CoordenaÃÃo de AperfeiÃoamento de NÃvel Superior / A hemorragia subaracnÃidea (HSA) pode advir de diversos agravos ao sistema nervoso central. A HSA pode aumentar a pressÃo intracraniana (PIC) a patamares de grande morbidade. AlÃm de sintomas neurolÃgicos e cardiovasculares, bem descritos na literatura; sintomas gastrintestinais como nÃuseas, vÃmitos e gastrenterites sÃo comuns, mas pouco estudados. O retardo do esvaziamento gÃstrico (EG) à uma das alteraÃÃes fisiolÃgicas encontrada em pacientes com hipertensÃo intracraniana (HIC). Tal distÃrbio reduz as respostas terapÃuticas tendo em vista a reduÃÃo na absorÃÃo dos nutrientes e fÃrmacos, alÃm de levar à aspiraÃÃo pulmonar, que pode levar a Ãbito. Avaliamos o efeito da HSA sobre as alteraÃÃes da motilidade gastrintestinal (Esvaziamento GÃstrico - EG; TrÃnsito Intestinal â TI e ComplacÃncia GÃstrica â CG), dos parÃmetros hemodinÃmicos (PressÃo Arterial MÃdia â PAM, FreqÃÃncia CardÃaca - FC) e sobre a PIC. Bem como os mecanismos neuro-humorais relacionados a essas alteraÃÃes. Utilizamos ratos Wistar (300-350g, N=113), sob auspÃcios do COBEA (CEUA/UFC- Protocolo 41/13). ApÃs anestesia (Ketamina/Xilasina 20-10mg/Kg-IP), os animais foram contidos por estereotÃxico sendo injetados 0,1; 0,2 ou 0,3ml na cisterna magna (sangue autÃlogo â grupo HSA ou Liquor sÃmile â grupo Sham). No momento da induÃÃo da HSA os animais foram submetidos à canulaÃÃo dos ventrÃculos laterais para monitoraÃÃo da PIC e dos vasos femorais Direito a fim de se obter dados hemodinÃmicos. ApÃs 72h da induÃÃo, e sob jejum (24h) com soluÃÃo de reidrataÃÃo oral ad libitum, procedemos aos estudos de EG, TI e CG. Para determinaÃÃo da taxa de EG, uma refeiÃÃo teste (1ml/100g) (vermelho-fenol 0,5mg/ml em glicose-5%) foi administrada via gavagem. Jà o TI foi determinado com administraÃÃo direta da refeiÃÃo no duodeno por meio de cÃnula previamente implantada. Jà a CG foi avaliada utilizando um sistema de barostato a 4, 8 e 12 cm de pressÃo de distensÃo gÃstrica. A PA, FC e PIC foram aferidas no momento da avaliaÃÃo da motilidade gastrintestinal. Os dados, mÃdiaÂEPM, foram analisados pelo teste âtâ de Student (P<0,05). A HSA retardou o EG (38,90Â2,73 vs 47,00Â0,72%; 52,85Â5,14 vs 31,12Â2,0% ou 22,89Â4,46 vs 46,24Â3,56%) e aumentou a PIC (3,33Â0,47 vs 16,10Â0,47cmH2O; 7,68Â0,650 vs 30,86Â0,82cmH2O ou 17,50Â1,29 vs 37,90Â1,38cmH2O) nos diferentes volumes de sangue, seja 0,1; 0,2 ou 0,3ml respectivamente, quando comparados ao controle. A HSA tambÃm promoveu retarde no TI e diminuiÃÃo da CG, aumento da PA e diminuiÃÃo da FC. A vagotomia subdiafragmÃtica, a esplancnotomia e o prÃ-tratamento com guanetidina reverteram o efeito da HSA sobre as alteraÃÃes do EG. Os resultados sugerem que os agravos gastrintestinais advindos da HSA refletem um padrÃo de dismotilidade secundÃrios a HIC, mostrando uma forte correlaÃÃo com os valores de PIC / Subarachnoid hemorrhage (SAH) can arise from various types of damage to the central nervous system. The HSA can increase intracranial pressure (ICP) to levels high morbidity. In addition to neurological and cardiovascular symptoms, well described in the literature; gastrointestinal symptoms such as nausea, vomiting and gastroenteritis are common but little studied. The delay gastric emptying (GE) is one of the physiological changes found in patients with intracranial hypertension (ICH). This disorder reduces therapeutic responses with a view to reducing the absorption of nutrients and drugs, and lead to lung aspiration, which can lead to death. We evaluated the effect of HSA on gastrointestinal motility disorders (Gastric Emptying - EG; Intestinal Transit â IT or Gastric Compliance - CG), hemodynamic parameters (Mean Arterial Pressure - MAP, Heart Rate - HR) and the PIC. As well as neurohumoral mechanisms related to these changes. We used Wistar rats (300 - 350g, N=113) under the auspices COBEA (CEUA/UFC- Protocol 41/13). After anesthesia (Ketamine/Xylazine 20-10mg/Kg-IP), the animals were restrained by stereotactic aparatus being injected 0.1, 0.2 or 0.3 ml in the cisterna magna (autologous blood - HSA group or Liquor simile - Control group). At the time of induction of HSA, the animals were subjected to cannulation of the lateral ventricles for measurement of ICP and rigth femoral vessels in order to obtain the hemodynamic data. After 72h of induction, and fasted (24h) animals with oral rehydration solution ad libitum, proceeded studies EG, IT and CG. To determine the rate of GE a test meal (1ml/100g - phenol red - 0.5 mg/ml in 5 % glucose) was administered by gavage. The IT was already determined on direct administration of the meal into the duodenum through previously implanted cannula. Since the CG was evaluated using a barostat system at 4, 8 and 12 cm of gastric pressure distension. The MAP, HR and ICP were measured when assessing gastrointestinal motility. Data, mean  SEM, were analyzed by the "t" Student test (p<0.05). The HSA delayed gastric emptying (38.90  2.73 vs 47.00  0.72 %; 52.85  5.14 vs 31.12  2.0 % and 22.89  4.46 vs 46,24  3.56 % ) and increased the ICP (3.33  0.47 vs 16.10  0.47 cmH2O; 7.68  0.650 vs 30.86Â0.82 cmH2O and 17.50  1.29 vs 37.90  1.38 cmH2O ) in different volumes of blood, either 0.1, 0.2 or 0.3 ml, respectively, when compared to control. The HSA also promoted delay in IT and GC, increased BP and decreased HR. The subdiaphragmatic vagotomy, the esplancnotomia and pretreatment with guanethidine reversed the effect of HSA on changes in EG. The results suggest that the SAH arising gastrointestinal diseases reflect a pattern of secondary gut dysmotility, showing a strong correlation with the values of ICP

Esta pesquisa analisa experimentalmente as diferenças de comportamento entre a versão clássica e a modificada da craniotomia subtemporal quanto à retração do lobo temporal. A retração é medida pelo ângulo de visão, através do microscópio, obtido ao mirar-se estruturas previamente estabelecidas. Estudou-se a correlação estatística entre a retração cerebral e os diâmetros transversos do crânio, a profundidade da fossa temporal e a altura da bifurcação medida em relação à tenda do cerebelo e à clinóide posterior. É considerada a relação entre estes achados e os aspectos pertinentes à opção entre as craniotomias pterional e subtemporal para o tratamento cirúrgico dos aneurismas da porção superior da artéria basilar. / This paper is an experimental analysis between the classic and the modified subtemporal procedures, regarding the cerebral retraction required to approach the interpeduncular cistern and the basilar artery bifurcation. The retraction is assumed to be proportional to the angle of sight, through the microscope, required to observe the basilar bifurcation and other structures. The statistical correlations between the degree of brain retraction and the transverse diameters of the skull, the vertical length of the temporal fossa and the position of the basilar bifurcation in relation to the posterior clinoid and the tentorium are analysed. Considerations are made regarding these findings and the many aspects involved in the options between the pterional and the subtemporal approaches in the surgical treatment of the basilar bifurcation aneurysms

