenção & controle , Idoso , Feminino , Humanos , Hiperlipidemias/complicações , Incidência , Ataque Isquêmico Transitório/complicações , Ataque Isquêmico Transitório/epidemiologia , Japão , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Recidiva , Fatores de Risco , Prevenção Secundária , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/epidemiologia
7.
J Jpn Phys Ther Assoc ; 18(1): 7-14, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26733761

RESUMO

PURPOSE: Generally, stroke patients can walk and stand up fluidly but fulfill the sit-to-walk (STW) task with difficulty. The purpose of this study was to investigate the relationship between movement fluidity and motor strategy in the initial contact of the STW task. METHOD: Thirty stroke patients and ten healthy subjects performed the STW task from a sitting position, and their movement was measured by a motion analysis system. The differences in data between patients and healthy subjects were analyzed using the Mann-Whitney U test. The relationship between fluidity index (FI) and other indices (kinetic and kinematic data in STW, functional independence measure [FIM], and Fugl-Meyer Assessment [FMA]) were analyzed using Spearman's rank correlation coefficient. RESULTS: The stroke patients had lower FI values than the healthy subjects and exhibited shortened step length and prolonged duration from onset to the first stance leg off. FI values correlated with trunk flexure angle at initial contact, first step length, and maximum vertical floor reaction force. The independent level of the FIM of stair climbing and walking ability and the FMA of balance also correlated with FI. CONCLUSION: There is a possibility that poor balance is one of the reasons why stroke patients are unable to start walking fluently from the sitting position. To perform the STW fluidly, patients must start walking before the trunk extension is fully completed. The relationship between FI and indices of physical ability, namely stair climbing and balance, may have therapeutic benefits for coaching the STW task to stroke patients.

8.
Prosthet Orthot Int ; 39(2): 140-9, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24469429

RESUMO

BACKGROUND: An ankle-foot orthosis using an oil damper is designed to enable natural movement of the ankle joint. Wearing an ankle-foot orthosis using an oil damper has been demonstrated to assist the first rocker in stroke patients, but its effect on their gait when not wearing it is unclear. OBJECTIVES: To determine the effect of use of ankle-foot orthosis using an oil damper on the gait of stroke patients with hemiparesis when not wearing the ankle-foot orthosis. STUDY DESIGN: Crossover study. METHODS: The gait of eight stroke patients in the chronic phase when not wearing an ankle-foot orthosis was measured, using a three-dimensional motion analysis system, before using the ankle-foot orthosis using an oil damper and then without and with using the ankle-foot orthosis using an oil damper after 3 weeks of use. Differences in gait were compared between the three measurement conditions. RESULTS: Use of ankle-foot orthosis using an oil damper significantly decreased preswing time and significantly increased the positive ankle joint power in stance when not wearing the ankle-foot orthosis using an oil damper. CONCLUSIONS: These changes indicate the promising therapeutic effects of ankle-foot orthosis using an oil damper use and suggest the ankle-foot orthosis using an oil damper's potential as a therapeutic device. CLINICAL RELEVANCE: After 3 weeks of use of an ankle-foot orthosis using an oil damper, which assists the first rocker, the gait of stroke patients in the chronic phase when not wearing the ankle-foot orthosis using an oil damper was improved. Preswing time was significantly decreased and positive ankle joint power was significantly increased. The ankle-foot orthosis using an oil damper, which assists the first rocker function with natural movement of the ankle joint during gait, has the potential to improve the gait of stroke patients after immediate-term use.


Assuntos
Tornozelo , Desenho de Equipamento/instrumentação , Órtoses do Pé , , Marcha/fisiologia , Acidente Vascular Cerebral/fisiopatologia , Acidente Vascular Cerebral/terapia , Adulto , Idoso , Articulação do Tornozelo/fisiologia , Fenômenos Biomecânicos/fisiologia , Estudos Cross-Over , Feminino , Humanos , Imageamento Tridimensional , Masculino , Pessoa de Meia-Idade , Movimento/fisiologia , Amplitude de Movimento Articular/fisiologia , Caminhada/fisiologia
9.
Int J Stroke ; 9(2): 232-9, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24015915

