Orientador: Fernando Cendes / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-19T20:24:08Z (GMT). No. of bitstreams: 1 Tedeschi_GuilhermeGarlipp_M.pdf: 7486635 bytes, checksum: b738f054440da6d0b0f0d6b7055bde2b (MD5) Previous issue date: 2012 / Resumo: Introdução: O Acidente Vascular Encefálico (AVE) é uma importante doença, com enorme implicação em fatores sociais e econômicos em todo o mundo, sobretudo no Brasil, onde é classificado como a maior causa de morte de origem cardiovascular, além de ser a principal responsável por grave morbidade, que traz incapacidade funcional e dependência ao paciente. A terapia com o Fator Ativador do Plasminogênio Tecidual (rt-PA), na fase aguda, imediatamente pós ictus do AVE, vem sendo muito utilizada mundialmente para o restabelecimento da circulação cerebral no AVE isquêmico, com grande influência na recuperação das habilidades motoras. Diversas são as formas de quantificar os danos ocorridos pelo AVE, entre eles o exame de Ressonância Magnética (RM), que é capaz de apresentar resultados precisos para diagnóstico clínicos e outros tipos de investigação menos explícitos, que contribuem para a mensuração da lesão celular e sua consequente recuperação. Objetivo: O presente estudo tem como objetivo principal, avaliar a espessura cortical dos pacientes, em dois diferentes períodos do AVE (Agudo e Crônico) e estabelecer associações em relação à função motora e o tempo de início da trombólise. Metodologia: Pacientes (33) com AVE isquêmico, trombolizados (T) e não trombolizados (NT), foram avaliados com RM e escalas funcionais (Fugl Meyer, MIF e FAC) em dois momentos da evolução da doença, sendo o agudo com 62,67 dias após o AVE e o crônico (follow up) com 419,22 dias após AVE. O tempo de início de tratamento com o trombolítico foi dividido em mais de 150 minutos (Grupo D) e Menos de 150 minutos (Grupo A). A análise estatística foi realizada pelo programa Freesurfer, ferramenta Qdec, que analisou as imagens (p<0,05) e pelo programa Systat 9. Resultados: A análise de todas as imagens (agudo e crônico) mostrou maior espessura cortical no grupo crônico, sendo que o mesmo acorre para o grupo T na fase crônica, para o grupo A na fase aguda e para o grupo D na fase crônica. Observou-se aumento na espessura cortical de áreas cerebrais específicas (Wernicke e giro pré central) entre as fases aguda e crônica. Observou-se também ganho funcional significativo (p < 0,05) em relação às escalas Fugl Meyer e MIF entre os períodos agudo e crônico / Abstract: Introduction: Stroke is an important disease with great implications in social and economic factors around the world, especially in Brazil, where is ranked as the first cardiovascular cause of death and the main cause of morbidity, which generates functional disability and some level of dependence on the patient. Thrombolysis with tissue plasminogen activator factor (rt-PA) on acute phase of stroke, immediately after ictus, has been widely used worldwide for the restoration of cerebral circulation in ischemic stroke, with great influence on the recovery of motor skills. There are several ways to quantify the damage incurred by stroke, including magnetic resonance imaging (MRI), which is able to provide accurate results for diagnostic and other not too explicit research results that contribute to the measurement of cell damage and its subsequent recovery. Objective: The main objective of the present study is to evaluate cortical thickness in two different periods of the stroke (Acute and Chronic) and establish associations in relation to motor function and the time of thrombolysis. Methodology: Patients (33) with ischemic stroke were evaluated with MRI and functional scales (Fugl Meyer, FIM and FAC) in two stroke stages, the acute phase with 62.67 days