Atualmente, muitos animais encaminhados para necropsia apresentam histórico de óbito ocorrido durante ou após procedimentos como banho e tosa, adestramento, traslados, permanência em hotéis e outras situações similares. Segundo relato de médicos veterinários e auxiliares presentes no local do óbito, grande parte desses animais ao serem manipulados apresentavam agressividade, ansiedade e agitação, e muitos vinham a óbito ainda nas mãos do próprio tosador, enquanto outros, minutos após a chegada em casa. Em um levantamento de exames necroscópicos contendo 1391 animais, realizados pelo Pet Legal Centro de Diagnósticos e Perícias na cidade de São Paulo, no período de 2004 a 2009, 95 cães e 16 gatos de ambos os sexos, e de diferentes raças e idades vieram a óbito durante os procedimentos descritos anteriormente. Em 28% dos casos, os animais vieram a óbito em conseqüência de traumatismos de origem mecânica contundente, tendo uma maior incidência de traumas em região de cabeça, caracterizados por fraturas e lesões de tecido nervoso, ocasionados por queda ou golpe, muitas vezes apresentando lesões de golpe e contragolpe. Em 72% dos casos, os animais vieram a óbito em conseqüência de um colapso respiratório, tendo como alterações principais a congestão, edema e hemorragias pulmonares, sendo esta última, determinante para o óbito. Nos casos de óbito por colapso respiratório, os animais apresentavam alterações em seu comportamento e na freqüência cardiorrespiratória, fato observado na ação de luta ou fuga e que faz parte da fase de alarme da síndrome geral de adaptação. Este é o primeiro trabalho em âmbito nacional que relata as causas de óbitos durante os procedimentos em petshops e similares, fornecendo as informações necessárias aos médicos veterinários, proprietários e principalmente às partes jurídicas, conferindo a esta última, respaldo forense no processo legal. / Nowadays, many animals sent for necropsy have a history of deaths that occurred during or after procedures such as bathing and grooming, training, transfers, staying in hotels and other similar situations. According to the report of veterinarians and assistants present in the place of death, most of these animals when manipulated were aggressive, anxious and agitated, and deceased even during groomer itself, while others, minutes after arriving home. In the survey of necropsies of 1391 animals, conducted at Pet Legal Centro de Diagnósticos e Perícias (a forensic service) in São Paulo from 2004 to 2009, 95 dogs and 16 cats of both sexes and of different breeds and ages deceased during the procedures described above. In 28% of cases the animals died as a result of blunt trauma of mechanical origin, with a higher incidence of trauma in the head, characterized by fractures and injuries to the nervous parenchyma, caused by fall or blow, often with coup and counter-coup lesions. In 72% of cases the animals died as a result of respiratory failure, having as main macroscopic alterations pulmonary congestion, edema and hemorrhage, the latter being a key determinant for death. In cases of death due to respiratory failure, the animals showed changes in their behavior and their cardio-respiratory frequency, which was observed in the action of \"fight or flight\" and is part of the alarm phase of the general syndrome adaptation. This is the first nationwide study reporting the causes of deaths during petshops and similars procedures, providing the necessary information to veterinarians, owners and especially in the legal, giving the latter, forensic support in the lawsuit.