RESUMO

BACKGROUND: Although statin therapy is beneficial for preventing first strokes, the benefit for recurrent stroke and its sub-types remains unknown in Asian populations. The aim of this study is to examine the role of pravastatin in the secondary prevention of stroke in Japanese patients. METHODS: This is a multicenter, randomized, open-label, parallel group study of patients with noncardioembolic ischemic stroke (atherothrombotic infarction, lacunar infarction, and infarction of undetermined etiology). All patients were diagnosed with hyperlipidemia and with a total cholesterol level between 180 and 240 mg/dl at enrollment. Patients in the treatment group receive 10 mg/day of pravastatin, and those in the control group receive no statin treatment. The primary end-point is the recurrence of stroke, including transient ischemic attack. The secondary end-points include the onset of respective stroke sub-types and functional outcomes related to stroke. The patients were enrolled for five-years and will be followed up for five-years. RESULTS: A total of 1578 eligible patients (age: 66·2 years, men: 68·8%), including 64·2% with lacunar infarction, 25·4% with atherothrombotic infarction, and 10·4% with infarction of undetermined etiology were included in this study. Lipid levels were generally well controlled (total cholesterol: 210·0 mg/dl, low density lipoprotein cholesterol: 129·5 mg/dl) at baseline. In addition, the disability of patients was relatively mild, and cognitive function was preserved in the majority of patients. CONCLUSION: This article reports the rationale, design, and baseline features of a randomized controlled trial to assess the effects of statin for the secondary prevention of stroke. Follow-ups of patients are in progress and will end in 2014.


Assuntos
Anticolesterolemiantes/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Pravastatina/uso terapêutico , Acidente Vascular Cerebral/prevenção & controle , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Japão/epidemiologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Pacientes Ambulatoriais , Prevenção Secundária , Índice de Gravidade de Doença , Estatísticas não Paramétricas , Resultado do Tratamento
10.
J Stroke Cerebrovasc Dis ; 21(3): 165-73, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22440950

RESUMO

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.


Assuntos
Anticoagulantes/administração & dosagem , Fibrilação Atrial/complicações , Benzimidazóis/administração & dosagem , Inibidores do Fator Xa , Acidente Vascular Cerebral/prevenção & controle , beta-Alanina/análogos & derivados , Anticoagulantes/efeitos adversos , Antitrombinas/administração & dosagem , Antitrombinas/efeitos adversos , Fibrilação Atrial/fisiopatologia , Benzimidazóis/efeitos adversos , Dabigatrana , Humanos , Acidente Vascular Cerebral/etiologia , beta-Alanina/administração & dosagem , beta-Alanina/efeitos adversos
11.
Nihon Ronen Igakkai Zasshi ; 49(6): 775-82, 2012.
Artigo em Japonês | MEDLINE | ID: mdl-23883643

RESUMO

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.


Assuntos
Fraturas do Quadril/reabilitação , Apoio Nutricional/métodos , Atividades Cotidianas , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Equipe de Assistência ao Paciente
13.
Hum Mol Genet ; 19(6): 1137-46, 2010 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-20042462

RESUMO

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.


Assuntos
Predisposição Genética para Doença , Fatores de Troca do Nucleotídeo Guanina/genética , Polimorfismo de Nucleotídeo Único/genética , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/genética , Trombose/complicações , Trombose/genética , Alelos , Isquemia Encefálica/complicações , Isquemia Encefálica/epidemiologia , Isquemia Encefálica/genética , Estudos de Casos e Controles , Linhagem Celular Tumoral , Ativação Enzimática , Éxons/genética , Estudo de Associação Genômica Ampla , Humanos , Incidência , Íntrons/genética , Japão/epidemiologia , Estimativa de Kaplan-Meier , Desequilíbrio de Ligação/genética , Ligação Proteica , Fatores de Troca de Nucleotídeo Guanina Rho , Fator de Transcrição Sp1/metabolismo , Acidente Vascular Cerebral/epidemiologia , Transcrição Gênica , Proteína rhoA de Ligação ao GTP/metabolismo
15.
Cell Mol Neurobiol ; 30(3): 453-60, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19830548

RESUMO

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.


Assuntos
Acidose/metabolismo , Sinalização do Cálcio/fisiologia , Cálcio/metabolismo , Hipóxia-Isquemia Encefálica/metabolismo , Degeneração Neural/metabolismo , Trocador de Sódio e Cálcio/metabolismo , Acidose/etiologia , Acidose/fisiopatologia , Amilorida/análogos & derivados , Amilorida/farmacologia , Morte Celular/efeitos dos fármacos , Morte Celular/fisiologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Citosol/metabolismo , Líquido Extracelular/metabolismo , Corantes Fluorescentes , Humanos , Concentração de Íons de Hidrogênio/efeitos dos fármacos , Hipóxia-Isquemia Encefálica/fisiopatologia , Degeneração Neural/etiologia , Degeneração Neural/fisiopatologia , Neuroglia/metabolismo , Neurônios/metabolismo , Propionatos/farmacologia , Sódio/metabolismo
16.
J Neurol Sci ; 287(1-2): 147-50, 2009 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-19740487

