Objetivo: Avaliar o uso de antitrombóticos em pacientes com fibrilação atrial (FA) em hospital cardiológico no Brasil (InCor).Métodos e resultados: Um estudo observacional transversal analisou os prontuários de todos os pacientes atendidos no InCor em cada um de 5 dias separados no ano de 2002 (Fase 1), sendo prospectivamente reanalisados após 1 ano (Fase 2). A prevalência da FA nos 3764 prontuários analisados foi de 8%. Antiplaquetários foram prescritos para 21,26% e 19,93%, anticoagulantes para 46,51% e 57,81%, e 32,23% e 22,26% não usavam nenhum antitrombótico nas Fases 1 e 2, respectivamente. Somente 15,60% e 23,25% apresentavam níveis de RNI terapêuticos.Conclusão: A anticoagulação é subutilizada nos pacientes com FA apesar do fato de serem tratados por cardiologistas em um hospital universitário / Objective: To assess antithrombotic therapy among atrial fibrillation (AF) patients in a Brazilian University Heart Hospital (InCor).Methods and results: A cross sectional study analyzed the charts of all patients treated at InCor in 5 separate days of 2002 (Phase 1), and prospectively reviewed them after one year (Phase 2). The prevalence of AF in the 3,764 assessed charts was of 8.0%. Antiplatelets were prescribed to 21.26% and 19.93%, anticoagulants to 46.51% and 57.81%, and 32.23% and 22.26% were not receiving any antithrombotic in Phases 1 and 2, respectively. Only 15.60% and 23.25% were within INR therapeutic range.Conclusion: Anticoagulation is underused in AF patients besides the fact of being treated by cardiologists in a University Hospital

Part 1: Monitoring Response to Single-Dose (1000cGy) Radiotherapy in a RIF-1 Tumor Model The current standard of measure for monitoring chemotherapeutic and radiotherapeutic treatment response is tumor volume. Unfortunately, changes in tumor volume are generally slow and tumor volume does not necessarily indicate the degree of tumor viability. The development of marker(s) with the ability to detect an early therapeutic response would greatly aid in patient management, opening the possibility for both rapid dose optimization and replacement of ineffective therapies with alternative treatment. Previous studies have shown that diffusion measurements using magnetic resonance imaging (MRI) techniques are sensitive to therapy-induced changes in cellular structure, allowing demarcation between regions of necrosis and viable tumor tissue. This sensitivity, based on the correlation between water apparent diffusion coefficient (ADC) values and tumor cellular density, may allow diffusion measurements to be employed in non-invasive monitoring of treatment response. Therapy-induced increases in tumor ADC preceding tumor regression have been reported in a variety of experimental tumor models and several human brain tumors. Despite the demonstrated diffusion sensitivity to therapeutic response in these particular studies, shortcomings still remain that hinder the efficacy of clinical application in oncology. Earlier studies have concentrated on the mean ADC present within the tumor, either within the entire tumor volume or a region of-interest (ROI) defined by the user, and their evolution pre-treatment and post-treatment. Because of inter- and intra-tumor heterogeneity, volume-averaged ADC measurements suffer from poor correlation with treatment efficacy. In addition, most studies make little or no attempt to characterize the entire tumor volume (necrotic, viable, edema). The identification of regions of differing tissue viability should aid in the staging of treatment, therefore making accurate and reproducible tissue segmentation an important goal. The results of earlier, single-parameter studies indicate that a multi-parametric approach in which several MR parameters are monitored (ADC, T2, M0) may provide greater power than that of the single parameter approach. A multi-parametric or multi-spectral (MS) analysis uses pattern-recognition techniques, such as clustering, for image segmentation. Clustering algorithms use characteristics of the multiple MR-parameter dataset to group tissue of similar type, e.g., fat, muscle, viable tumor, necrosis. Specifically, k-means (KM) is an unsupervised segmentation algorithm that groups together similar tissue based on the difference in MR parameter space between the image voxel of interest and the mean parameter values of the voxels in that cluster. In the first step of the classification algorithm, it is applied to separate the data into two clusters (k = 2), tissue and background noise voxels. All voxels classified as background noise are set to zero and removed from further processing. In the second step, KM is applied to the remaining tissue voxels to segment the data into multiple tissue types. In the case of tumors, it is not clear in advance how many different types of tissue exist. The number of clusters, k, should be varied to ensure that all relationships between tissues are found. In the final step, the resulting KM maps may be compared to histological slices taken from the same tissue as the imaging slices in order to identify the tissue type of each cluster. In line with the studies and analyses described above, quantitative MRI was performed to investigate the spatial correlation between ADC, spin-spin (T2) relaxation times, and proton density (M0) in murine radiation-induced fibrosarcoma (RIF-1) tumors following single-dose (l000cGy) radiotherapy using the KM algorithm (Chapters 3 and 4) and different combinations of features and/or clusters. For all cluster/feature combinations, an in-depth comparison between KM-derived volume estimates and conventional histology via the hematoxylin-eosin (H&E) staining procedure (for identification of viable tumor versus necrosis), as well as via hypoxic-inducible factor-lα. (HIF-1α) immunohistochemistry (for identification of regions of hypoxia versus well-oxygenated tissue) was performed (Chapter 3). The optimal cluster/feature combination was determined by minimizing the sum-of-squared-differences (SSD) between the actual datapoints and the ideal one-to-one correlation that should exist between KM-derived volume estimates and histology-derived volume estimates. The optimal cluster/feature combination was determined to be a 2-feature (ADC, T2) and 4-c1uster (2 regions each of viable tissue and necrosis) segmentation. This KM method was then applied in analysis of the radiotherapeutic response: first, to gain insight into the various processes whose combination yield the total ADC response over time; second, to identify the contribution of tissue heterogeneity to the treatment response and changes in tumor growth kinetics and cell kill (Chapter 4). Comparisons between control and various time-points out to 14 days post-radiotherapy permitted more accurate tissue characterization and prediction of therapeutic outcome over analysis using ADC alone. The results based on histological validation demonstrated: (1) MS analysis provides an improved tissue segmentation method over results obtained from conventional methods employing ADC alone; (2) MS analysis permits subdivision based on the degree of necrosis, as well as delineation between well-oxygenated and hypoxic viable tissue; and (3) Individual KM volumes corresponded well with both H&E volumes and regions with increased HIF-1α expression. The results based on the radiotherapeutic response demonstrated: (1) MS analysis provides a method for monitoring the range of tissue viability as a function of time post-treatment; (2) MS analysis permits assessment of the various contributions to the total ADC response post-treatment; (3) The relative fractions of well-oxygenated (i.e., radiosensitive) versus hypoxic (i.e., radioresistant) tissue pretreatment may be predictive of treatment response; and (4) The early ADC increase did not seem to be a result of radiation-induced vasogenic edema, but instead was most likely due to a slight reduction in cellular density following therapy. These studies provide a non-invasive method of tissue characterization that may be used in monitoring treatment response and optimizing drug dose-timing schemes, with the potential for predicting treatment efficacy. Part 2: Role of Spreading Depression in Ischemic Stroke Stroke is a prevalent disease that ranks as the 3rd leading cause of death and disability in the United States, according to NIH statistics, costing millions of dollars in medical costs and lost wages. At present, the mechanism by which focal ischemia evolves into infarction remains poorly understood. By determining the patho-physiological mechanisms involved in the evolution of focal brain ischemia, therapeutic strategies may be designed for instances of acute ischemic stroke. In the late 1980s, researchers discovered MRI techniques that allow the detection of stroke very early after onset. Such techniques as diffusion-weighted imaging and perfusion-weighted imaging (DWI and PWI) have been applied both clinically and experimentally. Previous studies employing these techniques suggest that cortical spreading depression plays a detrimental role in the evolution of focal brain ischemia. Spreading depression (SD) is characterized by a spontaneous and reversible depression of cortical electrical activity that spreads from the site of onset as a wave with a speed of 2-5 mm/min. It is accompanied by an ionic redistribution, with efflux of potassium ions (K+) and influx of sodium, chloride, and calcium (Na+, Cl-, Ca2+) ions, as well as water. This results in cellular swelling and a decreased extracellular space (ES), yielding a decline in ADC. A positive correlation between the number of both spontaneous and induced SDs and infarct volume has well been documented, supporting the idea that SD inhibition might be neuroprotective if initiated early after ischemic onset. Even though these studies show promise in their ability to track SD using diffusion mapping, changes in ADCs reflect cytotoxic edema and do not necessarily correspond to SD or SD-like depolarizations or calcium (Ca2+) influx, leading to cell death. Recent studies have reported the use of manganese ions (Mn2+) as a depolarization-dependent contrast agent in monitoring brain activation through the application of glutamate, as well as in the study focal ischemia. Since extracellular accumulation of potassium (K+) ions or glutamate in ischemic tissue is believed to play a central role in the initiation and propagation of SDs, and knowing that Mn2+, having an ionic radius similar to that of Ca2+, is