RESUMO
Smoking has detrimental effects on the cardiovascular system; however, some studies have reported better clinical outcomes after thrombolysis for ischemic stroke in smokers than in nonsmokers, a phenomenon known as the smoking paradox. Therefore, this study aimed to examine the smoking paradox in patients with ischemic stroke receiving reperfusion therapy. Data were collected from a multicenter hospital-based acute stroke registry in Fukuoka, Japan. The 1148 study patients were categorized into current and noncurrent smokers. The association between smoking and clinical outcomes, including neurological improvement (≥ 4-point decrease in the National Institutes of Health Stroke Scale during hospitalization or 0 points at discharge) and good functional outcomes (modified Rankin Scale score of 0-2) at 3 months, was evaluated using logistic regression analysis and propensity score-matched analysis. Among the participants, 231 (20.1%) were current smokers. The odds ratios (ORs) of favorable outcomes after adjusting for potential confounders were not significantly increased in current smokers (OR 0.85, 95% confidence interval [CI] 0.60-1.22 for neurological improvement; OR 0.95, 95% CI 0.65-1.38 for good functional outcome). No significant association was found in the propensity score-matched cohorts. Smoking cessation is strongly recommended since current smoking was not associated with better outcomes after reperfusion therapy.
Assuntos
AVC Isquêmico , Reperfusão , Fumar , Humanos , Masculino , Feminino , AVC Isquêmico/terapia , Idoso , Fumar/efeitos adversos , Resultado do Tratamento , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Japão/epidemiologia , Sistema de Registros , Terapia Trombolítica , Pontuação de PropensãoRESUMO
We present a case of a 41-year-old female presenting with recurrence of ischemic stroke on subtherapeutic doses of dabigatran. She had a history of embolic stroke of undetermined sources at the age of 40, and underwent implantable cardiac monitor implantation and had started dabigatran. One year after the first ischemic stroke, she presented with sudden dysarthria and left hemiparesis and was admitted to our hospital. An MRI of the head revealed acute cerebral infarction in the right corona radiata, and an MR angiography revealed right M2 occlusion. Cervical 3D-CTA revealed a protruding structure on the posterior wall of the carotid artery bulb, which was diagnosed as carotid web. She underwent carotid endarterectomy, and the specimen was pathologically confirmed to be vascular malformation due to fibromuscular dysplasia.
Assuntos
Endarterectomia das Carótidas , AVC Isquêmico , Acidente Vascular Cerebral , Feminino , Humanos , Adulto , Dabigatrana , Infarto Cerebral , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/cirurgia , Artérias CarótidasRESUMO
There are still many patients suffering from ischemic stroke and related disabilities worldwide. To develop a treatment that promotes functional recovery after acute ischemic stroke, we need to elucidate endogenous tissue repair mechanisms. The concept of a neurovascular unit (NVU) indicates the importance of a complex orchestration of cell-cell interactions and their microenvironment in the physiology and pathophysiology of various central nervous system diseases, particularly ischemic stroke. In this concept, microvascular pericytes play a crucial role in regulating the blood-brain barrier integrity, cerebral blood flow (CBF), and vascular stability. Recent evidence suggests that pericytes are also involved in the tissue repair leading to functional recovery following acute ischemic stroke through the interaction with other cell types constituting the NVU; pericytes may organize CBF recovery, macrophage-mediated clearance of myelin debris, intrainfarct fibrosis, and periinfarct astrogliosis and remyelination. In this review, we will discuss the physiological and pathophysiological functions of pericytes, their involvement in the molecular mechanisms underlying tissue repair and functional recovery after ischemic stroke, and a therapeutic strategy to promote endogenous regeneration.
