Ischemic heart disease (IHD) is a leading cause of global mortality. Emerging evidence suggests a potential role of the gut microbiome in IHD development. The present study explored the association between alpha diversity, representing microbial richness and evenness, and IHD, as well as the relationship between specific gut microbial species and IHD risk. The study uses a longitudinal design with data from the two cohorts within the Swedish Infrastructure for Medical Population-based Life-course and Environmental Research (SIMPLER). Survival analysis is employed to calculate the hazard rate for all associations. Because of thecompositionality of the gut microbiome species-level data a centered log-ratio (CLR) transformation is applied before the main analysis. We find no associations between alpha diversity and risk of IHD in the age and sex-adjusted model as well as in the main model adjusted for age, sex, smoking, education, physical activity, hypertension, high cholesterol, and intakes of fish, red and processed meat, fermented dairy, fruit and vegetables and alcohol. Five species are found to be statistically significantly associated with IHD in the main model before correction for multiple testing, which is statistically non-significant after the correction.

Orientador: Noma Sueli Pinheiro Modolo / Resumo: Introdução: a lesão por isquemia-reperfusão (LIR) é uma importante causa de lesãorenal aguda experimentada na prática clínica. A restauração da perfusão aos tecidosapós um período de isquemia inicia uma cascata de inflamação associada ao acúmulode íons, formação de espécies reativas de oxigênio (ERO), disfunção endotelial eativação imune. O condicionamento isquêmico é a aplicação de breves ciclos deinterrupção seguidas de restauração do fluxo sanguíneo, tendo o objetivo de adaptaros tecidos à isquemia. Pode ser aplicado antes do estímulo principal, como précondicionamento(PCI), ou depois, sendo denominado pós-condicionamento (PCoI).Metodologia: estudo experimental realizado com 40 ratos wistar, divididos em cincogrupos para análise comparativa: Sham (S): laparotomia; Controle (C): laparotomia e30 min de isquemia; Pré-condicionamento (PRE): laparotomia, PCI e 30 min deisquemia; Pré e Pós-condicionamento (PRE/POS): laparotomia, PCI, 30 min deisquemia e PCoI; Pós-condicionamento (POS): laparotomia, 30 min de isquemia ePCoI. A comparação entre os grupos foi realizada pela análise bioquímica sérica decreatinina, ureia, lipocalina associada à gelatinase de neutrófilos (NGAL) e histolologia.Resultados: apenas o grupo Sham apresentou valores estatisticamente menores dosmarcadores de lesão renal e menor incidência de lesão tubular renal à histologia(S<C=PRÉ=PRÉ/PÓS=PÓS).Discussão e conclusão: no presente estudo, o PCI e o PoCI, isoladamente ou emc... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Background: Ischemia-reperfusion injury (IRI) is an unavoidable aspect of transplantation, as well as an important cause of acute kidney injury in clinical practice. Restoration of the blood supply after an ischemic period activates an inflammatory cascade associated with multiple processes, including ion accumulation, free reactive oxygen species (ROS) formation, endothelial dysfunction, and immune activation. Ischemic “conditioning” refers to the application of a brief series of ischemic periods followed by reperfusion in the setting of major ischemia. In ischemic preconditioning (IPC), the conditioning stimulus is applied before the major ischemic event, whereas in ischemic postconditioning (IPoC), it is applied after the event. Methods: Forty Wistar rats were randomized into five groups: Sham (S): laparotomy; Control (C): laparotomy and 30 min ischemia; Preconditioning (PRE): laparotomy, IPC, and 30 min ischemia; Preconditioning and Postconditioning (PRE/POST): laparotomy, IPC, 30 min ischemia, and IPoC; Postconditioning (POST): laparotomy, 30 min ischemia, and IPoC. Serum analyses of creatinine and neutrophil gelatinaseassociated lipocalin (NGAL) were performed, and renal histology was also examined. Results: Severe tubular injury and increases in creatinine were observed in all groups except the S group, and no significant differences were detected between the other groups (S<C=PRE=PRE/POST=POST). Conclusions: IPC and IPoC, together or separately, were unable to exert a... (Complete abstract click electronic access below) / Doutor