O terceiro período do parto inicia-se após a expulsão do feto e termina com o desprendimento da placenta. A perda sanguínea pós-parto está diretamente associada com o tempo de desprendimento placentário e a contratilidade uterina. A recomendação do manejo ativo do terceiro período do parto pela ICM/FIGO e OMS se pauta nas evidências científicas do seu potencial em reduzir morbimortalidade materna. Este compreende as seguintes intervenções: administração profilática de ocitócitos, após o nascimento do bebê, clampeamento e secção do cordão umbilical precoces; tração controlada do cordão e massagem em fundo uterino, com a finalidade de reduzir a perda sanguínea pós-parto. Objetivo: identificar como é realizado o manejo do terceiro período clínico na condução de partos normais em uma maternidade-escola e analisar os resultados obstétricos no puerpério imediato. Metodologia: A amostra constituiu-se de 142 parturientes. A coleta de dados foi realizada por meio de observação não participante, respaldada por formulário testado previamente em estudo piloto. Resultados: A dequitação foi espontânea em 98,6% dos partos, com duração média de 8,79 ± 7,48 minutos. O clampeamento e secção precoces do cordão umbilical foram a intervenção mais realizada (93,7%); seguidos pela tração controlada de cordão (87,3%); massagem em fundo uterino (70,4%); contato precoce (52,8%); aleitamento precoce (34,5%); uso de ergotamina (3,5%). A ocitocina foi utilizada apenas como terapêutica adicional após o parto (73,9%), dosagem média de 9,48 ± 9,47 UI. Foram identificadas as seguintes complicações: sangramento em média quantidade (15,5%); curagem (4,2%) e sangramento em grande quantidade (3,5%). Não foi encontrado associação estatisticamente significantes ( teste exato de Fisher ) entre os componentes do manejo ativo e ocorrência de sangramento em média ou grande quantidade. Foi identificado associação significante entre o peso fetal (p= 0,043), e quase significância para a cor branca (p= 0,074) e o sangramento pós-parto. Não foi encontrada associação com outras variáveis independentes. Considerações finais: Embora o manejo ativo do terceiro período do parto apresente evidências científicas sobre sua eficácia, os resultados revelam que ainda persiste resistência em relação à sua aplicação e que muitos dos seus componentes não foram aderidos na instituição estudada, sendo realizado um manejo \"misto\" (componentes do manejo ativo e do manejo expectante). A presença de complicação bem como sua seriedade foi de pequena freqüência. Destacamos a necessidade de continuidade de estudos sobre a temática e especialmente quanto a avaliação objetiva da perda sanguínea e repercussões clínicas no puerpério. / The third stage of labor starts after expulsion of the fetus and ends with the detachment of the placenta. The post-partum blood loss is directly associated to the time of placental detachment and uterine contractility. The active management recommendations for the third stage of labor, issued by ICM/FIGO and WHO, are based on scientific evidence concerning its potential to reduce maternal morbidity and mortality. It encompasses the following interventions: prophylactic administration of oxytocins, after delivery of the baby; early clamping and cutting of the umbilical cord; controlled traction of the cord and massage of the uterine fundus, with the purpose of reducing post-partum blood loss. Objective: to identify the way of managing the third clinical stage of a normal delivery in a teaching maternity hospital and to analyze the obstetric results in the immediate puerperium. Methodology: The sample consisted of 142 women in labor. Data collection was performed by non-participating observation, backed-up by a form previously tested in a pilot study. Results: Afterbirth was spontaneous in 98.6% of the deliveries, with an average duration of 8.79±7.48 minutes. Early clamping and cutting of the umbilical cord were the most frequently performed intervention (93.7%), followed by controlled traction of the cord (87.3%), massage of the uterine fundus (70.4%); early contact (52.8%); early breastfeeding (34.5%); use of ergotamine (3.5%). Oxytocin was used only as an additional therapeutic after delivery (73.9%), at a mean dosage of 9.48±9.47 IU. The following complications were identified: medium-amount bleeding (15.5%); curage (4.2%), and large-amount bleeding (3.5%). No statistically significant association was found (Fisher\'s exact test) between the components of the active management and the occurrence of medium- or large-amount bleeding. A statistically significant association between fetal weight and post-partum bleeding (p=0.043), and an almost significant association between Caucasian ethnicity and post-partum bleeding (p=0.074) were identified. No association with other independent variables was found. Final considerations: Although there is scientific evidence indicating that the active management in the third stage of labor is effective, our results reveal that resistance to adopt it persists and that there was no adhesion to many of its components in the studied institution, where a \"mixed\" management is done (components of the active management and of the passive management). The frequency of complications and their severity were low. We stress the need for further studies on this subject, especially regarding an objective evaluation of blood loss and its clinical repercussions during the puerperium.