Assuntos
AVC Isquêmico , Acidente Vascular Cerebral , Humanos , Pericitos/metabolismo , AVC Isquêmico/metabolismo , Acidente Vascular Cerebral/tratamento farmacológico , Barreira Hematoencefálica/metabolismo , MacrófagosRESUMO
NOX4 is a major reactive oxygen species-producing enzyme that modulates cell stress responses. We here examined the effect of Nox4 deletion on demyelination-remyelination, the most common pathological change in the brain. We used a model of cuprizone (CPZ)-associated demyelination-remyelination in wild-type and Nox4-deficient (Nox4-/- ) mice. While the CPZ-induced demyelination in the corpus callosum after 4 weeks of CPZ intoxication was slightly less pronounced in Nox4-/- mice than that in wild-type mice, remyelination following CPZ withdrawal was significantly enhanced in Nox4-/- mice with an increased accumulation of IBA1-positive microglia/macrophages in the demyelinating corpus callosum. Consistently, locomotor function, as assessed by the beam walking test, was significantly better during the remyelination phase in Nox4-/- mice. Nox4 deletion did not affect autonomous growth of primary-culture oligodendrocyte precursor cells. Although Nox4 expression was higher in cultured macrophages than in microglia, Nox4-/- microglia and macrophages both showed enhanced phagocytic capacity of myelin debris and produced increased amounts of trophic factors upon phagocytosis. The expression of trophic factors was higher, in parallel with the accumulation of IBA1-positive cells, in the corpus callosum in Nox4-/- mice than that in wild-type mice. Nox4 deletion suppressed phagocytosis-induced increase in mitochondrial membrane potential, enhancing phagocytic capacity of macrophages. Treatment with culture medium of Nox4-/- macrophages engulfing myelin debris, but not that of Nox4-/- astrocytes, enhanced cell growth and expression of myelin-associated proteins in cultured oligodendrocyte precursor cells. Collectively, Nox4 deletion promoted remyelination after CPZ-induced demyelination by enhancing microglia/macrophage-mediated clearance of myelin debris and the production of trophic factors leading to oligodendrogenesis.
Assuntos
Doenças Desmielinizantes , Remielinização , Animais , Camundongos , Microglia/metabolismo , Cuprizona/toxicidade , Doenças Desmielinizantes/patologia , Bainha de Mielina/metabolismo , Macrófagos/metabolismo , Corpo Caloso/patologia , Proteínas da Mielina/metabolismo , Camundongos Endogâmicos C57BL , Oligodendroglia/metabolismo , Modelos Animais de Doenças , NADPH Oxidase 4/metabolismoRESUMO
BACKGROUND: Very few comparative studies have focused on the differences in the causes of ischemic stroke between young adults and non-young adults. This study was performed to determine what causes of ischemic stroke are more important in young adults than in non-young adults using a large-scale multicenter hospital-based stroke registry in Fukuoka, Japan. METHODS AND RESULTS: We investigated data on 15,860 consecutive patients aged ≥18 years with acute ischemic stroke (mean age: 73.5 ± 12.4 years, 58.2% men) who were hospitalized between 2007 and 2019. In total, 779 patients were categorized as young adults (≤50 years of age). Although vascular risk factors, including hypertension, diabetes mellitus, and dyslipidemia, were less frequent in young adults than in non-young adults, the prevalence of diabetes mellitus and dyslipidemia in young adults aged >40 years were comparable to those of non-young adults. Lifestyle-related risk factors such as smoking, drinking, and obesity were more frequent in young adults than in non-young adults. As young adults became older, the proportions of cardioembolism and stroke of other determined etiologies decreased, but those of large-artery atherosclerosis and small-vessel occlusion increased. Some embolic sources (high-risk sources: arterial myxoma, dilated cardiomyopathy, and intracardiac thrombus; medium-risk sources: atrial septal defect, nonbacterial thrombotic endocarditis, patent foramen ovale, and left ventricular hypokinesis) and uncommon causes (vascular diseases: reversible cerebral vasoconstriction syndrome, moyamoya disease, other vascular causes, arterial dissection, and cerebral venous thrombosis; hematologic diseases: antiphospholipid syndrome and protein S deficiency) were more prevalent in young adults than in non-young adults, and these trends decreased with age. CONCLUSIONS: Certain embolic sources and uncommon causes may be etiologically important causes of ischemic stroke in young adults. However, the contribution of conventional vascular risk factors and lifestyle-related risk factors is not negligible with advancing age, even in young adults.