post-stroke and chronic phase (follow up), with 419.22 days after stroke. The time of thrombolytic treatment was divided into more than 150 minutes (Group D) and less than 150 minutes (Group A). MRI images statistical analysis were performed by the software Freesurf, Qdec tool (p < 0.05) and other analysis were performed by Systat 9. Results: The analysis of all images showed increased cortical thickness in chronic group. Same results were found at T group in the chronic phase, at A group in acute phase and at D group in the chronic phase. Increased cortical thickness was observed in specific areas (Wernicke and precentral gyrus) between acute and chronic phases. Functional gain was significant (p < 0.05) compared to the scales Fugl Meyer and FIM periods between acute and chronic / Mestrado / Neurociencias / Mestre em Fisiopatologia Médica

Calpains, a highly conserved family of calcium-dependent cysteine proteases, are divided in two groups; classical and non-conventional calpains. Calpain-1 and calpain-2, the classical ones, are ubiquitously expressed and abundant in the CNS. Findings through different experimental approaches, predominantly pharmacological calpain inhibitors, proposed the necessity of the proteases for the modulation of various biological events particularly in the CNS, or a functional link between calpain and neurodegeneration. Significant functions associated with calpain activity are neuronal proliferation/differentiation, signal transduction, apoptosis, and synaptic plasticity; or neuronal death in Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, and ischemic stroke. However, due to limited insights of the approaches taken, such as non-specificity of the inhibitors, the exact roles of calpains in the CNS and the key mechanisms underlying them remain controversial. Calpain-1/calpain-2 germline knock-out are embryonic lethal at a very early stage hindering the use of these lines as mouse models for CNS studies. Accordingly, this thesis research introduced a unique brain-specific calpain-1/calpain-2 knock-out and explored the role of the proteases in brain development/function and in neuronal death. The first set of analyses examined how the elimination of calpain-1/calpain-2 activities in mouse brain impacts CNS development in general and synaptic plasticity in CA1 neurons of hippocampus. CNS-specific elimination of CAPNS1, the common small subunit, abolished calpain-1/calpain-2 activities in mouse brain. In contrast to Calpain-1/calpain-2 germ line knock-outs, the brain-specific knock-outs are viable and the general development of mouse brain is normal. However, morphology of dendrites in pyramidal neurons of the hippocampal CA1 region showed significantly decreased dendritic branching complexity and spine density. Consistent with dendrite morphological abnormalities, electrophysiological analyses revealed a significant decrease in field excitatory postsynaptic potentials, long term potentiation, and learning and memory in the hippocampal CA1 neurons of the mutants. In the second part of this research we investigated the direct role of the calpains in neuronal death and their potential downstream targets in in vitro models of PD and ischemic stroke. Our findings indicated that ablation of calpains activity improves survival of different types of neurons against mitochondrial toxin 1-methyl-4-phenylpyridinium (MPP+), glutamate, and hypoxia. Importantly, we demonstrated an increase in p35-cleavage to p25, a cyclin dependent kinase 5 (Cdk5) activator, and that restoration of p25 significantly suppresses the neuronal survival associated with calpain deficiency. Taken together, this work unequivocally establishes two central roles of calpain-1/calpain-2 in CNS function in plasticity and neuronal death.

