5 Summary: Currently, the outcomes from traumatic exsanguination cardiac arrest (CA) show that over 50% of deaths due to trauma occur at the scene, where medical care is limited. Less than 10% of patients who become pulseless from trauma survive. However, in an appropriate setting, some of those traumatic injuries could be surgically repairable. Emergency preservation and resuscitation (EPR) is a novel approach for resuscitation of exsanguination CA victims. EPR uses deep hypothermic preservation for prolonged CA to buy time for transport, damage control surgery, and delayed resuscitation with cardiopulmonary bypass (CPB). Initially, we used a dog model to maximize clinical relevance. We showed that the efficacy of EPR is related to the depth of hypothermia and duration of CA. Pharmacologic adjuncts tested to augment hypothermia generally failed. Extended hemorrhagic shock did not prevent the success of EPR vs. conventional resuscitation if extended post-resuscitative hypothermia was provided. Oxygenation of the flush allowed extending of survivable duration of deep hypothermic CA. Because of the lack of molecular tools available for use in dogs, we developed a rat EPR model to study the cellular and molecular mechanisms underlying deep hypothermic neuroprotection to allow us to define specific targets for...

Made available in DSpace on 2014-07-29T15:30:35Z (GMT). No. of bitstreams: 1 Dissertacao de Benigno Alberto Moraes Rocha.pdf: 429604 bytes, checksum: e7166c606b960cf25df199a5ddc928fd (MD5) Previous issue date: 2008-02-29 / In Brazil, dengue is present in almost all states and territories, with a circulation of three different serotypes (DEN 1, DEN 2 and DEN 3), resulting in about 500 000 cases reported in 2007 (PAHO 2008; MS / SVS 2008a). This dissertation consists of a literature review, with emphasis on the epidemiology of dengue in Brazil and two articles that are designed to analyze the clinical and epidemiological characteristics of this condition, focusing on children under 15 years old, in Goiânia. The first article provides a profile analysis 59. 157 reported cases of dengue (SINAN), in Goiania, from 2001 to 2006. It also presents a reliability evaluation of the clinical classification of dengue, as recorded in the SINAN, compared with a revised classification proposed by the authors. There was an increase of dengue fever with complications or Dengue hemorrhagic fever in all age groups (p <0.05), children showed more hemorrhagic manifestations, however, no difference in the proportion of severe cases among adults and children. The results showed a low capacity of the surveillance system for classifying cases potentially serious in children under 15 years old (Kappa = 0.22; 95% CI 0.20 to 0.24). The second article examines 162 children under 15 years with acute febrile illness suggestive of dengue fever, attended from 2005 to 2006. We collected blood samples for detection of IgM anti-dengue (MAC-ELISA), molecular biology test (RT-PCR) and virus isolation. Half the cases were laboratory confirmed by serology and 84 and five by RT-PCR and / or virus isolation and identification of DEN 3 in all. Myalgia, arthralgia, rash, thrombocytopenia and leukopenia were more frequent among confirmed cases (p <0.05). PPV and NPV for suspected dengue cases, by clinical criteria, were respectively 54.8% and 40.0%. Recommended clinical criteria for diagnosis of dengue were reluctant for this specific age group, even in a region of high endemicity. / No Brasil, a dengue esta presente em quase todos os estados e territórios, com circulação de três sorotipos diferentes (DEN 1, DEN 2 e DEN 3), resultando em cerca de 500 mil casos notificados, em 2007 (PAHO 2008; MS/SVS 2008a). A presente dissertação de mestrado é composta por uma revisão da literatura, com ênfase na epidemiologia da dengue no Brasil e por dois artigos que se propõem analisar as características clínicas e epidemiológicas desse agravo, com enfoque em menores de 15 anos de idade, em Goiânia. O primeiro artigo traz uma análise do perfil de 59. 