Orientador: Giovanni Faria Silva / Banca: Pedro Achilles / Banca: Luiza Maria Filomena Romanello / Banca: José Luiz Pimenta Modena / Banca: Ciro Garcia Montes / Resumo: A Hemorragia Digestiva Alta (HDA) é uma das desordens digestivas mais comumente diagnosticadas no mundo. As principais causas são a úlcera peptica gastroduodenal (UPGD) e a lesão aguda da mucosa gastroduodenal (LAMGD). Apesar dos avanços tecnológicos ocorridos nas últimas décadas, não se observou um declínio das taxas de mortalidade, que variam entre 11% e 33%. Esforços consideráveis tem sido realizados para a identificação precoce dos preditores de mau prognóstico, possibilitando à equipe médica a identificação dos grupos de alto risco e, com isso, uma intervenção mais agressiva e precoce. Análise comparativa dos preditores de recidiva hemorrágica ou óbito nos pacientes com HDA por UPGD ou LAMGD e análise de sobrevida dos grupos. Análise retrospectiva dos pacientes adultos com HDA por UPGD ou LAMGD submetidos a endoscopia digestiva alta (EDA) no período de jan/01 a dez/04 no HC da Faculdade de Medicina de Botucatu - UNESP. Critérios de inclusao: pacientes com HDA por UPGD ou LAMGD submetidos à EDA. Critérios de exclusão: HDA de outra etiologia. Análise estatística: testes de associação (Qui- Quadrado e teste exato de Fisher), testes de comparação entre os grupos, regressão logística múltipla, teste de Log Rank e regressão de Cox. 255 casas de HDA, sendo 57 por LAMGD e 198 por UPGD. Os grupos foram homogêneos com relação à idade, gênero, uso de anti-inflamatórios não esteroides (AINES), presença de comorbidades, níveis de hematócrito e hemoglobina e índices de recidiva hemorragica e óbito. No grupo com LAMGD,a idade media foi 60,4 anos (±18,7) e 64% dos doentes eram homens. O uso de AINES foi relatado por 46% dos doentes e 58% apresentavam comorbidades. Recidiva hemorrágica ocorreu em 3,5% dos pacientes e óbito em 10%. O preditor de ressangramento foi a necessidade de grande volume de transfusão sanguínea (OR: 2,03; IC:1,07-3,83)... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: The upper gastrointestinal bleeding (UGIB) is one of the most commonly diagnosed digestive disorders in the world. The main causes are the peptic ulcer disease (PUD) and erosive disease. Despite technological advances occurring in recent decades there was not a decline in mortality rates, ranging between 11% and 33%. Considerable efforts have been made to identify early predictors of poor prognosis, allowing the medical team to identify high risk patients and, thus, a more aggressive and early intervention. Comparative analysis of predictors of rebleeding or death in patients with UGIB by PUD or erosive disease and analysis of survival of groups. Retrospective analysis of adult patients with UGIB by PUD or erosive disease underwent endoscopy from January 2001 to December 2004 in the Botucatu Medical School - UNESP. Inclusion criteria: patients with UGIB by PUD or erosive disease underwent endoscopy. Exclusion Criteria: UGIB by another etiology. Statistical analysis: chisquare and Fisher exact test, tests for comparison between groups, multivariate logistic regression models, Log Rank test and Cox proportional hazards regression. 255 cases of UGIB, being 57 by erosive disease and 198 by PUD. The groups were homogeneous with respect to age, gender, use of nonsteroidal anti-inflammatory drugs (NSAIDS)... Complete abstract click electronic access below) / Doutor