L’accident vasculaire cérébral ischémique reste un problème majeur de santé publique, contre lequel l’arsenal thérapeutique reste très limité. L’atorvastatine (AT), utilisée en prévention cardiovasculaire, possède des effets pléiotropes lui conférant un pouvoir protecteur dans l’AVC. Les objectifs de cette thèse étaient d’évaluer et de caractériser les effets neuro- et vasculoprotecteurs de l’AT dans l’ischémie cérébrale, et la part jouée par le récepteur nucléaire PPARα. Des souris C57BL/6J sauvages et KO-PPARα ont été soumises à ischémie-reperfusion (I/R) cérébrale. Elles étaient traitées par AT préventivement pendant 14 jours ou après I/R pendant 24 ou 72 heures. L’effet neuroprotecteur est évalué histologiquement et par des tests fonctionnels moteurs. L’effet vasculoprotecteur est évalué sur l’artère cérébrale moyenne par étude de la fonction endothéliale et sur les microvaisseaux cérébraux par étude de leur structure et des interactions leucocytes-endothélium. Le traitement préventif et aigu par AT induit une diminution du volume lésionnel, et une amélioration de la récupération fonctionnelle chez les animaux traités à la phase aiguë. Le traitement aigu permet de préserver la fonction endothéliale et l’intégrité des microvaisseaux cérébraux, et de limiter les interactions leucocytes-endothélium. PPARα est nécessaire aux effets neuro- et vasculoprotecteurs de l’AT dans l’ischémie cérébrale. Ce travail met en évidence l’intérêt de l’atorvastatine en tant qu’agent neuroprotecteur pléiotrope dans l’ischémie cérébrale. / Ischemic stroke still is a heavy public health burden, as effective therapeutic means remain scarce. Atorvastatin (AT), widely used as a preventive treatment in the cardiovascular field, possesses pleiotropic effects that give it protective properties in stroke. The goals of this work were to assess and characterize the neuro- and vasculoprotective effects of AT in cerebral ischemia, and the part played by PPARα. Wild-type and PPARα-KO C57BL/6J mice were submitted to cerebral ischemia-reperfusion (I/R). They were treated with AT before I/R for 14 days or acutely after I/R for 24 or 72 hours. Neuroprotection is assessed histologically and by a motor functional evaluation. Vasculoprotection is assessed on the middle cerebral artery by evaluating the endothelial function and on cerebral microvessels by evaluating their structure and the interactions between leukocytes and the vascular wall. Preventive and acute treatments with AT induce a reduction in lesion volumes, functional recovery was improved in acutely treated animals. The acute treatment with AT preserves the endothelial function and the microvascular integrity, and reduces the interactions between leukocytes and the endothelium. PPARα is necessary for AT neuro- and vasculoprotective effects to take place. This works highlights the interest of atorvastatin as a pleiotropic neuroprotective agent in ischemic stroke.

From gametogenesis until death an organism’s genome is under constant bombardment from endogenous and exogenous sources of DNA damage. To maintain genomic integrity amid this damage, cells have evolved responses which allow them to either preserve viability for recovery or initiate self-destructive pathways depending on the severity of DNA damage. One protein involved in initiating and carrying out these responses is the protein kinase ataxia telangiectasia and Rad3-related (ATR). ATR is known primarily for its regulatory role in initiating the checkpoint-signaling cascade following DNA damage and replicative stress. These signaling events lead to cell cycle arrest, DNA repair, or apoptosis when damage is too extreme. In addition to these kinase-dependent roles, ATR also is capable of directly blocking the intrinsic apoptotic pathway through structural sequestration of the proapoptotic protein tBid. The sum of these regulatory events is a delicate balancing act resulting in either cell death or cell survival depending on the severity of the damage and the differentiation state of the cell in question. In the following studies, we sought to investigate the complex interplay of ATR’s kinase and structural roles in determining cellular fate. First, we investigated the structural role of prolyl isomerization of ATR across development by using mouse models of two isomerically locked forms of ATR which were previously shown to lock cytoplasmic ATR into a single isomer. Studies showed that ATR which is locked in ATR-L (trans-ATR, hATR-P429A/mATR-P432A) is embryonically lethal and that heterozygotes tend to have neurological and other developmental abnormalities. This contrasts with ATR-H (cis-ATR, hATR-S428A/mATR-S431A), which is viable, but naturally prone to cancer development. Next, we used various in vitro stroke-like conditions to test if ATR inhibition could serve as a therapeutic target for stroke. We found that ATR inhibition is protective in non-dividing neuron-like cells; whereas, it potentiates death in cycling glial and immune-like cycling cells. Thus, ATR inhibition could likely be a target for both neuron sparing and immunosuppressive anti-stroke therapeutic strategies. Taken together, these studies provide insightful information into the structural and pathological roles of ATR in development and disease.