Assuntos
Isquemia Encefálica , Diabetes Mellitus , Dislipidemias , Forame Oval Patente , AVC Isquêmico , Acidente Vascular Cerebral , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Isquemia Encefálica/complicações , Isquemia Encefálica/epidemiologia , Dislipidemias/complicações , Feminino , Forame Oval Patente/complicações , Hospitais , Humanos , AVC Isquêmico/epidemiologia , AVC Isquêmico/etiologia , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/etiologiaRESUMO
BACKGROUND AND PURPOSE: Poststroke tissue repair, comprised of macrophage-mediated clearance of myelin debris and pericyte-mediated fibrotic response within the infarct area, is an important process for functional recovery. Herein, we investigated the reciprocal interaction between pericytes and macrophages during poststroke repair and functional recovery. METHODS: We performed a permanent middle cerebral artery occlusion in both wild-type and pericyte-deficient PDGFRß (platelet-derived growth factor receptor ß) heterozygous knockout (Pdgfrb+/-) mice and compared histological changes and neurological functions between the 2 groups. We also examined the effects of conditioned medium harvested from cultured pericytes, or bone marrow-derived macrophages, on the functions of other cell types. RESULTS: Localization of PDGFRß-positive pericytes and F4/80-positive macrophages was temporally and spatially very similar following permanent middle cerebral artery occlusion. Intrainfarct accumulation of macrophages was significantly attenuated in Pdgfrb+/- mice. Intrainfarct pericytes expressed CCL2 (C-C motif ligand 2) and CSF1 (colony stimulating factor 1), both of which were significantly lower in Pdgfrb+/- mice. Cultured pericytes expressed Ccl2 and Csf1, both of which were significantly increased by PDGF-BB and suppressed by a PDGFRß inhibitor. Pericyte conditioned medium significantly enhanced migration and proliferation of bone marrow-derived macrophages. Poststroke clearance of myelin debris was significantly attenuated in Pdgfrb+/- mice. Pericyte conditioned medium promoted phagocytic activity in bone marrow-derived macrophages, also enhancing both STAT3 (signal transducer and activator of transcription 3) phosphorylation and expression of scavenger receptors, Msr1 and Lrp1. Macrophages processing myelin debris produced trophic factors, enhancing PDGFRß signaling in pericytes leading to the production of ECM (extracellular matrix) proteins and oligodendrogenesis. Functional recovery was significantly attenuated in Pdgfrb+/- mice, parallel with the extent of tissue repair. CONCLUSIONS: A reciprocal interaction between pericytes and macrophages is important for poststroke tissue repair and functional recovery.
Assuntos
Infarto da Artéria Cerebral Média/metabolismo , Macrófagos/metabolismo , Pericitos/metabolismo , Recuperação de Função Fisiológica/fisiologia , Acidente Vascular Cerebral/metabolismo , Cicatrização/fisiologia , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Meios de Cultivo Condicionados , Infarto da Artéria Cerebral Média/patologia , Macrófagos/patologia , Camundongos , Camundongos Knockout , Pericitos/patologia , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Acidente Vascular Cerebral/patologiaRESUMO
Epstein-Barr virus (EBV) infection is occasionally accompanied by central nervous system (CNS) complications, particularly in immunosuppressed patients. However, the symptoms and clinical features of EBV infection in the CNS are rather heterogeneous and remain unknown. We herein describe the first reported adult case manifesting nonconvulsive status epilepticus (NCSE), possibly associated with reactivation of EBV in an immunosuppressive state. A 63-year-old man with a history of acute myeloid leukemia and taking immunosuppressants was admitted due to progressively impaired consciousness without any focal neurological signs, including paralysis or convulsions. Arterial spin labeling magnetic resonance imaging (ASL-MRI) and brain perfusion single-photon emission computed tomography showed hyperperfusion in the right temporal region, despite no morphological abnormalities in other MRI sequences. White blood cell counts, EBV viral load, and virus-capsid antigen IgG in cerebrospinal fluid were elevated. We diagnosed him with EBV-associated encephalopathy presenting with NCSE. Administration of levetiracetam, an antiepileptic, improved the consciousness and the abnormal hyperperfusion. This case suggests a new concept of EBV-associated encephalopathy leading to epilepsy, particularly in immunosuppressed patients.
RESUMO
We report a 58-year-old woman who suddenly developed brain infarction with weakness of the left lower extremity and left perioral dysesthesia during postoperative tamoxifen therapy for breast cancer and prednisolone therapy for rheumatoid arthritis. Diffusion-weighted images detected multiple areas of hyperintensity in the posterior circulation system of the brain. Despite extensive examinations, we could not identify any embolic sources except hypoplasia of the right vertebral artery. We found decreased activity of protein C against its antigen level (activity: 59% versus antigen: 122%) with enhanced activity of coagulation factor VIII (178%) and von Willebrand factor (285%). DNA sequencing identified trinucleotide deletion of the PROC gene leading to 1 amino acid deletion at Lys-193 (p.Lys193del). We speculate that the PROC gene polymorphism may have participated in tamoxifen- and prednisolone- associated hypercoagulable state, leading to development of an embolic stroke in this patient.