RESUMO

PURPOSE: Since attention should be paid to acute stroke patients who may easily worsen, we investigated the predisposing factors for acute deterioration of minor ischemic stroke in Japanese patients. METHODS: We retrospectively investigated 543 patients who were admitted within 7 days of the occurrence of an acute minor stroke with National Institute of Health Stroke Scale (NIHSS) score of 4 or less, between January 2002 and September 2005. Deterioration of neurological findings was defined as the worsening by 2 points or more of the NIHSS score during admission to the hospital. RESULTS: Out of 543 patients, deterioration was noted in 37 patients (6.8%: deterioration group), and not in the other 506 patients (93.2%: non-deterioration group). Multivariate analysis demonstrated that the factors associated with worsening were atherothrombotic brain infarction (deterioration group vs. non-deterioration group: 35.1% vs. 18.0%, P=0.049), elevated systolic blood pressure (170.5+/-32.4 mm Hg vs. 160.4+/-27.4 mm Hg, P=0.033), serum glucose level on admission (146.1+/-60.5mg/dL vs. 121.7+/-54.9 mg/dL, P=0.048), and presence of paralysis (73.0% vs. 54.9%, P=0.003) and vertigo (16.2% vs. 7.9%, P=0.034). The more factors there were that were associated with worsening (atherothrombotic infarction; systolic blood pressure >140 mm Hg; serum glucose level >140 mg/dL; and paralysis, vertigo, and dizziness), the more frequently the deterioration occurred (number of worsening factors 0-2: 4.6%, 3: 12.8%, 4: 32.3%). Although over 80% of patients in the group without deterioration had good functional outcome at discharge, over 90% of patients with deterioration either were discharged to nursing home care or died. CONCLUSION: In this study, the predisposing factors for acute deterioration in minor ischemic stroke were atherothrombotic brain infarction; high blood pressure; elevated serum glucose level; and paralysis, vertigo, and dizziness. Once patients with minor ischemic stroke deteriorated, their functional outcome at discharge was significantly worse than those who had not deteriorated.


Assuntos
Hiperglicemia/epidemiologia , Hipertensão/epidemiologia , Arteriosclerose Intracraniana/epidemiologia , Acidente Vascular Cerebral/epidemiologia , Doença Aguda/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Glicemia/fisiologia , Pressão Sanguínea/fisiologia , Causalidade , Comorbidade , Progressão da Doença , Tontura/epidemiologia , Tontura/fisiopatologia , Feminino , Humanos , Hiperglicemia/fisiopatologia , Hipertensão/fisiopatologia , Arteriosclerose Intracraniana/fisiopatologia , Masculino , Pessoa de Meia-Idade , Paralisia/epidemiologia , Paralisia/fisiopatologia , Valor Preditivo dos Testes , Prognóstico , Recuperação de Função Fisiológica/fisiologia , Estudos Retrospectivos , Acidente Vascular Cerebral/fisiopatologia , Vertigem/epidemiologia , Vertigem/fisiopatologia
17.
Angiology ; 60(3): 276-82, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19497924

RESUMO

PURPOSE: This study aimed to clarify the angiographic characteristics of radiation-induced carotid stenosis. METHODS: We evaluated 11 carotid arteries of patients after radiotherapy (radiotherapy group) and 26 carotid arteries of age- and gender-matched patients without a history of radiotherapy (control group). All patients had carotid stenosis detected by digital subtraction angiography (DSA). We developed an original coordinate system on the DSA to determine the accurate length and location of the carotid lesion. RESULTS: Radiation-induced carotid lesions were significantly longer than carotid lesions caused by atherosclerosis. The maximal stenosis of radiation-induced carotid lesions tended to be at the end of the stenotic area and within a wider range than the nonradiation-induced lesions, including in the proximal common carotid artery (CCA). CONCLUSIONS: Radiation-induced stenotic lesions seem to exist in a wide range of carotid artery, including the CCA, along the vessel, and show maximal stenosis near the end of the stenotic area.