157 casos notificados de dengue (SINAN), em Goiânia, de 2001 a 2006. Apresenta, também, uma avaliação da confiabilidade da classificação clínica de dengue, conforme registrada no SINAN, em comparação com uma classificação revisada, propostas pelos autores. Houve aumento de dengue com complicação ou dengue hemorrágica, em todas as faixas etárias (p<0,05), Crianças apresentaram mais manifestações hemorrágicas, entretanto, não houve diferença na proporção de formas graves entre adultos e crianças. Foi evidenciada uma baixa capacidade do sistema de vigilância para classificar casos potencialmente graves, em menores de 15 anos de idade (Kappa = 0,22; IC95% 0,20-0,24). O segundo artigo analisa 162 menores de 15 anos, com quadro febril agudo, sugestivo de dengue, atendidas entre 2005 a 2006. Foram colhidas amostras de sangue para detecção de IgM anti-dengue (MAC-ELISA); teste de biologia molecular (RT-PCR) e isolamento viral. Metade dos casos foram confirmados laboratorialmente, sendo 84 por sorologia e cinco por RT-PCR e/ou isolamento viral, com identificação de DEN 3 em todos eles. Mialgia,artralgia, exantema, plaquetopenia e leucopenia foram mais freqüentes entre os casos confirmados (p< 0,05). VPP e VPN para casos suspeitos de dengue, pelos critérios clínicos, foram, respectivamente, de 54,8% e 40,0%. Critérios clínicos preconizados para o diagnóstico de dengue mostraram-se pouco específicos para esta faixa etária, mesmo em região de alta endemicidade.

Escherichia coli é um microrganismo presente no trato intestinal do homem e de animais de sangue quente, fazendo parte da microbiota, coexistindo sem causar danos ao hospedeiro. No entanto, algumas linhagens desse microrganismo podem ser patogênicas e causar doenças tanto ao homem como aos animais. E. coli produtoras de toxina de Shiga (STEC), consideradas patógenos de origem alimentar, podem causar desde diarréias brandas até severas e sanguinolentas a complicações graves, como colite hemorrágica (HC), síndrome urêmica hemolítica (HUS) e púrpura trombótica trombocitopênica (TTP). O gado é considerado um importante reservatório deste patógeno e a contaminação de seres humanos ocorre, na maioria das vezes, através do consumo de alimentos ou água contaminados. O presente trabalho teve como objetivos avaliar a ocorrência de E. coli O157:H7 e outras STEC em amostras de couro de animais bovinos e de suas respectivas carcaças, na etapa de pré-evisceração, e meia-carcaças, na etapa de pós-evisceração; identificar os genes que codificam para os fatores de virulência (stx1 , stx2, eaeA e ehxA) dos isolados obtidos; evidenciar cepas de E. coli O157:H7 através da pesquisa do gene uidA; identificar os sorotipos dos isolados; verificar a citotoxicidade dos isolados de STEC em células Vero e avaliar a sensibilidade a diferentes antibióticos. De 198 animais amostrados, sete (3,5%) apresentaram cepas de STEC. Em seis (3%) destes, STEC foi detectada no couro e em um (0,5%) foi isolada de meia-carcaça, não tendo sido detectada em amostras de carcaça. As 23 cepas isoladas do couro apresentaram o perfil stx2, eaeA, uidA e ehxA, podendo ser consideradas E. coli enterohemorrágica (EHEC), e a isolada de meia carcaça apresentou o perfil stx2, uidA e ehxA. Das 24 cepas isoladas, 13 (54,2%) pertenciam ao sorotipo O157:H7. Além deste sorotipo, foram isoladas cepas de outros sorotipos previamente descritos e associados a doenças humanas severas no Brasil e em outros países, como O174:H21, O6:H49, ONT:H7, ONT:H8 e OR:H10. Dos sete animais com cepas positivas para stx2e ehxA, cinco (71,4%) apresentaram cepas com atividade citotóxica em células Vero e um (14,2%) apresentou cepas positivas na avaliação da produção de entero-hemolisina. Com relação ao teste com antibióticos, quatro (16,7%) das 24 cepas testadas apresentaram resistência a um ou mais antibióticos, sendo três (12,5%) a estreptomicina e uma (4,2%) a estreptomicina e ampicilina. Diante destes resultados, pode-se dizer que a produção de entero-hemolisina e a pesquisa dos genes ehxA e uidA não demonstraram ser bons marcadores na pesquisa do sorotipo O157:H7. A presença de cepa de STEC na meia-carcaça alerta para a necessidade de vigilância da presença destes microrganismos, uma vez que eles poderiam contaminar o produto final, colocando em risco a saúde do consumidor. / Escherichia coli is a microorganism present in the intestinal tract of humans and warm-blood animals, being