Assuntos
Coagulação Sanguínea/genética , Embolia Intracraniana/etiologia , Deficiência de Proteína C/genética , Proteína C/genética , Deleção de Sequência , Acidente Vascular Cerebral/etiologia , Anticoagulantes/uso terapêutico , Antineoplásicos Hormonais/efeitos adversos , Coagulação Sanguínea/efeitos dos fármacos , Feminino , Predisposição Genética para Doença , Glucocorticoides/efeitos adversos , Humanos , Embolia Intracraniana/sangue , Embolia Intracraniana/diagnóstico por imagem , Embolia Intracraniana/tratamento farmacológico , Metilprednisolona/efeitos adversos , Pessoa de Meia-Idade , Fármacos Neuroprotetores/uso terapêutico , Fenótipo , Deficiência de Proteína C/sangue , Deficiência de Proteína C/complicações , Deficiência de Proteína C/diagnóstico , Recidiva , Fatores de Risco , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/tratamento farmacológico , Tamoxifeno/efeitos adversos , Resultado do TratamentoRESUMO
Background and Purpose- Smoking is an established risk factor for stroke; however, it is uncertain whether prestroke smoking status affects clinical outcomes of acute ischemic stroke. This study aimed to elucidate the association between smoking status and functional outcomes after acute ischemic stroke. Methods- Using a multicenter hospital-based stroke registry in Japan, we investigated 10 825 patients with acute ischemic stroke hospitalized between July 2007 and December 2017 who had been independent before stroke onset. Smoking status was categorized into those who had never smoked (nonsmokers), former smokers, and current smokers. Clinical outcomes included poor functional outcome (modified Rankin Scale score ≥2) and functional dependence (modified Rankin Scale score 2-5) at 3 months. We adjusted for potential confounding factors using a logistic regression analysis. Results- The mean age of patients was 70.2±12.2 years, and 37.0% were women. There were 4396 (42.7%) nonsmokers, 3328 (32.4%) former smokers, and 2561 (24.9%) current smokers. The odds ratio (95% CI) for poor functional outcome after adjusting for confounders increased in current smokers (1.29 [1.11-1.49] versus nonsmokers) but not in former smokers (1.05 [0.92-1.21] versus nonsmokers). However, among the former smokers, the odds ratio of poor functional outcome was higher in those who quit smoking within 2 years of stroke onset (1.75 [1.15-2.66] versus nonsmokers). The risk of poor functional outcome tended to increase as the number of daily cigarettes increased in current smokers (P for trend=0.002). All these associations were maintained for functional dependence. Conclusions- Current and recent smoking is associated with an increased risk of unfavorable functional outcomes at 3 months after acute ischemic stroke. Registration- URL: http://www.fukuoka-stroke.net/english/index.html. Unique identifier: 000000800.
Assuntos
Isquemia Encefálica/epidemiologia , Sistema de Registros , Fumar/efeitos adversos , Acidente Vascular Cerebral/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de RiscoRESUMO
The timing of anti-coagulation therapy initiation after acute cardioembolic stroke remains controversial. We investigated the effects of post-stroke administration of a factor Xa inhibitor in mice, focusing on tissue repair and functional restoration outcomes. We initiated administration of rivaroxaban, a Xa inhibitor, immediately after permanent distal middle cerebral artery occlusion (pMCAO) in CB-17 mice harboring few leptomeningeal anastomoses at baseline. Rivaroxaban initiated immediately after pMCAO hindered the recovery of blood flow in ischemic areas by inhibiting leptomeningeal anastomosis development, and led to impaired restoration of neurologic functions with less extensive peri-infarct astrogliosis. Within infarct areas, angiogenesis and fibrotic responses were attenuated in rivaroxaban-fed mice. Furthermore, inflammatory responses, including the accumulation of neutrophils and monocytes/macrophages, local secretion of pro-inflammatory cytokines, and breakdown of the blood-brain barrier, were enhanced in infarct areas in mice treated immediately with rivaroxaban following pMCAO. The detrimental effects were not found when rivaroxaban was initiated after transient MCAO or on day 7 after pMCAO. Collectively, early post-stroke initiation of a factor Xa inhibitor may suppress leptomeningeal anastomosis development and blood flow recovery in ischemic areas, thereby resulting in attenuated tissue repair and functional restoration unless occluded large arteries are successfully recanalized.