Background: Mechanical thrombectomy is the gold standard for treating patients with certain acute ischemic stroke (AIS) due to large vessel occlusion (LVO). However, even with major advancements and increasing procedural volumes, acute endovascular therapy remains a high-risk procedure with a considerable 90-day mortality rate, affected by a variety of factors. Purpose: To investigate various clinical and procedural factors associated with 90-day mortality in patients undergoing mechanical thrombectomy for emergent treatment of AIS and determine which of these factors made unique contributions to post-thrombectomy prognosis. Methods: We examined a prospective registry of 323 patients treated with endovascular thrombectomy for AIS between 2016 and 2019 at a high-volume comprehensive stroke center in central Massachusetts. We developed two multivariable logistic regression models adjusting for the contributions of baseline characteristics and recanalization parameters, to identify potential predictors of mortality at 90 days. Results: Among 323 AIS patients treated with mechanical thrombectomy, the overall rate of successful recanalization was 86% and the overall post-procedure mortality rate was 29% by 90 days. After univariate analysis, a baseline multivariable model comprised of: history of stroke (OR 0.28, 95% CI 0.09 – 0.68), pre-stroke modified Rankin Scale (mRS 2: OR 3.75, 95% CI), severe admission National Institutes of Health Stroke Scale (NIHSS 21–42: OR 12.36, 95% CI 1.48 – 103.27), internal carotid artery (ICA) occlusion (OR 2.77, 95% CI 1.18 – 6.55), and posterior circulation occlusion (OR 2.69, 95% CI 1.06 – 6.83) was prognostic of 90-day mortality. A second multivariable model also found the procedural factors of: clot obtained after each pass (OR 0.49, 95% CI 0.24 – 1.00), successful recanalization (OR 0.21, 95% CI 0.06 – 0.8) and symptomatic intracranial hemorrhage (sICH; OR 17.89, 95% CI 5.22 – 61.29) to be identifiable predictors of post-thrombectomy mortality. Conclusion: Death within 90 days after thrombectomy was increased among patients with higher pre-stroke disability, higher stroke severity on admission, ICA or posterior occlusion, and those with sICH complication. A history of stroke, clot extraction after each device pass, and successful recanalization are associated with decreased 90-day mortality. These identifiable contributors may inform patient selection, prognosis evolution, and shared decision-making regarding emergent thrombectomy for treatment of AIS.

L'ischémie cérébrale est une pathologie complexe impliquant une cascade de mécanismes cellulaires qui conduisent, entre autres, à une augmentation de l’autophagie dans les neurones. Bien que l’activation de l’autophagie dans l’AVC ischémique soit aujourd’hui un fait avéré, le rôle de l'activateur tissulaire du plasminogène (tPA ; médicament utilisé dans la phase aigüe de l’AVC ischémique et neuromodulateur du système nerveux central) n’a jamais été décrit. Le tPA est une sérine protéase initialement découverte dans le compartiment vasculaire jouant un rôle important dans la fibrinolyse. Mais le tPA est aussi exprimé dans le parenchyme cérébral où il intervient dans le système glutamatergique, la plasticité synaptique et la survie neuronale. Afin de mieux comprendre les effets moléculaires du tPA dans l’autophagie, nous avons utilisé un modèle in vitro d'ischémie cérébrale consistant à sevrer en oxygène et en glucose (OGD) puis à réoxygéner des neurones corticaux primaires murins avec ou sans