handled in a manner similar to Ca2+, these studies suggest the possible use of manganese ions (Mn2+) in tracking SD or SD-like depolarizations in the evolution of focal brain ischemia. In order to determine the utility of Mn2+ as a marker for SD, two sets of T1-weighted MRI experiments were performed before applying Mn2+ in an experimental stroke model (Chapter 6). First, for verification purposes, a glutamate administration group was evaluated to validate our use of the manganese-enhanced MRI (MEMRI) method previously developed by Aoki et al, a modification of the original by Lin and Koretsky. When satisfied that the contrast enhancement was specific to glutamate only, a second set of experiments was performed. Here, experimental SD was elicited by chemical stimulation (direct application of concentrated potassium chloride [KC1] on the exposed cortical surface) and compared with control conditions (perfusion of sodium chloride [NaC1] on exposed brain cortex). This study demonstrated: (1) Mn2+, specific to Ca2+ channel activity, is a more accurate marker for SD than DWI or T2 methods; (2) Cortical restriction of MEMRI enhancement supports the contention that apical dendrites are necessary for SD propagation; (3) Subcortical enhancement is a result of corticalsubcortical neuronal connectivity; and (4) Because of the relatively slow clearance of Mn2+, MEMRI permits higher spatial resolution and signal-to-noise ratios (SNRs) via increased signal averaging. Based on these results, preliminary experiments involving the study of SD in focal ischemia using Mn2+ were performed (Chapter 7). Initial results indicate: (1) MEMRI of ischemia, when compared with standard DWI/PWI methods, may provide a method for estimating the likelihood of progression to infarct at acute time points post onset of stroke. These studies provide a foundation for further investigation into the role of SD in stroke, and the application of Mn2+ towards the design of therapeutic strategies targeting SD inhibition. Conclusions and Medical Significance The research within this dissertation employed magnetic resonance imaging techniques for monitoring the temporal evolution of pathological disease states such as focal ischemia and cancer, with and without therapeutic intervention. Optimization of these techniques in experimental models will open the possibility for future application in a clinical setting. Clinical availability of these non-invasive methods, with the ability to detect an early therapeutic response or to provide staging and prediction of tissue fate, would greatly aid in patient management of both cancer and stroke.

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Post-stroke fatigue is a common problem that may limit participation in everyday activities. Emerging evidence suggests that group-based training in fatigue management may be an efficient means of reducing the effects of post-stroke fatigue. This mixed methods, quasi-experimental study proposed to determine whether a group-based educational program could be successful in relieving post-stroke fatigue and improving participation in daily activities. A convenience sample of stroke survivors (n=20) from retirement communities in southeastern PA were invited to participate in the research. Participants were screened for depression, motor and cognitive recovery, and sleep quality. Fatigue was measured using the Fatigue Severity Scale (FSS) and activity participation was measured using the Physical Self-Maintenance Scale- Instrumental Activities of Daily Living (PSMS-IADL). The measures were administered in a double pre-test, double post-test format over three seven-week phases; a non-intervention period; a group-based intervention period, and a post-intervention period. Qualitative information was gathered using a self-made Intervention Satisfaction Survey. Data analysis involved measures of central tendency for the demographic information. Tabulations of the survey responses were completed to judge the effectiveness of the group-based program or its’ components from the participants’ perspectives. Results indicated a statistically significant reduction in reported fatigue post-intervention (p= .022), which continued for seven-weeks (p= .240). There was a strong effect size for the post-intervention reduction of fatigue (r= .69). There was a trend toward improved participation in daily activities. Distribution across groups for presence of social support, age, sex, and level of care was found to be equivalent after one-way chi square analysis. There was no significant influence of these variables on fatigue or participation when used as grouping variables in RM-ANOVA. Participants reported feeling most confident scheduling activity to include rest periods and least confident managing sleep problems. Limitations include small sample size, demographics not being representative of the general stroke population, use of self-report measures with possible ceiling effect of PSMS-IADL, instrumentation effect given multiple administrations, and history effects as groups occurred at different time of the year. Overall, the results indicate that participation in a group-based educational program was effective in reducing post-stroke fatigue in chronic stroke.