Assuntos
Rivaroxabana/metabolismo , Acidente Vascular Cerebral/tratamento farmacológico , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Isquemia Encefálica/fisiopatologia , Modelos Animais de Doenças , Fator Xa/metabolismo , Inibidores do Fator Xa/metabolismo , Inibidores do Fator Xa/farmacologia , Fibrinolíticos/farmacologia , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/fisiopatologia , Masculino , Camundongos , Rivaroxabana/farmacologia , Acidente Vascular Cerebral/fisiopatologia , Fatores de TempoAssuntos
Adenosina Trifosfatases/genética , Aterosclerose/genética , Isquemia Encefálica/genética , Variação Genética , Doença de Moyamoya/genética , Acidente Vascular Cerebral/genética , Ubiquitina-Proteína Ligases/genética , Povo Asiático/genética , Aterosclerose/diagnóstico , Aterosclerose/etnologia , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/etnologia , Estudos de Casos e Controles , Frequência do Gene , Predisposição Genética para Doença , Humanos , Japão/epidemiologia , Doença de Moyamoya/diagnóstico , Doença de Moyamoya/etnologia , Fenótipo , Medição de Risco , Fatores de Risco , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/etnologia , População Branca/genéticaRESUMO
Reactive oxygen species (ROS) modulate the growth of neural stem/precursor cells (NS/PCs) and participate in hippocampus-associated learning and memory. However, the origin of these regulatory ROS in NS/PCs is not fully understood. In the present study, we found that Nox4, a ROS-producing NADPH oxidase family protein, is expressed in primary cultured NS/PCs and in those of the adult mouse brain. Nox inhibitors VAS 2870 and GKT137831 or Nox4 deletion attenuated bFGF-induced proliferation of cultured NS/PCs, while lentivirus-mediated Nox4 overexpression increased the production of H2O2, the phosphorylation of Akt, and the proliferation of cultured NS/PCs. Nox4 did not significantly affect the potential of cultured NS/PCs to differentiate into neurons or astrocytes. The histological and functional development of the hippocampus appeared normal in Nox4-/- mice. Although pathological and functional damages in the hippocampus induced by the neurotoxin trimethyltin were not significantly different between wild-type and Nox4-/- mice, the post-injury reactive proliferation of NS/PCs and neurogenesis in the subgranular zone (SGZ) of the dentate gyrus were significantly impaired in Nox4-/- animals. Restoration from the trimethyltin-induced impairment in recognition and spatial working memory was also significantly attenuated in Nox4-/- mice. Collectively, our findings suggest that Nox4 participates in NS/PC proliferation and neurogenesis in the hippocampus following injury, thereby helping to restore memory function.
Assuntos
Proliferação de Células/fisiologia , Hipocampo/metabolismo , NADPH Oxidase 4/metabolismo , Células-Tronco Neurais/metabolismo , Neurogênese/fisiologia , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Hipocampo/efeitos dos fármacos , Peróxido de Hidrogênio/metabolismo , Aprendizagem/efeitos dos fármacos , Aprendizagem/fisiologia , Masculino , Memória/efeitos dos fármacos , Memória/fisiologia , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , NADPH Oxidase 2/metabolismo , NADPH Oxidase 4/genética , Células-Tronco Neurais/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurotoxinas , Compostos de TrimetilestanhoRESUMO
We report a 35-year-old woman who suddenly developed left hemiparesis and dysarthria at 13days after treatment with intrathecal and intravenous methotrexate for intravascular large B cell lymphoma with possible central nervous system infiltration. Seven hours after onset, she developed further right hemiparesis and aphasia. However, the majority of neurologic symptoms disappeared spontaneously and completely by 34hours. We also recorded the dynamic progression and regression of abnormal signals in the bilateral corona radiata on diffusion-weighted imaging, in parallel with neurologic symptoms. The rapid reversal of MR abnormalities and neurologic symptoms allowed us to diagnose methotrexate encephalopathy, and exclude intravascular large B cell lymphoma recurrence and regular brain infarction. The case provides new data on the dynamic changes of abnormal signals on magnetic resonance imaging in methotrexate encephalopathy over a short recovery time.