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Submitted by VINÍCIUS MONTEIRO ARANTES null (viniciusma43@yahoo.com.br) on 2016-04-07T17:19:19Z No. of bitstreams: 1 Vinicius Monteiro Arantes (Doutorado) - Pós defesa.pdf: 1192517 bytes, checksum: 45c5c5f675af52789c6d2d6a395b44b0 (MD5) / Approved for entry into archive by Felipe Augusto Arakaki (arakaki@reitoria.unesp.br) on 2016-04-08T11:47:33Z (GMT) No. of bitstreams: 1 arantes_vm_dr_bot.pdf: 1192517 bytes, checksum: 45c5c5f675af52789c6d2d6a395b44b0 (MD5) / Made available in DSpace on 2016-04-08T11:47:33Z (GMT). No. of bitstreams: 1 arantes_vm_dr_bot.pdf: 1192517 bytes, checksum: 45c5c5f675af52789c6d2d6a395b44b0 (MD5) Previous issue date: 2016-02-23 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Introdução: a lesão por isquemia-reperfusão (LIR) é uma importante causa de lesão renal aguda experimentada na prática clínica. A restauração da perfusão aos tecidos após um período de isquemia inicia uma cascata de inflamação associada ao acúmulo de íons, formação de espécies reativas de oxigênio (ERO), disfunção endotelial e ativação imune. O condicionamento isquêmico é a aplicação de breves ciclos de interrupção seguidas de restauração do fluxo sanguíneo, tendo o objetivo de adaptar os tecidos à isquemia. Pode ser aplicado antes do estímulo principal, como précondicionamento (PCI), ou depois, sendo denominado pós-condicionamento (PCoI). Metodologia: estudo experimental realizado com 40 ratos wistar, divididos em cinco grupos para análise comparativa: Sham (S): laparotomia; Controle (C): laparotomia e 30 min de isquemia; Pré-condicionamento (PRE): laparotomia, PCI e 30 min de isquemia; Pré e Pós-condicionamento (PRE/POS): laparotomia, PCI, 30 min de isquemia e PCoI; Pós-condicionamento (POS): laparotomia, 30 min de isquemia e PCoI. A comparação entre os grupos foi realizada pela análise bioquímica sérica de creatinina, ureia, lipocalina associada à gelatinase de neutrófilos (NGAL) e histolologia. Resultados: apenas o grupo Sham apresentou valores estatisticamente menores dos marcadores de lesão renal e menor incidência de lesão tubular renal à histologia (S<C=PRÉ=PRÉ/PÓS=PÓS). Discussão e conclusão: no presente estudo, o PCI e o PoCI, isoladamente ou em conjunto, foram incapazes de prevenir dano estrutural tubular renal. A duração do período isquêmico é um aspecto crítico nas estratégias de condicionamento. Os resultados encontrados indicam que o condicionamento pode não melhorar os desfechos, e em alguns casos pode ser prejudicial. / Background: Ischemia-reperfusion injury (IRI) is an unavoidable aspect of transplantation, as well as an important cause of acute kidney injury in clinical practice. Restoration of the blood supply after an ischemic period activates an inflammatory cascade associated with multiple processes, including ion accumulation, free reactive oxygen species (ROS) formation, endothelial dysfunction, and immune activation. Ischemic “conditioning” refers to the application of a brief series of ischemic periods followed by reperfusion in the setting of major ischemia. In ischemic preconditioning (IPC), the conditioning stimulus is applied before the major ischemic event, whereas in ischemic postconditioning (IPoC), it is applied after the event. Methods: Forty Wistar rats were randomized into five groups: Sham (S): laparotomy; Control (C): laparotomy and 30 min ischemia; Preconditioning (PRE): laparotomy, IPC, and 30 min ischemia; Preconditioning and Postconditioning (PRE/POST): laparotomy, IPC, 30 min ischemia, and IPoC; Postconditioning (POST): laparotomy, 30 min ischemia, and IPoC. Serum analyses of creatinine and neutrophil gelatinaseassociated lipocalin (NGAL) were performed, and renal histology was also examined. Results: Severe tubular injury and increases in creatinine were observed in all groups except the S group, and no significant differences were detected between the other groups (S<C=PRE=PRE/POST=POST). Conclusions: IPC and IPoC, together or separately, were unable to exert a protective effect against tubular cell injury and preserve kidney function. The duration of the ischemic period is a critical aspect of the conditioning strategy. Our results indicate that conditioning may not improve the outcome, and it may even be harmful.