Com o objetivo de estudar as diferenças de potencial hemorrágico entre metaloproteinases de venenos de serpentes (SVMPs), compararamos a ação da jararagina, toxina hemorrágica da classe P-III, e da BnP1, SVMP da classe P-I fracamente hemorrágica, quanto à ação em proteínas de matriz extracelular (MEC), células endoteliais e distribuição na MEC e endotélio. Nos ensaios de ligação em fase sólida, apenas a jararagina e a jarararagina-C (domínios tipo disintegrina e rico em cisteínas) se ligaram ao colágeno I e IV. Em HUVECs, a jararagina e BnP1 induziram apoptose, mas em modelo de pele, apenas a jararagina induziu intensa hemorragia, acompanhada de degradação do colágeno fibrilar e colágeno IV na região da hipoderme. A jararagina e jararagina-C localizaram-se na parede dos capilares sangüíneos co-localizando-se como o colágeno IV. Esses resultados sugerem que a ligação ao colágeno é importante para a hemorragia induzida pelas SVMPs da classe P-III, promovendo seu acúmulo nas proximidades dos vasos sanguíneos tornando a catalise dos componentes da MEC mais eficiente. / In order to enlighten the mechanisms of hemorrhage induced by snake venom metalloproteinases (SVMPs), the effects of jararhagin, a highly hemorrhagic P-III SVMP and BnP1, a weakly hemorrhagic P-I SVMP, on extracellular matrix (ECM) proteins, endothelial cells, and distribution in MEC and endothelium, was compared. In solid phase assay, only jararhagin and jararhagin-C (disintegrin-like and cysteine-rich domains) bond to collagen I and IV. In HUVECs, jararhagin and BnP1 induced apoptosis, but in skin model only jararhagin induced intense hemorrhage with degradation of the fibrillar collagen and collagen I, in hypodermis region. Jararhagin and jararhagin-C concentrated in blood vessels walls, co-localizing with collagen IV. These results suggest that the collagen binding is important to hemorrhage induced by P-III SVMPs, promoting their accumulation near to the blood vessels, making the catalysis of the basement membrane components more efficient.

The aim of this thesis was to explore variations in stroke prevention and the effect of prevention on outcome. The studies were based on patients registered in the Swedish Stroke Register between 2001 and 2009 and although used to different extents in each paper, additional information was retrieved through linkage to The National Patient Register, the Cause of Death Register, the Prescribed Drug Register and the Total Population Register. Cardiovascular risk factors were prevalent among ischemic stroke (IS) patients; however, they were not always prescribed the drugs recommended, and increasing age was an important negative predictor (Paper I). After IS, the rate of hemorrhage in patients prescribed antiplatelet agents (2.4 per 100 person-years) was double to results from randomized controlled trails, but was similar for patients prescribed warfarin (2.5 per 100 person-years).  Age ≥75 years and previous hemorrhage were associated with a moderately increased risk of future hemorrhage (Paper II). Among IS patients with atrial fibrillation, one-third was prescribed warfarin and two-thirds were prescribed antiplatelets. After adjustment for a propensity score (used to adjust for the non-randomized design), warfarin was associated with a reduced risk of death (0.67; 95% CI, 0.63-0.71) (Paper III). The rate of subsequent hemorrhagic stroke was 0.4 per 100 person-years and the risk did not change (HR 1.04; 95% CI, 0.73-1.48) when later years of the 2000s (inclusion period 2005-8: follow-up until 2009) was compared with earlier years (inclusion period 2001-4: follow-up until 2005) (Paper IV, cohort). Although the risk of first-ever hemorrhagic stroke more than doubled with warfarin than without, the risk did not change between 2006 and 2009 (Paper IV, case-control). In summary, the prescription of secondary preventive drugs varies with age, even though cardiovascular risk factors are prevalent in all ages. The risk of death and hemorrhage are affected by the type of antithrombotic prescribed. Therefore, it is important individual’s stroke and bleeding risks in stroke prevention are assessed.