Assuntos
Antimetabólitos Antineoplásicos/efeitos adversos , Isquemia Encefálica/diagnóstico por imagem , Imagem de Difusão por Ressonância Magnética , Encefalite/induzido quimicamente , Encefalite/diagnóstico por imagem , Linfoma de Células B/tratamento farmacológico , Metotrexato/efeitos adversos , Acidente Vascular Cerebral/diagnóstico por imagem , Adulto , Diagnóstico Diferencial , Disartria/induzido quimicamente , Diagnóstico Precoce , Feminino , Humanos , Linfoma de Células B/patologia , Paresia/induzido quimicamente , Valor Preditivo dos TestesRESUMO
Importance: It is unknown whether poststroke outcome varies between different potential causes in patients with cryptogenic stroke. Objective: To investigate whether functional outcome differs according to potential embolic sources after cryptogenic stroke. Design, Setting, and Participants: This multicenter, hospital-based, prospective stroke registry cohort study investigated potential embolic sources on admission and assessed 3-month outcome in patients with ischemic stroke hospitalized at 7 stroke centers in the Fukuoka Stroke Registry. This registry enlisted 9866 consecutive patients with acute ischemic stroke who were enrolled from June 11, 2007, to May 31, 2016, in Fukuoka, Japan. Patients with small vessel occlusion (n = 3130), extracranial and intracranial atherosclerosis causing at least 50% luminal stenosis in arteries supplying the area of ischemia (n = 2011), and other specific uncommon causes of stroke identified (n = 301) were excluded. Potential embolic sources were diagnosed in patients with embolic stroke of undetermined source (ESUS) based on the following criteria proposed by the Cryptogenic Stroke/ESUS International Working Group: minor-risk potential cardioembolic sources (MCS) (n = 209), covert paroxysmal atrial fibrillation (CPAF) (n = 43), cancer associated (CA) (n = 79), arteriogenic emboli (AE) (n = 522), paradoxical embolism (PE) (n = 190), and undetermined embolism (unidentified or ≥2 potential embolic sources) (UE) (n = 1120). Main Outcomes and Measures: The association between potential causes and functional outcome was evaluated in reference to cardioembolic stroke (CE) caused by major-risk cardioembolic sources after adjusting for age, sex, National Institutes of Health Stroke Scale score on admission, and reperfusion therapy using logistic regression analysis. Functional dependency (modified Rankin Scale score, 3-5) was evaluated at 3 months after onset. Results: The study enrolled 2261 patients with CE (mean [SD] age, 78.4 [10.7] years, 51.8% male) and 2163 patients with ESUS (mean [SD] age, 72.4 [12.6] years, 57.1% male). Compared with CE (median National Institutes of Health Stroke Scale score, 8 [interquartile range {IQR}, 3-17]), baseline neurological deficits did not differ in MCS (median, 7 [IQR, 2-18]), CPAF (median, 6 [IQR, 2-18]), and CA (median, 5 [IQR, 2-13]) but were less severe in AE (median, 2 [IQR, 1-4]), PE (median, 2 [IQR, 1-4]), and UE (median, 3 [IQR, 1-7]). Multivariable-adjusted odds ratios of functional dependency significantly increased in CA (3.61; 95% CI, 1.52-8.54 vs CE) but decreased in PE (0.33; 95% CI, 0.16-0.71 vs CE). Conclusions and Relevance: Potential causes are associated with poststroke outcome in patients with cryptogenic stroke. Embolic sources potentially underlying cryptogenic stroke should be considered significant variables associated with outcome.