part of the normal microbiota and harmless to the host. However, some strains are able to cause human and animal infections. Shiga toxin-producing E. coli (STEC), regarded as foodborne pathogens, can cause since mild or severe and bloody diarrhea to major complications, such as hemorrhagic colitis (HC), hemolytic-uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP). Cattle are considered the main reservoir of this pathogen and the transmission to humans happens, most of the times, due to the consumption of contaminated food or water. The aim of the present research was to determine the prevalence of E. coli O157:H7 and other STEC on hide samples of beef cattle and on their corresponding carcasses, sampled prior to evisceration, and half-carcasses, sampled after evisceration; identity the genes that code for the virulence factors (stx1, stx2, eaeA e ehxA) of the isolates; detect E. coli O157:H7 strains using the gene uidA as epidemiological marker; identify the serotypes of the STEC isolates; verify the citotoxicity of the isolates in Vero cells and evaluate their resistance to different antibiotics. From 198 animals sampled, seven (3.5%) carried STEC strains. In six (3%) of them, STEC was detected on hide and in one (0.5%) it was isolated from half-carcass. The 23 strains isolated from hide presented the profile stx2, eaeA, uidA e ehxA, and were regarded as enterohemorrhagic Escherichia coli (EHEC), and the one isolated from half-carcass presented the profile stx2, uidA e ehxA. From the 24 isolated strains, 13 (54.2%) belonged to the serotype O157:H7. Besides this serotype, other strains belonging to serotypes that have been previously described and associated with severe human infections in Brazil and other countries, such as O174:H21 , O6:H49, ONT:H7, ONT:H8 and OR:H10, were isolated. From seven animals with strains harboring stx2, and ehxA, five (71.4%) presented verocytotoxigenic strains and one (14.2%) presented enterohemolisin producing strains. Regarding the antibiotics tested, four (16.7%) of the 24 isolated strains were resistant to some antibiotic, being three (12.5%) to streptomycin and one (4.2%) to streptomycin and ampicilin. Faced with these results, the production of enterohemolisin and the search of the genes ehxA and uidA can not be considered good epidemiological markers for the serotype O157:H7. The isolation of STEC strain from the half-carcass alerts for the need of surveillance on the presence of these microorganisms, since they may contaminate the final product, representing a risk to consumers health.

Les accidents vasculaires cérébraux (AVC) constituent un problème majeur de santé publique. Ils sont en majorité de type ischémique, c’est-à-dire liés à l’occlusion d’une artère cérébrale. Le seul traitement actuel de ces AVC ischémiques est la thrombolyse par l’activateur tissulaire du plasminogène recombinant (rt-PA). Cependant, ce traitement est associé à un risque élevé d’hémorragies intracérébrales post-ischémiques, encore appelées transformations hémorragiques (TH), qui contribuent à la dégradation neurologique des patients. Il apparaît donc indispensable de développer des stratégies à associer au rt-PA, afin de protéger le lit vasculaire et de réduire les TH. L’objectif de ce travail de thèse était d’étudier l’implication d’une enzyme, la poly(ADP-ribose)polymérase ou PARP, dans les effets délétères du rt-PA, et plus particulièrement au niveau de la barrière hémato-encéphalique (BHE). Nos travaux ont été menés dans un modèle d’ischémie cérébrale réalisé chez la souris. Dans ce modèle, nous avons mis en évidence le rôle de la PARP dans les TH induites par le rt-PA, grâce à deux techniques : le Western blot d’hémoglobine, permettant d’évaluer la quantité de sang présente dans le parenchyme cérébral, et l’Imagerie par Résonnance Magnétique. Afin de préciser les cibles de la PARP sous-tendant sa contribution aux TH post-thrombolyse, nous nous sommes intéressés à différents constituants de la BHE : la claudine-5, l’occludine et ZO-1 (zonula occludens-1), protéines des jonctions serrées, la VE-cadhérine des jonctions adhérentes et le collagène IV et la laminine, constituants de la lame basale. Nous avons montré que l’ischémie s’accompagne d’une