Background: Early differentiation between transient ischemic attack (TIA) and minor ischemic stroke (MIS) impacts on the patient’s individual diagnostic work-up and treatment. Furthermore, estimations regarding persisting impairments after MIS are essential to guide rehabilitation programs. This study evaluated a combined clinical- and serum biomarker-based approach for the differentiation between TIA and MIS as well as the mid-term prognostication of the functional outcome, which is applicable within the first 24 h after symptom onset. Methods: Prospectively collected data were used for a retrospective analysis including the neurological deficit at admission (National Institutes of Health Stroke Scale, NIHSS) and the following serum biomarkers covering different pathophysiological aspects of stroke: Coagulation (fibrinogen, antithrombin), inflammation (C reactive protein), neuronal damage in the cellular [neuron specific enolase], and the extracellular compartment [matrix metalloproteinase-9, hyaluronic acid]. Further, cerebral magnetic resonance imaging was performed at baseline and day 7, while functional outcome was evaluated with the modified Rankin Scale (mRS) after 3, 6, and 12 months. Results: Based on data from 96 patients (age 64 ± 14 years), 23 TIA patients (NIHSS 0.6 ± 1.1) were compared with 73 MIS patients (NIHSS 2.4 ± 2.0). In a binary logistic regression analysis, the combination of NIHSS and serum biomarkers differentiated MIS from TIA with a sensitivity of 91.8% and a specificity of 60.9% [area under the curve (AUC) 0.84]. In patients with NIHSS 0 at admission, this panel resulted in a still acceptable sensitivity of 81.3% (specificity 71.4%, AUC 0.69) for the differentiation between MIS (n = 16) and TIA (n = 14). By adding age, remarkable sensitivities of 98.4, 100, and 98.2% for the prediction of an excellent outcome (mRS 0 or 1) were achieved with respect to time points investigated within the 1-year follow-up. However, the specificity was moderate and decreased over time (83.3, 70, 58.3%; AUC 0.96, 0.92, 0.91). Conclusion: This pilot study provides evidence that the NIHSS combined with selected serum biomarkers covering pathophysiological aspects of stroke may represent a useful tool to differentiate between MIS and TIA within 24 h after symptom onset. Further, this approach may accurately predict the mid-term outcome in minor stroke patients, which might help to allocate rehabilitative resources.

Ischämietoleranz bezeichnet das Phänomen, dass ein kurzer ischämischer, metabolischer oder physikalischer Stimulus das Gehirn paradoxerweise "resistent" macht gegenüber einer darauffolgenden, längerdauernden Ischämie. In einer retrospektiven Studie versuchten wir die Hypothese zu untermauern, dass transiente ischämische Attacken (als kurzdauernde ischämische Stimuli) vor einem Infarkt (prodromale TIAs) protektiv sind gegen eine nachfolgende zerebrale Ischämie. Es zeigte sich dabei, dass Patienten mit prodromalen TIAs ein geringeres Defizit und einen günstigeren Verlauf zeigten und im CT seltener Infarktfrühzeichen hatten. Somit könnten transiente ischämische Attacken, vor einem Schlaganfall, analog zu der Situation am Herzen und wie in zahlreichen in vivo Modellen gezeigt, ein klinisches Korrelat zur hypoxischen Präkonditionierung darstellen. Im experimentellen Teil der vorliegenden Arbeit wird gezeigt, dass sich hypoxische Präkonditionierung in vitro in neuronalen Kulturen modellieren lässt. Eine kurzzeitige Sauerstoff-Glucose-Deprivation (OGD) 1-3 Tage vor einer längeren OGD führt zu einem signifikanten Schutz von Neuronen, bis zu 90%. Hypoxietoleranz kann auch durch andere metabolische Stimuli, wie Inhibition von Atmungskettenenzymen durch 3-NPA im gleichen Zeitrahmen simuliert werden. Eine genaue Kenntnis der endogenen Neuroprotektion durch Ischämietoleranz könnte in Zukunft helfen, den Schaden durch ischämische Infarkte und ischämische Enzephalopathien zu minimieren. / Ischemic tolerance is a phenomenon