INTRODUÇÃO: A perda óssea acelerada é uma das reconhecidas complicações da hemiplegia pós-acidente vascular encefálico (AVE), mas pouco se sabe sobre o ritmo de perda na fase crônica e seus determinantes. O objetivo deste estudo foi avaliar a evolução tardia da densidade mineral óssea (DMO) em pacientes hemiplégicos crônicos, bem como identificar possíveis fatores associados. MÉTODOS: Foi realizado um estudo longitudinal envolvendo pacientes ambulatoriais com hemiplegia há mais de 12 meses. Pacientes com doenças e outras condições associadas à perda óssea foram excluídos. Avaliações clínica e densitométrica foram realizadas no início e após aproximadamente 16 meses, e foram analisados fatores de risco para perda óssea. RESULTADOS: Cinquenta e sete pacientes foram estudados, sendo 40 do sexo masculino, com média de 59,3 anos e tempo médio de hemiplegia de 33,4 meses. Ao comparar os hemicorpos acometido e não acometido, foi observada perda óssea mais acentuada em antebraço acometido (p=0,001), mas não em fêmur acometido. Foi observada perda óssea significativa em 56% dos pacientes em antebraço e 22,6% em fêmur, no lado acometido. Maior tempo de AVE foi protetor para a perda óssea em antebraço (OR = 0,96, IC 95%: 0,92 0,99; p=0,015), e o uso de anticoagulantes e/ou anticonvulsivantes (OR = 5,83, IC 95%:1,25 27,3; p=0,025) e espasticidade moderada/intensa (OR = 8,29, IC 95%:1,10 62,4; p=0,040) foram determinantes para perda óssea em fêmur. CONCLUSÕES: O presente estudo evidenciou que a perda óssea é comum e frequente em antebraço acometido em pacientes com hemiplegia crônica, com tendência à estabilização da perda com o passar do tempo. Espasticidade mais intensa e uso de anticoagulantes e/ou anticonvulsivantes foram associados à perda óssea em fêmur. Estes achados indicam que pacientes hemiplégicos crônicos devem ser monitorados e tratados para perda óssea, com atenção para os determinantes identificados, e que o membro superior acometido deve ser incluído na avaliação da DMO / INTRODUCTION: Accelerated bone loss is a well-known early complication of hemiplegia. However, less is known about chronicphase bone loss and its determinants. The objective of this study was to evaluate long-term changes in bone mineral density (BMD) in chronic hemiplegic patients, and investigate possible related factors. METHODS: A longitudinal study involving chronic stroke-related hemiplegic patients was conducted. Clinical and densitometric evaluations were performed at baseline and after approximately 16 months, and risk factors for bone loss were analyzed. RESULTS: Fiftyseven patients were studied (40 males) with a mean of 59.3 years and with mean time since hemiplegia of 33.4 months. Decrease in BMD was more pronounced in affected forearms compared to the nonaffected forearms (p=0.001). No difference was found between affected and non-affected femurs. Bone loss was observed in 56% of the affected forearms and 22.6% of the affected femurs. Longer time since stroke was protective for bone loss in the forearm (OR = 0.96, 95% CI: 0.92 0.99; p=0.015), and the use of anticoagulation/antiepileptic drugs (OR = 5.83, 95% CI: 1.25 27.3; p=0.025) and moderate/severe spasticity (OR = 8.29, 95% CI: 1.10 62.4; p=0.040) were associated to bone loss in the femur. CONCLUSIONS: Bone loss is common and more frequent in the affected forearm in chronic hemiplegic patients with tendency to stabilize over time. Greater spasticity and use of anticoagulation and/or antiepileptic drugs were proved to be associated with bone loss at the femur. Our findings indicate that chronic hemiplegic patients should be monitored and treated for bone loss, with attention to the identified determinants, and that the upper paretic limb should be included in BMD evaluation

Continuous-flow left ventricular assist devices provide mechanical circulatory assistance for patients suffering from end-stage heart failure that are awaiting or ineligible for heart transplantation. Although actuarial survival and quality of life with these devices is comparable to allograft transplant, they are associated with severe adverse events, including cerebrovascular accidents. Recent advances in continuous-flow technology aim to mitigate the risk of stroke by including design features that minimize flow stasis, turbulence and endothelial dysfunction, as well as promote near-normal pulse pressures. The proposed study is a multicenter, prospective, randomized clinical trial that aims to compare the stroke-free survival and associated incidence and risk of cerebrovascular accidents between three continuous-flow left ventricular assist devices in patients with refractory, end-stage heart failure planning to undergo bridge-to-transplant or destination therapy. Patients will be randomized to receive one of three devices (HeartMate II, Thoratec Corporation, Pleasanton, CA; HeartWare HVAD, HeartWare International Inc., Framingham, MA; HeartMate III, Thoratec Corporation, Pleasanton, CA). Patients will be monitored for stroke-free survival and incidence of cerebrovascular accident for 24 months post-implantation. Investigators will compare stroke-free survival with Kaplan-Meier survival curves and log-rank testing; in addition, investigators will examine each device’s level of risk for causing a cerebrovascular accident with chi square and odds ratio analysis. The data from this study will be used to guide treatment paradigms, device assignment and future development of technologies that mitigate stroke risk in this high-risk population.