Assuntos
Embolia/etiologia , Desempenho Físico Funcional , Acidente Vascular Cerebral/tratamento farmacológico , Resultado do Tratamento , Idoso , Idoso de 80 Anos ou mais , Embolia/complicações , Embolia/epidemiologia , Feminino , Humanos , Japão/epidemiologia , Modelos Logísticos , Masculino , Razão de Chances , Estudos Prospectivos , Sistema de Registros/estatística & dados numéricos , Fatores de Risco , Acidente Vascular Cerebral/epidemiologiaRESUMO
Excessive DNA damage induced by ionising radiation (IR) to normal tissue cells is known to trigger cellular senescence, a process termed stress-induced premature senescence (SIPS). SIPS is often accompanied by the production of reactive oxygen species (ROS), and this is reported to be important for the initiation and maintenance of SIPS. However, the source of ROS during SIPS after IR and their significance in radiation-induced normal tissue damage remain elusive. In the present study, we tested the hypothesis that the NADPH oxidase (NOX) family of proteins mediates ROS production in SIPS-induced cells after IR and plays a role in SIPS-associated biological events. X-irradiation of primary mouse embryonic fibroblasts (MEFs) resulted in cellular senescence and the concomitant increase of intracellular ROS. Among all six murine NOX isoforms (NOX1-4 and DUOX1/2), only NOX4 was detectable under basal conditions and was upregulated following IR. In addition, radiation-induced ROS production was diminished by genetic or pharmacological inhibition of NOX4. Meanwhile, NOX4 deficiency did not affect the induction of cellular senescence after IR. Furthermore, the migration of human monocytic U937 cells to the culture medium collected from irradiated MEFs was significantly reduced by NOX4 inhibition, suggesting that NOX4 promotes the recruitment of inflammatory cells. Collectively, our findings imply that NOX4 mediates ROS production in radiation-induced senescent cells and contributes to normal tissue damage after IR via the recruitment of inflammatory cells and the exacerbation of tissue inflammation.
Assuntos
Senescência Celular/fisiologia , Inflamação/metabolismo , NADPH Oxidase 4/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Movimento Celular , Células Cultivadas , Humanos , Estresse OxidativoRESUMO
Intravascular lymphoma (IVL) is a rare disease characterized by the proliferation of lymphoma cells in the lumen of the small blood vessels. Although early diagnosis of IVL is important to prolong survival of the patients, its atypical symptoms and clinical course often delay its diagnosis. More than half of the patients are diagnosed at autopsy. We report a 68-year-old man who presented with transient ideomotor apraxia and mildly elevated soluble interleukin-2 receptor levels. He was initially diagnosed with aortogenic embolic stroke. He developed rapidly progressive neurological manifestations with enlargement of brain lesions on brain computed tomography and magnetic resonance imaging and died 3 months after symptom onset. The diagnosis of IVL could not be made by random skin biopsy, but was finally made at autopsy. For the early diagnosis, sufficient random skin biopsy or brain biopsy should be planned when suspected.
RESUMO
OBJECTIVE: Angiopoietin-like protein 2 (ANGPTL2), a proinflammatory mediator, has been reported to accelerate the development of insulin resistance, endothelial dysfunction, and atherosclerosis in mice. However, no cohort studies have examined the relationship between serum ANGPTL2 levels and the development of cardiovascular disease (CVD) in a general population. APPROACH AND RESULTS: A total of 3005 community-dwelling Japanese aged ≥40 years without a history of CVD were divided into 4 groups according to the quartiles of serum ANGPTL2 concentrations (Q1, lowest and Q4, highest) and followed up for 10 years. The hazards ratios and their 95% confidence intervals for the development of CVD (coronary heart disease or stroke) were estimated using a Cox proportional hazards model. During the follow-up, 219 first-ever CVD events were observed. The risk of CVD increased significantly with elevating ANGPTL2 levels after adjustment for age, sex, serum total cholesterol, use of lipid-lowering agents, ECG abnormalities, smoking habits, alcohol intake, and regular exercise (hazards ratios [95% confidence interval], Q1, 1.00 [reference]; Q2, 1.27 [0.80-2.04]; Q3, 1.48 [0.95-2.32]; and Q4, 1.85 [1.20-2.85]; P=0.003 for trend). After additional adjustment for metabolic syndrome components and serum high-sensitivity C-reactive protein levels as an inflammatory marker, the association was attenuated but remained significant (hazards ratios [95% confidence interval], Q1, 1.00 [reference]; Q2, 1.21 [0.76-1.94]; Q3, 1.38 [0.87-2.17]; and Q4, 1.66 [1.05-2.60]; P=0.02 for trend). CONCLUSIONS: Our findings suggest that elevated serum ANGPTL2 levels are a novel risk factor for the development of CVD in the general population. This association is partially mediated by metabolic disorders and inflammation.