where a brief episode of ischemia renders the brain resistant against a subsequent, longerlasting ischemic event. In a retrospective study we tested the hypothesis that transient ischemic attacks (as brief ischemic stimuli) before cerebral ischemia (prodromal TIA's) may have a protective effect. Here we show that patients with prodromal TIA's have less severe neurologic impairment, a better clinical course and have less early infarct signs. Therefore we siggest that TIA's, before stroke could represent a clinical correlate to hypoxic preconditioning, as shown in the heart. Experimentally we were able to model hypoxic preconditioning in vitro using neuronal cultures. Brief oxygen-glucose deprivation (OGD) 1-3 days before longer lasting OGD protects neurons, up to 90%. Hypoxic tolerance was also simulated by metabolic stimuli like inhibition of the respiratory chain by 3-NPA. Increasing knowledge of this endogenous neuroprotection by ischemic tolerance might help to minimize neuronal damage following ischemic strokes and hypoxic encephalopathy.

Abstract The repair of thoracoabdominal aortic aneurysms carries a substantial risk of ischaemic perioperative spinal cord injury. Although several protective methods have been developed, the risk of paraplegia has not been eliminated. Moreover, aortic aneurysms, including arch aneurysms, are complex clinical challenges requiring cerebral protection with hypothermic circulatory arrest (HCA). Hypothermia lowers the rate of cerebral metabolism and allows a temporary halt of the systemic circulation. However, there is still a risk for cerebral damage and a need for additional neuroprotective methods. During the last 15 years, our research group has used a porcine model to investigate a variety of neuroprotective tools. In this thesis, an animal model was utilized to study the efficacy of remote ischaemic preconditioning (RIPC) to ameliorate ischaemic damage to the central nervous system, and to shed light on the potential mechanism. Moreover, diazoxide, the pharmacological mimetic of RIPC, was tested in the HCA animal model. In the first Study (I), RIPC showed beneficial effect on the spinal cord against ischaemic insult as recorded with motor-evoked potentials. Strikingly, the beneficial effect of RIPC was observed even before the ischaemia. In the second Study (II), some beneficial effect of RIPC was seen in the immunohistochemical analysis of the spinal cord ischemia but the result remains inconclusive. Similarly, the diazoxide-treated animals had better hemodynamic status postoperatively and mildy better antioxidant activity of the brain in the third Study (III). The fourth study (IV) was a review of the current knowledge of RIPC from the cardiovascular point of view. Our studies indicate that RIPC might be a potential adjunct for preventing neuronal ischaemic injury in the setting of thoracoabdominal aortic surgery. Our result indicates that further preclinical studies with diazoxide are required before studies can be conducted in humans. / Tiivistelmä Torakoabdominaalisen aortan aneurysman kirurginen korjaaminen sisältää riskin iskeemiselle selkäytimen vauriolle. Vaikka useita suojaavia tekniikoita on kehitetty, paraplegian riskiä ei ole saatu poistettua kokonaan. Kirurgisen korjaamisen haasteellisuus moninkertaistuu, jos aneurysma on laajentunut myös aortan kaareen. Tällöin vaaditaan hypotermista verenkierron pysäytystä (HCA). Hypotermia alentaa aivojen metabolista aktiivisuutta merkittävästi ja siten verenkierron väliaikainen pysäytys on mahdollista. Tästä huolimatta hypotermiseen verenkierron pysäytykseen liittyy riski aivokudoksen vauriolle. Meidän tutkimusryhmämme on tutkinut useita keskushermostoa suojaavia tekniikoita ja lääkeaineita viimeisen 15 vuoden aikana. Käytämme sikaa koe-eläin mallina, jota on tämänkin väitöskirjan osajulkaisuissa käytetty. Tämän väitöskirjatyön tarkoituksena on ollut tutkia sekä esialtistavan raajaiskemian (RIPC) että farmakologisen mimeetin, diazoxiden, keskushermostoa