tPA. Nous avons confirmé, dans un premier temps, que l’OGD induit une autophagie délétère via une diminution de l’axe PI3K/Akt/mTORC1. Nous avons ensuite étudié l’effet du tPA sur l’autophagie induite par l’OGD. Nos résultats démontrent que le tPA protège les neurones de la mort induite par l’OGD en réduisant l’autophagie via l’activation du récepteur du facteur de croissance à l'insuline (IGF-1R, un récepteur tyrosine kinase) et de la voie PI3K/Akt/mTOR. Ce travail de thèse a donc permis de décrire le rôle neuroprotecteur et anti-autophagique du tPA, et d’identifier un nouveau récepteur cible du tPA : IGF-1R. / Cerebral ischemia is a complex pathology involving a cascade of cellular mechanisms leading, among other things, to an increase of neuronal autophagy. The activation of autophagy in ischemic stroke conditions is now well accepted, but the role of tissue-type plasminogen activator (tPA, a drug used in the acute phase of ischemic stroke, and a neuromodulator) on this pathway has never been studied. tPA is a serine protease originally discovered in the vascular compartment, that plays an important role in fibrinolysis. Interestingly, tPA is also expressed in the cerebral parenchyma where it is involved in the glutamatergic neurotransmission, synaptic plasticity and neuronal survival. To better understand molecular effects of tPA on autophagy, we used an in vitro model of cerebral ischemia consisting in an oxygen and glucose deprivation (OGD) followed by reoxygenation, on murine primary cortical neurons with or without tPA. First we reported that OGD enhances deleterious autophagy through the decrease of PI3K/Akt/mTOR pathways. Then, we investigated the effect of tPA on OGD-induced autophagy. Our results demonstrate that tPA protects neurons from OGD-induced death by reducing autophagy through Insulin Growth Factor Receptor (IGF-1R, a tyrosine kinase receptor) and an increase of PI3K/Akt/mTOR pathways. This thesis has made it possible to describe the neuroprotective and anti-autophagic effect of tPA, and to identify a new target receptor for tPA: IGF-1R.

Abstract In Finland, the costs of stroke are approximately 1.1 billion euros annually due to long disability and hospitalization episodes. Sleep apnea is a risk factor for stroke. The prevalence of sleep apnea among stroke patients is unknown because sleep recording is not usually performed on stroke patients. There are no previous studies investigating the association of thrombolysis on the prognosis of sleep apnea. The relation between sleep apnea and cardiovascular events is still unclear. In this prospective, observational study, I recruited voluntary, consecutive ischemic stroke patients over the age of 18 years who were or were not eligible for thrombolysis treatment. The investigators did not affect the treatment and patients were not randomized to thrombolysis. The final analysis included 204 patients; of these, 110 underwent thrombolysis therapy and 94 were treated without thrombolysis. Cardiorespiratory polygraphy was carried out with a portable three-channel device (ApneaLinkPlus™, Resmed, Sydney, Australia) at the ward within 48 hours after the onset of stroke symptoms. The cardiorespiratory polygraphy was repeated at home after a six-month follow-up. Both automatic scoring and manual scoring pointed out excellent agreement in arterial oxyhemoglobin decrease of &#62; 4% (ODI4), lowest arterial oxyhemoglobin saturation (SaO2) or percentage of time spent below 90 percent saturation. The automated scoring underestimated