dégradation de la claudine-5, de ZO-1, et de la VE-cadhérine qui est aggravée par le rt-PA ; l’administration d’un puissant inhibiteur de PARP, le PJ34, permet de s’opposer à la dégradation de ces protéines par le rt-PA. Une réduction de la dégradation de la laminine par le rt-PA a également été observée avec le PJ34. Grâce à une collaboration avec le Pr Bérézowski de Lens, nous avons pu montrer dans un modèle in vitro que le PJ34 est capable de traverser la BHE, à la fois dans des conditions « physiologiques » et dans des conditions mimant l’ischémie cérébrale (oxygen/glucose deprivation). Afin de déterminer les voies de signalisation modulées par la PARP conduisant à la dégradation de la BHE et aux TH, nous avons travaillé sur un modèle in vitro de cultures de cellules endothéliales (lignée bEnd.3). Sur ce modèle, nous avons d’ores et déjà pu mettre en évidence une mort cellulaire après un stress excitotoxique et le rôle de la PARP dans cette mort. L’ensemble de ces travaux a permis de démontrer le rôle de la PARP dans la dégradation de différents constituants de la BHE par le rt-PA à la suite de l’ischémie cérébrale. Les futures études in vitro sur cultures cellulaires devraient nous permettre d’explorer les mécanismes mis en jeu dans cette situation pathologique. Une meilleure connaissance de ces mécanismes renforcera l’intérêt des inhibiteurs de PARP pour la prévention des TH post-thrombolyse chez les patients victimes d’AVC ischémiques. / Stroke is a leading public health problem, the majority of which is ischemic, i.e. caused by the occlusion of a cerebral artery. The only pharmacological approved treatment for acute ischemic stroke is thrombolysis by recombinant tissue plasminogen activator (rt-PA). However, this treatment increases the risk of intracerebral hemorrhages, also called hemorrhagic transformations (HT), which contribute to the neurologic aggravation of the patients. It therefore appears essential to develop strategies protecting the vascular bed after cerebral ischemia in order to reduce these HT. The aim of the present work was therefore to study the implication of a nuclear enzyme, the poly(ADP-ribose)polymerase (PARP) in the vascular effects of rt-PA , with special concern for the blood-brain barrier (BBB). Focal cerebral ischemia was performed in mice by permanent endovascular occlusion of the left middle cerebral artery. In this model, we demonstrated the role of PARP in the rt-PA induced HT by two methods: the Western blot of hemoglobin to evaluate the quantity of blood in the cerebral parenchyma, and magnetic resonance imaging. In order to clarify the targets of PARP underlying its contribution to post-thrombolysis HT, we studied several components of the BBB by Western blot: proteins of tight junctions [claudin-5, occludin and zonula occludens-1 (ZO-1)], protein of adherens junction (VE-cadherin) and proteins of basal membrane (collagen IV and laminin). We demonstrated that ischemia induced a marked decrease of claudin-5, ZO-1 and VE-cadherin, which was aggravated by rt-PA. Administration of a potent PARP inhibitor, PJ34, counteracted the degradation of these proteins by rt-PA. A reduction of the degradation of the laminin by rt-PA was also shown with PJ34. Thanks to a collaboration with Pr Berezowski from Lens, we showed in an in vitro BBB model that PJ34 is able to cross the BBB in physiological condition and during oxygen and glucose deprivation, a condition that mimicks cerebral ischemia. In order to determine the molecular pathways modulated by PARP leading to the degradation of the BBB and to HT, we developed an in vitro model of endothelial cell culture (cell line bEnd.3). In this model, we have already shown a cell death after an excitotoxic stress and the role of PARP in this cell death. This work thus demonstrated the role of PARP in the degradation of different components of the BBB induced by rt-PA after cerebral ischemia. The future in vitro studies on cell culture will enable us to further understand the mechanisms implicated in this pathologic situation. A better knowledge of these mechanisms will increase the interest of the use of PARP inhibitors in the prevention of post-thrombolysis HT in patients suffering from ischemic stroke.