suojaavia vaikutuksia sekä niiden mahdollista vaikutusmekanismia. Ensimmäisessä osajulkaisussa esialtistava raajaiskemia paransi selkäytimen iskemian sietokykyä, mikä näkyi alaraajojen motorisissa herätepotentiaaleissa. Merkittävintä tutkimuksessa oli, että esialtistavan raajaiskemian edulliset vaikutuksen selkäytimeen oli nähtävissä jo ennen iskemiaa. Toisessa osajulkaisussa esialtistava raajaiskemialla oli nähtävissä edullisia, mutta ei varauksettomia, vaikutuksia selkäytimen iskemian immunohistokemiallisessa analyysissä. Kolmannessa osatyössä diazoxidin vaikutukset iskemiaa vastaan nähtiin parempana hemodynaamisena tilana ja antioksidatiivisen aktiivisuuden lisääntymisenä aivoissa, mutta tulos on myös tulkinnanvarainen. Neljäs osajulkaisu kokosi tämän hetken tietämyksen esialtistavasta raajaiskemiasta. Tutkimuksissamme osoitimme, että esialtistava raajaiskemiassa on potentiaalia tulla yhdeksi välineeksi keskushermoston iskemiaa vastaan torakoabdominaalisen aortan kirurgiassa. Lisäksi diazoxidin mahdolliset neuroprotektiiviset vaikutukset vaativat lisää koe-eläintutkimuksia ennen ihmiskokeisiin siirtymistä.

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The Georgia Department of Public Health has been engaged in a registry-based quality improvement initiative to monitor and improve the quality of stroke care. It is important to evaluate effectiveness of the quality improvement initiative in order to expand the effort to other sites or disease conditions. The studies, included in this dissertation, addressed whether acute ischemic stroke patients cared for by hospitals participating in the Georgia Coverdell Acute Stroke Registry (GCASR) had a better survival than those treated at other facilities, assessed whether quality of care as measured by nationally accepted ten performance measures is associated with improved patient outcome and evaluated the impact of intravenous alteplase treatment on 1-year mortality. Three data sources – GCASR, Georgia Discharge Data System and the death data – were used for analyses. These data sources were linked applying both a hierarchical deterministic and a probabilistic linkage methods. Survival after stroke incident was analyzed using the extended Cox proportional hazard model. Generalized estimating equation (glimmix procedure) and conditional logistic regression were applied, respectively, to assess the association of quality of care and intravenous alteplase use with 1-year mortality. Acute ischemic stroke patients treated at nonparticipating facilities had a hazard ratio for death of 1.14 (95% confidence interval, 1.03–1.26; p-value = .01) after the first week of admission compared with patients cared for by hospitals participating in the registry. Among patients treated in GCASR-participating hospitals, patients who received the lowest and intermediate quality care respectively had a 3.94 (95%CI: 3.27, 4.75; p-value <0.0001) and a 1.38 (95%CI: 1.12, 1.62; p-value=0.002) times higher odds of dying in one year compared to those who got the best quality stroke care. Patients who were eligible but did not receive IV alteplase had a 1.49 (95%CI: 1.09-2.04; p-value=0.01) times higher odds of dying within one year than those who were treated with the thrombolytic agent. The results strongly suggest that registry-based quality improvement effort has brought significant improvements in ischemic stroke patients’ outcomes. Therefore, it is critical that hospitals adopt a quality improvement strategy to change the process of care delivery for a better patient outcome.

Κυριότερος σκοπός είναι η αξιολόγηση των συστημάτων Υπολογιστικής Τομογραφίας και Μαγνητικού Συντονισμού κατά την εφαρμογή της τεχνικής Δυναμικής Αιμάτωσης (Perfusion). Επίσης η δημιουργία και εφαρμογή αναλυτικού και αποτελεσματικού πρωτοκόλλου στην οξεία ισχαιμία με σκοπό την άμεση βοήθεια του ισχαιμικού εγκεφάλου. / Thesis MSc in order to highlight the usefulness of CT Brain Perfusion in acute brain ischemia.