the severity of sleep apnea, recognized poorly the type of event, and missed 18.6% of sleep apnea diagnoses. The total prevalence of sleep apnea in this study was 91.2% on admission to hospital. The stroke patients treated with thrombolysis had more, and more severe sleep apnea in the first sleep recording compared to those without thrombolysis therapy. After follow-up, the prevalence of sleep apnea still remained high, and sleep apnea was aggravated in two thirds of the stroke patients. The study patients without thrombolysis treatment had six-fold higher risk for incident sleep apnea after the follow-up. The stroke patients with thrombolysis therapy and visible stroke on CT had more nocturnal hypoxemia and higher obstructive apnea index than the patients without stroke lesion on follow-up CT 24 hours after thrombolysis treatment. The larger the ischemic stroke volume, the greater the time spent with saturation below 90%. / Tiivistelmä Aivoinfarkti on yleinen ja kansanterveydellisesti sekä taloudellisesti merkittävä sairaus, jonka aiheuttamat kustannukset Suomessa ovat noin 1.1 miljardia euroa pitkistä työkyvyttömyys- ja sairaalajaksoista johtuen. Uniapnea on aivoinfarktille altistava tekijä. Uniapnean esiintyvyys suomalaisilla aivoinfarktipotilailla ei ole arvioitavissa, koska aivoinfarktin sairastaneille ei yleensä tehdä unirekisteröintiä. Kannettavat yöpolygrafialaitteet saattaisivat olla vaihtoehto aivoinfarktipotilaiden uniapnean diagnosoinnille. Tutkittua tietoa liuotushoidon yhteydestä uniapnean ennusteeseen ei ole. Uniapnean sekä sydän- ja verisuonitapahtumien syy-yhteys on edelleen epäselvä. Rekrytoin prospektiiviseen tutkimukseeni vapaaehtoisia, peräkkäisiä yli 18-vuotiaita iskeemiseen aivoinfarktiin sairastuneita liuotushoidettuja ja liuotushoitoon soveltumattomia potilaita. Tutkimuksen lopullinen potilasmäärä oli 204, joista 110 sai liuotushoidon ja 94 hoidettiin ilman liuotusta. Kaikille potilaille tehtiin yöpolygrafia kannettavalla, kolmikanavaisella yöpolygrafialaitteella (Apnealink Plus, Resmed, Sydney, Australia) osastolla 48 tunnin kuluessa sairastumisesta. Yöpolygrafia toistettiin potilaan kotona kuuden kuukauden kuluttua. Sekä automaattitulos että manuaalisesti arvioitu unirekisteröintitulos olivat erittäin yhteneväisiä, kun arvion kohteena olivat happikyllästeisyyden neljän prosenttiyksikön suuruiset pudotukset tuntia kohti, matalin veren happikyllästeisyys tai alle 90 % happikyllästeisyyden osuus yöstä. Automaattianalyysi aliarvioi uniapnean vaikeuden, havaitsi huonosti hengityskatkosten tyypin eikä löytänyt 18,6 prosenttia uniapneadiagnooseista. Uniapnean esiintyvyys koko aineistossa oli sairaalaan tullessa 91,2 %. Liuotushoidetuilla potilailla todettiin ensimmäisessä rekisteröinnissä enemmän uniapneaa ja se oli vaikeampaa kuin ei-liuotushoidetuilla. Seurannassa uniapnean määrä pysyi edelleen korkeana ja uniapnea vaikeutui kahdella potilaalla kolmesta. Liuotushoitoon soveltumattomilla aivoinfarktipotilailla todettiin liuotushoidon saaneisiin verrattuna kuusinkertainen riski sairastua uniapneaan puolen vuoden aikana. Liuotushoidetuilla aivoinfarktipotilailla, joilla oli infarktimuutos kuvantamistutkimuksessa, oli yöllistä valtimoveren happikyllästeisyyden huononemista ja ylähengitysteiden ahtautumisesta johtuvia hengityskatkoksia enemmän kuin niillä potilailla, joilla ei todettu iskeemisiä muutoksia aivokuvantamisessa 24 tuntia liuotushoidon jälkeen. Mitä suurempi aivoinfarktin tilavuus, sitä suuremman osuuden yöstä veren happikyllästeisyys oli alle 90 %.