L’association lésionnelle d’une contusion pulmonaire et d’un état de choc hémorragique est fréquente et constitue un réel chalenge thérapeutique. La prise en charge de ce choc va nécessiter une réanimation hémodynamique dans laquelle le remplissage vasculaire tient une place centrale. Mais dans ce contexte de poumon contus, il devra être raisonné car délétère sur le plan pulmonaire, notamment en terme d'oedème et d'altération de la compliance. Ce remplissage devra donc être titré, basé sur des objectifs tensionnels clairs et un monitorage hémodynamique fiable. L'utilisation de solutés à haut pouvoir d'expansion volémique (sérum salé hypertonique, colloïdes) présente un intérêt, de même que l'introduction précoce de vasopresseurs. Le monitorage hémodynamique permettra de conduire cette réanimation sur des objectifs de pression artérielle, sur des indices de précharge dépendance et sur la mesure de l'eau pulmonaire extravasculaire. Notre travail, basé sur des études expérimentales et cliniques, a pour objectif de caractériser les modalités actuelles de prise en charge d’une contusion pulmonaire, sur les plans hémodynamiques et respiratoires. / Pulmonary contusion is often associated with hemorrhagic shock, constituting a challenge in trauma care. For patients who have sustained lung contusions, fluid resuscitation should be carefully performed, because injured lungs are particularly vulnerable to massive fluid infusions with an increased risk of pulmonary edema and compliance impairment. Fluid administration should be included in an optimized and goal directed resuscitation, based on blood pressure objectives and hemodynamical monitoring. The use of fluids with high volume-expanding capacities (hypertonic saline, colloids) is probably interesting, as well as early introduction of vasopressors. Hemodynamic monitoring will allow to conduct resuscitation on blood pressure objectives, on preload parameters and on extravascular lung water measurement.Our work, based on experimental and clinical studies, objective to characterize the current modalities of ventilatory and hemodynamical aspect of pulmonary contusion care.

Le virus Lassa entraine une fièvre hémorragique endémique en Afrique de l’Ouest et représente un problème de santé publique. Les connaissances sur la pathogénèse et les réponses immunitaires associées à la maladie sont partielles. Nous avons suivi les paramètres pathologiques, virologiques et immunologiques associés aux infections létales et non létales du LASV chez le singe cynomolgus. Le tableau clinique a été caractérisé par une dépression, une anorexie, une perte de poids et une asthénie chez les animaux survivants, tandis que ces mêmes symptômes ont été accompagnés de fièvre, de difficultés respiratoires et d’épistaxis chez les animaux infectés par une dose létale. Seuls ces derniers ont montré une perturbation des paramètres de coagulation, une rhabdomyolyse et une hausse des marqueurs de lésions rénales. Nous avons observé un tropisme radicalement différent en fonction de la sévérité de la maladie, avec une dissémination virale dans les organes plus importante et plus rapide chez les animaux décédés, la présence de particules infectieuses plus nombreuses et des modifications anatomopathologiques plus sévères. Une réponse immunitaire innée et adaptative précoce et puissante a été associée avec le contrôle de l’infection et la survie tandis que les infections fatales ont été caractérisées par une réponse inflammatoire ressemblant au choc septique, une défaillance de la réponse immunitaire ainsi qu’une réplication virale incontrôlée. Cette étude permet d’améliorer nos connaissances de la pathogénèse de la fièvre de Lassa et d’apporter des marqueurs d’infection prédictifs de la maladie / Lassa virus causes a hemorrhagic fever endemic in West Africa and represents a threat for civilians. The pathogenesis and the immune responses associated with the disease are poorly understood. We followed pathological, virological and immunological parameters associated with fatal and non-fatal Lassa virus infection in the cynomolgus monkey. The clinical picture was characterized by depression, anorexia, weight loss and asthenia in survivors whereas the same symptoms were supported by fever, respiratory difficulties and epistaxis in animals infected with the lethal dose. Only fatalities have shown coagulation parameters dysfunction, rhabdomyolysis and an increase of renal function markers. We observed a different viral tropism in a function of the disease severity, with viral dissemination in organs that was more important and faster in fatalities, the appearance of numerous infectious particles number and more severe pathologic changes. Early and robust innate and adaptive immune response has been associated with the control of infection and recovery whereas fatal infections were characterized by a sepsis like inflammatory response, defective immune response as well as uncontrolled viral replication. This study sheds light on the pathogenesis of Lassa fever and reveals infection markers predictive of the disease outcome