INTRODUÇÃO: A perda óssea acelerada é uma das reconhecidas complicações da hemiplegia pós-acidente vascular encefálico (AVE), mas pouco se sabe sobre o ritmo de perda na fase crônica e seus determinantes. O objetivo deste estudo foi avaliar a evolução tardia da densidade mineral óssea (DMO) em pacientes hemiplégicos crônicos, bem como identificar possíveis fatores associados. MÉTODOS: Foi realizado um estudo longitudinal envolvendo pacientes ambulatoriais com hemiplegia há mais de 12 meses. Pacientes com doenças e outras condições associadas à perda óssea foram excluídos. Avaliações clínica e densitométrica foram realizadas no início e após aproximadamente 16 meses, e foram analisados fatores de risco para perda óssea. RESULTADOS: Cinquenta e sete pacientes foram estudados, sendo 40 do sexo masculino, com média de 59,3 anos e tempo médio de hemiplegia de 33,4 meses. Ao comparar os hemicorpos acometido e não acometido, foi observada perda óssea mais acentuada em antebraço acometido (p=0,001), mas não em fêmur acometido. Foi observada perda óssea significativa em 56% dos pacientes em antebraço e 22,6% em fêmur, no lado acometido. Maior tempo de AVE foi protetor para a perda óssea em antebraço (OR = 0,96, IC 95%: 0,92 0,99; p=0,015), e o uso de anticoagulantes e/ou anticonvulsivantes (OR = 5,83, IC 95%:1,25 27,3; p=0,025) e espasticidade moderada/intensa (OR = 8,29, IC 95%:1,10 62,4; p=0,040) foram determinantes para perda óssea em fêmur. CONCLUSÕES: O presente estudo evidenciou que a perda óssea é comum e frequente em antebraço acometido em pacientes com hemiplegia crônica, com tendência à estabilização da perda com o passar do tempo. Espasticidade mais intensa e uso de anticoagulantes e/ou anticonvulsivantes foram associados à perda óssea em fêmur. Estes achados indicam que pacientes hemiplégicos crônicos devem ser monitorados e tratados para perda óssea, com atenção para os determinantes identificados, e que o membro superior acometido deve ser incluído na avaliação da DMO / INTRODUCTION: Accelerated bone loss is a well-known early complication of hemiplegia. However, less is known about chronicphase bone loss and its determinants. The objective of this study was to evaluate long-term changes in bone mineral density (BMD) in chronic hemiplegic patients, and investigate possible related factors. METHODS: A longitudinal study involving chronic stroke-related hemiplegic patients was conducted. Clinical and densitometric evaluations were performed at baseline and after approximately 16 months, and risk factors for bone loss were analyzed. RESULTS: Fiftyseven patients were studied (40 males) with a mean of 59.3 years and with mean time since hemiplegia of 33.4 months. Decrease in BMD was more pronounced in affected forearms compared to the nonaffected forearms (p=0.001). No difference was found between affected and non-affected femurs. Bone loss was observed in 56% of the affected forearms and 22.6% of the affected femurs. Longer time since stroke was protective for bone loss in the forearm (OR = 0.96, 95% CI: 0.92 0.99; p=0.015), and the use of anticoagulation/antiepileptic drugs (OR = 5.83, 95% CI: 1.25 27.3; p=0.025) and moderate/severe spasticity (OR = 8.29, 95% CI: 1.10 62.4; p=0.040) were associated to bone loss in the femur. CONCLUSIONS: Bone loss is common and more frequent in the affected forearm in chronic hemiplegic patients with tendency to stabilize over time. Greater spasticity and use of anticoagulation and/or antiepileptic drugs were proved to be associated with bone loss at the femur. Our findings indicate that chronic hemiplegic patients should be monitored and treated for bone loss, with attention to the identified determinants, and that the upper paretic limb should be included in BMD evaluation