With high energy consumption and a low capacity for energy storage, the brain is highly dependent on a continuous supply of oxygen and nutrients from the bloodstream. Ischemic stroke, caused by the occlusion of a cerebral blood vessel, compromises cerebral blood flow (CBF), resulting in detrimental effects on brain homeostasis, vascular function, and neuronal health. Sex differences in ischemic stroke are known, with women having lower rates of stroke due to a protective role of estrogens on vascular health, and more severe strokes following reduced estrogen production after menopause. Rho-associated protein kinase (ROCK), an important regulator of vascular tone, also regulates vascular function in a sex-specific manner, and its deletion is neuroprotective following ischemic stroke. The current study explores the overlapping roles of ROCK and endogenous hormone influence on the acute CBF response to a photothrombotic (PT) model of ischemic stroke in mice. CBF was measured following stroke in the somatosensory cortex in mice with a heterozygous deletion of the ROCK2 isoform (ROCK2+/-) and in wild-type (WT) littermates. To remove endogenous hormones, male mice were gonadectomized (Gdx) and female mice were ovariectomized (Ovx), and control animals received a sham surgery (“intact”) prior to stroke induction. Intact WT males showed a delayed CBF drop compared to intact WT females, where peak drop in CBF wasn’t observed until 48 hours following stroke. Gonadectomy in males did not alter this response, however ovariectomy in females produced a “male-like” response. ROCK2+/- males also showed such phenotypic response, and Gdx did not alter this response, suggesting ROCK2 deletion or endogenous male hormones do not alter CBF response in males in this stroke model. Alternatively, intact ROCK2+/- females showed a striking difference in CBF values compared to intact WT females, where they displayed higher CBF values immediately post-stroke and also showed a peak drop in CBF at 48 hours post-stroke. Ovx did not change the CBF response in ROCK2+/- females. Overall, there is a marked difference between males and females in their acute CBF responses to PT stroke, which appears to be mediated by endogenous female sex hormones and ROCK2. All groups except for intact WT females show a delayed drop in CBF values, reaching a maximal drop in CBF at 48 hours following stroke induction. This may be due to hyperreactivity of female platelets and upregulation of RhoA/ROCK signaling in female platelets. Further research is required to confirm this speculation. This study reveals important sex-differences and the involvement of ROCK2 in acute CBF responses to PT stroke in mice.

Background: Clinical factors associated with exclusion from recombinant tissue plasminogen activator in both men and women are not completely understood. The aim of this study is to determine whether there is a gender difference in clinical risk factors that excluded ischemic stroke patients with a history of smoking from recombinant tissue plasminogen activator. Methods: Retrospective data from a stroke registry were analyzed, and multivariable linear regression models were used to determine gender differences. Logistic regression models determined exclusion clinical risk factors for thrombolysis in male and female acute ischemic stroke patients with a history of smoking, while sequentially adjusting for sociodemographic, clinical, and stroke-related variables. The Kaplan–Meier survival analysis was used to determine the exclusion probabilities of men and women with a history of smoking within the stroke population. Results: Of the 1,446 acute ischemic stroke patients eligible for recombinant tissue plasminogen activator, 379 patients with a history of smoking were examined, of which 181 received recombinant tissue plasminogen activator while 198 were excluded from receiving recombinant tissue plasminogen activator. Of the 198 patients, 75 females and 123 males were excluded from receiving recombinant tissue plasminogen activator. After multivariable adjustment for age, National Institutes of Health scores, and stroke-related factors, females who present with weakness/paresis on initial examination (OR = 0.117, 95% CI, 0.025–0.548) and men who present with a history of previous transient ischemic attack (OR = 0.169, 95% CI, 0.044–0.655), antiplatelet medication use (OR = 0.456, 95% CI, 0.230–0.906), and weakness/paresis on initial examination (OR = 0.171, 95% CI, 0.056–0.521) were less likely to be excluded from recombinant tissue plasminogen activator (thrombolysis therapy). Conclusions: In an ischemic stroke population with a history of smoking, female smokers are more likely to be excluded from thrombolysis therapy in comparison to men, even after adjustment for confounding variables.

京都大学 / 0048 / 新制・課程博士 / 博士(社会健康医学) / 甲第19277号 / 社医博第68号 / 新制||社医||9(附属図書館) / 32279 / 京都大学大学院医学研究科社会健康医学系専攻 / (主査)教授 松原 和夫, 教授 今中 雄一, 教授 髙橋 良輔 / 学位規則第4条第1項該当 / Doctor of Public Health / Kyoto University / DFAM