Introduction: Alors que le choc hémorragique représente la première cause de mortalité précoce chez les patients subissant un traumatisme sévère, la défaillance d’organes est responsable d’une mortalité tardive chez cette population. Les alarmines, molécules libérées en situation d’ischémie-reperfusion et capables d’induire une réponse inflammatoire systémique et locale, représentent potentiellement une cible thérapeutique afin de minimiser la défaillance d’organes post-traumatique. L’acide urique est une molécule pro-inflammatoire et pro-apoptotique libérée en situation de choc hémorragique dont les effets au niveau des organes sont peu investigués. Le premier volet de ce mémoire présente une preuve de concept que l’acide urique joue un rôle clé dans l’atteinte hépatique et intestinale dans un modèle animal de choc hémorragique, et sera présenté sous forme de manuscrit soumis. Le deuxième volet de ce mémoire présente des données préliminaires d’une étude clinique prospective visant à évaluer la cinétique de l’acide urique chez une cohorte de patients traumatisés. Volet animal: Un choc hémorragique a été induit chez des rats Wistar en retirant du volume circulant titré à une tension artérielle moyenne (TAM) de 30-35 mmHg pendant 60 minutes. Les rats ont été réanimés avec une solution composée de sang retiré et de lactate ringer (1 :1), avec ou sans Uricase, une enzyme recombinante qui métabolise l’acide urique. Les résultats démontrent une diminution significative de plusieurs marqueurs d’hépatolyse (AST, ALT), inflammatoire (ICAM-1, MPO, TNF-alpha, IL-1, Caspase-1) et apoptotique (Caspase-3, -8, Bax/BCL-2, pAKT/AKT) au sein du groupe uricase. L’intervention sur l’acide urique a également pu prévenir l’augmentation de la perméabilité intestinale suite au choc hémorragique, de même que la translocation de produits bactériens en circulation (LPS). Volet clinique: Vingt patients subissant un choc hémorragique traumatique ont été recrutés de façon prospective à l’Hôpital Sacré-Cœur de Montréal, dans le cadre d’un projet pilote soutenu par le consortium de trauma du FRSQ. Des prélèvements d’acide urique sérique ont été effectués de façon sériée pendant 7 jours. Les critères de faisabilité, notamment les taux de consentement (95%) et d’observance des prélèvements sériés (90% pour le premier prélèvement, 65% pour les prélèvements aux 4 heures, et 73% pour les prélèvements aux 8 heures) ont été jugés acceptables. Les cinétiques d’acide urique étaient reproductibles dans l’ensemble de la cohorte (R2 = 0.87). L’aire sous la courbe était significativement plus élevée chez les patients avec un score de défaillance d’organes plus élevé à 72h (SOFA6). Conclusions: Bien que les mécanismes demeurent à élucider, ces travaux démontrent que l’acide urique est important médiateur dans l’atteinte des organes suivant un choc hémorragique. Cette molécule représente potentiellement une cible thérapeutique dont l’objectif ultime est de minimiser la défaillance d’organes suite au choc hémorragique. / While hemorrhagic shock is the first cause of early mortality among severe trauma patients, organ failure leads to late mortality and morbidity in this population. Alarmins, molecules released after ischemia-reperfusion, are able to activate local and systemic inflammatory pathways and potentially represent a therapeutic target to minimize organ failure. Uric acid is a pro-inflammatory and pro-apoptotic molecule released after hemorrhagic shock and its role pertaining to organ failure is incompletely studied. The first part of this thesis presents a proof of concept that uric acid plays a key role in liver and intestinal damage in an animal model of hemorrhagic shock; it will be presented in the format of a submitted article. The second part of this thesis presents preliminary data from a prospective observational clinical study evaluating uric acid kinetics in a cohort of trauma patients. Animal study Hemorrhagic shock was induced with blood withdrawal among Wistar rats for a target mean arterial blood pressure of 30-35 mmHg for 60 minutes. Animals were resuscitated with a 1 :1 mix of Ringer Lactate and drawn blood with or without Uricase, a recombinant enzyme that metabolizes uric