Subarachnoid hemorrhage (SAH) is a disease with high risk of mortality and morbidity. Elderly patients have an even higher risk of poor outcome. The incidence of SAH increases with age and the elderly constitute a substantial and increasing proportion of the population. Thus, the management of elderly SAH patients is an imminent clinical challenge. Time trends in clinical management and outcome were investigated in 281 SAH patients aged ≥65 years admitted over an 18-year period. The volume of elderly patients, especially patients ≥70 years and patients in worse clinical condition increased over time. The proportion of patients with favorable outcome increased over time, without an increase in severely disabled patients. Technical results and clinical outcome of endovascular aneurysm treatment (EVT) was investigated in 62 elderly SAH patients. EVT can be performed in elderly SAH patients with high technical success, acceptable aneurysm occlusion degree, acceptable procedural complication rate, and fair outcome results. EVT was compared to neurosurgical clipping (NST) in 278 elderly SAH patients in the International Subarachnoid Aneurysm Trial. In good grade elderly SAH patients, EVT should probably be the favored treatment for internal carotid and posterior communicating artery aneurysms, while elderly patients with middle cerebral artery aneurysms appear to benefit from NST. Occurrence of secondary insults and their impact on clinical deterioration were studied in 99 patients with severe SAH. High intracranial pressure increased and high cerebral perfusion pressure decreased the risk of clinical deterioration. Elderly patients had less intracranial hypertension insults and more hypertensive, hypotensive and hypoxemic insults. Good outcome was achieved in 24% of elderly patients with severe SAH, and the proportion of severe disability was similar to that of younger patients. Patient age was not a significant predictor for vasospasm in 413 SAH patients when admission and treatment variables were adjusted for with multiple logistic regression.

The minimization of blood loss represents a significant clinical need in the arena of surgery, trauma, and emergency response medicine. Fibrinogen is our body's native polymer system activated in response to tissue and vasculature injury, and forms the foundation of the most widely employed surgical sealant and hemostatic agent. Non-covalent knob:hole interactions are central to the assembly of fibrin that leads to network and clot formation. This project exploits these affinity interactions as a strategy to direct fibrin polymerization dynamics and network structure so as to develop a temperature-triggered polymerizing fibrin mixture for surgical applications. Short peptides modeled after fibrin knob sequences have been shown to alter fibrin matrix structure by competing with native fibrin knobs for binding to the available holes on fibrinogen and fibrin. The fusion of such knob peptides to a non-native component should facilitate binding of the fused component to fibrinogen/fibrin, and may permit the concomitant modification of the fibrin matrix. We examined this hypothesis in a three-step approach involving (a) analyzing the ability of tetrapeptide knob sequences to confer fibrin(ogen) affinity on a non-fibrin protein, (b) investigating the effect of knob display architecture on fibrin(ogen) structure, and (c) designing a temperature-responsive knob-displaying construct to modulate fibrin(ogen) affinity at different temperature regimes, thus altering fibrin(ogen) structure.

Subarachnoid hemorrhage (SAH) comprises 7% of all stroke cases, and is associated with a disproportionately high morbidity and mortality with few therapeutic options available. The goal of this project was to understand the mechanism of neurological deterioration after experimental SAH, with a focus on cerebral vasospasm and brain injury after SAH. We tested the hypothesis that endothelial nitric oxide synthase (eNOS) is upregulated and uncoupled after SA, resulting in exacerbated neurological injury in a mouse model of SAH. The project entailed the investigation of eNOS-dimer uncoupling, its association with oxidative and nitrosative stress in the brain parenchyma and finally its association with secondary complications after SAH. In our studies we demonstrated the crucial role eNOS plays in anti-microthromboembolism, anti-apoptosis and maintenance of physiological superoxide (O2-)/NO balance. This study suggests that SAH up-regulates and disrupts eNOS, producing peroxynitrite (OONO-) and other radicals that further exacerbate the oxidative insult and neurological injury.