Assuntos
Angiopoietinas/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/epidemiologia , Distribuição por Idade , Idoso , Proteína 2 Semelhante a Angiopoietina , Proteínas Semelhantes a Angiopoietina , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , Doenças Cardiovasculares/diagnóstico , Feminino , Humanos , Incidência , Inflamação/sangue , Inflamação/epidemiologia , Japão/epidemiologia , Modelos Lineares , Modelos Logísticos , Masculino , Doenças Metabólicas/sangue , Doenças Metabólicas/epidemiologia , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Distribuição por Sexo , Fatores de Tempo , Regulação para CimaRESUMO
BACKGROUND: Oral anticoagulants (OACs) reduce the incidence of embolic events associated with non-valvular atrial fibrillation (NVAF); however, ischemic stroke can still occur in such patients. Although there are various causes of ischemic stroke in patients with NVAF, their medication status at onset has scarcely been studied. This retrospective study aimed to determine the underlying causes of ischemic stroke in patients with NVAF in relation to pre-stroke anticoagulation. METHODS: Among Japanese patients with acute ischemic stroke enrolled in the Fukuoka Stroke Registry from June 2007 to May 2013, 1,302 patients with NVAF who had been hospitalized within 24 h of onset were included in this study, and their backgrounds, pre-stroke use of OACs and prothrombin time-international normalized ratio (PT-INR) on admission were investigated. Strokes were regarded as being non-cardioembolic (CE) type when causes other than NVAF had been identified. The sub-therapeutic range (TR) for warfarin was defined according to Japanese guidelines for pharmacotherapy of atrial fibrillation. RESULTS: Atrial fibrillation had been diagnosed prior to onset of stroke in 704 of 1,302 patients (54%). However, it had not been detected before or on admission, but identified later during hospitalization in 270 patients (21%). Of the patients who had atrial fibrillation on admission but had not been diagnosed as having it, 108 (8%) had not received any medication before onset of stroke and 220 (17%) had received medications other than OACs. OACs had been administered to 415 (59%) of the patients with known atrial fibrillation. The proportion of pre-stroke CHADS2 or CHA2DS2-VASc scores ≥1 ranged from 93 to 99% depending on whether atrial fibrillation had been diagnosed or anticoagulation therapy administered before stroke onset. The PT-INR was in the sub-TR on admission in 283 of 399 patients (71%) receiving warfarin. Male sex, smoking and previous stroke were more prevalent in patients with values within or over the TR of PT-INR than in those in the sub-TR. Non-CE stroke was more prevalent in patients with values above the lower therapeutic limit of the recommended PT-INR than in those in the sub-TR (p < 0.001). The number of CE strokes was much smaller in patients with high admission PT-INR values; this was not observed for non-CE ischemic strokes (p < 0.001). CONCLUSIONS: In the clinical setting, under-diagnosis, underuse and sub-therapeutic doses of OACs are major causes of ischemic stroke in patients with NVAF. However, non-CE ischemic strokes may develop in patients receiving therapeutic doses of warfarin.
Assuntos
Anticoagulantes/administração & dosagem , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/epidemiologia , Isquemia Encefálica/epidemiologia , Isquemia Encefálica/prevenção & controle , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/prevenção & controle , Varfarina/administração & dosagem , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Fibrilação Atrial/sangue , Fibrilação Atrial/diagnóstico , Coagulação Sanguínea/efeitos dos fármacos , Isquemia Encefálica/sangue , Isquemia Encefálica/diagnóstico , Feminino , Humanos , Coeficiente Internacional Normatizado , Japão/epidemiologia , Masculino , Prevalência , Tempo de Protrombina , Sistema de Registros , Estudos Retrospectivos , Fatores de Risco , Fatores Sexuais , Fumar/efeitos adversos , Fumar/sangue , Fumar/epidemiologia , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/diagnóstico , Resultado do TratamentoRESUMO
A 62-year-old man complained of gait disturbance, bladder and bowel dysfunction and paresthesia of both legs one month before admission. His symptoms were suggestive of cauda equina syndrome. After admission, he developed rapid progressive numbness and weakness of both legs and a disturbance of consciousness. A random skin biopsy was performed and a histological diagnosis of intravascular large B cell lymphoma (IVLBCL) was reached. His symptoms were improved after rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) therapy.