acid. Results show a statistically significant decrease in hepatocellular damage (plasma AST and ALT), inflammatory markers (ICAM-1, MPO, TNF-alpha, IL-1, Caspase-1) and apoptotic markers (Caspase-3, -8, Bax/BCL-2, pAKT/AKT) among the Uricase group. The intervention on uric acid also prevented increased intestinal permeability and bacterial product (LPS) translocation. Clinical study Twenty patients sustaining major trauma with hemorrhagic shock were prospectively recruited at Montreal Sacré-Cœur Hospital, in the context of a pilot study funded by the FRSQ trauma consortium. Uric acid concentration was determined serially for 7 days after trauma. Feasibility criteria, notably consent rate (95%), sampling observance rate (90% for first sample, 65% for samples every 4 hours, and 73% for samples every 8 hours) were considered acceptable. Uric acid kinetics were reproducible among the entire cohort (R2 = 0.87). The area under the curve was significantly increased among patients with higher sequential organ failure assessment score at 72h (SOFA³6). Conclusions Although mechanisms remain to be elucidated, these studies show that uric acid is an important mediator for the development of organ damage after hemorrhagic shock. This molecule potentially represents a therapeutic target with the ultimate goal of minimizing organ failure after hemorrhagic shock.

Dengue fever (DF) and dengue hemorrhagic fever (DHF) are emerging infectious diseases which are endemic in many regions of the globe, many of which are resource-poor areas. DHF and DF impose a severe economic health burden in tropical and subtropical areas. Dengue virus causes an acute febrile illness that can be a self-limited febrile illness, as seen in most cases of DF, or a life-threatening illness with plasma leakage and shock, as seen in cases of DHF. A systematic review of the literature revealed gaps in the knowledge base of clinical laboratory findings of dengue illness with regards to longitudinal dynamics and classification and predictive modeling of disease severity. The objective of this thesis was to investigate the utility of clinical laboratory variables for classification and prediction of disease outcomes. The data used in this investigation was derived from a prospective study of Thai children presenting to either of two study hospitals within 72 hours of onset of an acute febrile illness. Systematic data collection, including clinical laboratory parameters, and routine clinical management continued each day until 24 hours after the fever had subsided. A final diagnosis of DHF, DF, or other febrile illness (OFI) was assigned by an expert physician after chart review. The first research objective of this study was to describe the temporal dynamics of clinical laboratory parameters among subjects with DHF, DF, or OFI. Data were analyzed using lowess curves and population-average models. Quadratic functions of clinical variables over time were established and demonstrated significantly divergent patterns between the various diagnostic groups. The second research objective was to establish and validate tools for classification of illness severity using easily obtained clinical laboratory measures. Bivariate logistic regression models were established using data from one hospital in an urban area of Thailand as a training data set and validated with a second data set from a hospital in a rural area of Thailand. The validated models maintained a high sensitivity and specificity in distinguishing severe dengue illnesses without using the hallmark indicators of plasma leakage. The third research objective used classification and regression tree (CART) analysis to established diagnostic decisions trees using data obtained on the day of study enrollment, within the first 3 days of acute illness. Decision trees with high sensitivity were established for severe dengue defined either as: 1) DHF with evidence of shock (dengue shock syndrome, DSS); or 2) DSS or dengue with significant pleural effusion. This study expands existing knowledge of the potential utility of clinical laboratory variables during different phases of dengue illness. The application of the results of these studies should lead to promising opportunities in the fields of epidemiological research and disease surveillance to reduce the health burden, and improve the clinical management, of dengue illness. Future directions involve application of these algorithms to different study populations and age groups. Additionally, other analytical techniques, such as those involving CART analysis, can be explored with these data.

No description available.

No description available.