Assuntos
Angiografia Digital , Estenose das Carótidas/diagnóstico por imagem , Neoplasias Otorrinolaringológicas/radioterapia , Lesões por Radiação/diagnóstico por imagem , Idoso , Idoso de 80 Anos ou mais , Artérias Carótidas/efeitos da radiação , Diagnóstico Diferencial , Feminino , Seguimentos , Humanos , Ataque Isquêmico Transitório/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Dosagem Radioterapêutica , Fatores de Risco , Acidente Vascular Cerebral/diagnóstico por imagem
18.
J Neurol Sci ; 285(1-2): 78-84, 2009 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-19535098

RESUMO

BACKGROUND AND PURPOSE: Midkine is a heparin-binding growth factor having various biological activities including chemotaxis of inflammatory cells, angiogenesis and migration of neuronal cells. These biological activities are expected to have a great impact on the pathology of brain infarction in subacute phase. Therefore, we investigated the effect of post-ischemic gene transfer of midkine in the phase. METHODS: Brain ischemia was produced by the photothrombotic distal middle cerebral artery occlusion in spontaneously hypertensive rats. We measured cerebral blood flow by laser Doppler flowmetry. At 90 min after induction of brain ischemia, adenovirus vectors encoding mouse midkine (AdMK) or enhanced green fluorescence protein (AdGFP) were injected into the lateral ventricle. At 7 days after brain ischemia, the infarct volume, angiogenesis, inflammation and neuronal regeneration were evaluated. RESULTS: There were no differences in cerebral blood flow changes between AdMK and AdGFP groups. However, infarct volume of AdMK group was significantly smaller than AdGFP group by 33%. The vascular density, the numbers of leukocytes in blood vessels, infiltrated macrophages and proliferated neuronal precursor cells were not significantly different between both groups. Contrastingly the numbers of migrating neuronal precursor cells toward the brain infarction were significantly increased in AdMK group than AdGFP group. CONCLUSIONS: Neuroprotective effect of midkine gene transfer persisted until the subacute phase of brain infarction. Midkine may contribute to neuronal regeneration. These results suggest the usefulness of midkine gene transfer for treatment of brain infarction.


Assuntos
Isquemia Encefálica/terapia , Citocinas/genética , Terapia Genética , Infarto da Artéria Cerebral Média/terapia , Neurogênese , Adenoviridae/genética , Animais , Encéfalo/irrigação sanguínea , Encéfalo/patologia , Encéfalo/fisiopatologia , Isquemia Encefálica/fisiopatologia , Circulação Cerebrovascular/fisiologia , Citocinas/metabolismo , Técnicas de Transferência de Genes , Vetores Genéticos , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Infarto da Artéria Cerebral Média/fisiopatologia , Fluxometria por Laser-Doppler , Masculino , Camundongos , Midkina , Regeneração Nervosa , Neuroimunomodulação , Ratos , Ratos Endogâmicos SHR , Fatores de Tempo
19.
Stroke ; 40(4): 1245-51, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19246712

RESUMO

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.


Assuntos
Isquemia Encefálica/etnologia , Isquemia Encefálica/genética , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/genética , Acidente Vascular Cerebral/etnologia , Acidente Vascular Cerebral/genética , Idoso , Idoso de 80 Anos ou mais , Povo Asiático/genética , Povo Asiático/estatística & dados numéricos , Estudos de Casos e Controles , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Feminino , Marcadores Genéticos , Predisposição Genética para Doença/etnologia , Haplótipos , Humanos , Hipertensão/etnologia , Hipertensão/genética , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos
20.
Microvasc Res ; 77(3): 327-34, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19154746

RESUMO

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.


Assuntos
Amilorida/farmacologia , Sinalização do Cálcio/efeitos dos fármacos , Peróxido de Hidrogênio/farmacologia , Oxidantes/farmacologia , Pericitos/efeitos dos fármacos , Bloqueadores dos Canais de Sódio/farmacologia , Canais Iônicos Sensíveis a Ácido , Amilorida/análogos & derivados , Encéfalo/irrigação sanguínea , Cálcio/metabolismo , Proteínas de Transporte de Cátions/genética , Proteínas de Transporte de Cátions/metabolismo , Linhagem Celular , Citosol/química , Citosol/metabolismo , Ditiotreitol/farmacologia , Antagonismo de Drogas , Inativação Gênica , Humanos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Pericitos/metabolismo , Canais de Sódio/genética , Canais de Sódio/metabolismo , Trocador de Sódio e Cálcio/genética , Trocador de Sódio e Cálcio/metabolismo , Trocador 1 de Sódio-Hidrogênio , Trocadores de Sódio-Hidrogênio/genética , Trocadores de Sódio-Hidrogênio/metabolismo
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