A lipemia pós-prandial (LPP) se caracteriza pelo aumento das concentrações de lipídeos sanguíneos, provocado por meio de refeição ou jejum e está diretamente relacionada com o sedentarismo e a formação da placa aterosclerótica. A adolescência é um período crítico no controle do peso e a inatividade física está associada com desenvolvimento de doenças cardiovasculares (DCV) prematuras. O exercício atua como um importante agente protetor contra o desenvolvimento e progressão de diversas doenças crônicas. Apesar dos efeitos do exercício sobre a LPP serem relativamente bem descritos, os seus efeitos sobre crianças e adolescentes têm sido negligenciados. Além disso, um dos aspectos intervenientes sobre a LPP é a intensidade de exercício. Dessa forma, o objetivo do estudo foi verificar os efeitos do exercício de intensidade média e alta na lipemia e glicemia pós-prandiais em adolescentes eutróficos saudáveis após refeição hiperlipídica. Treze adolescentes do sexo masculino, com idade entre 12 e 16 anos, foram selecionados e realizaram três protocolos: exercício de média intensidade (MI), exercício de alta intensidade (AI) e repouso (REP). No MI, os participantes pedalaram durante 45 minutos a 10% abaixo do 2° limiar ventilatório, seguidos de 180 minutos de repouso. No AI, os participantes pedalaram a 10% acima do 2° limiar ventilatório até alcançarem o mesmo gasto energético do MI. No REP, os participantes permaneceram em repouso durante todo o período. Foi fornecida uma refeição rica em gordura após cada protocolo. Amostras de sangue foram coletadas nos tempos 0 (jejum), 45min (logo após exercício), 105min (1h após a refeição), 135min, 165min, 195min e 225min em cada protocolo. Os níveis de triglicerídeos (TG), colesterol total (CT), HDL, LDL e glicose foram mensurados. Não houve diferenças entre as condições em relação aos níveis de CT, HDL, LDL e glicose. Foi encontrada uma redução significativa (p<0,05) nos níveis de TG (mg/dl) na condição MI quando comparado ao REP e AI no minuto 105 (70,1 + 10,3 vs. 92,2 + 32,4 e 82,2 +10,4) e 135 (68,4 + 14,4 vs. 97,3 + 15,6 e 91,54 + 24,9), respectivamente, e no minuto 165 entre REP e MI (103,14 + 24,2 vs. 82,4 + 18,8). A área sob a curva de TG (mg/dl/min) no MI foi 17,19% significativamente inferior quando comparado ao REP (16.437 vs 19.848) e 12,82% inferior quando comparado ao AI (16.437 vs 18.856). Em conclusão, o exercício de MI mostrou-se eficaz na redução dos triglicerídeos pós-prandiais em adolescentes saudáveis, quando comparado ao repouso e ao exercício de AI. / Postprandial lipemia (PPL) is characterized by increased concentrations of blood lipids, caused by meal or fasting and is directly related to a sedentary lifestyle and the formation of atherosclerotic plaque. Adolescence is a critical period in weight and physical inactivity is associated with premature cardiovascular disease (CVD) development. Exercise acts as an important protective mediator against the development and progression of several chronic diseases. Despite the effects of exercise on LPP are relatively well described, its effects on children and adolescents have been neglected. Moreover, one of the factors on aspects LPP is the intensity of exercise. Thus, the aim of this study was to investigate the effects of exercise of medium and high intensity on postprandial lipemia and glycemia in healthy normal adolescents after a high fat meal. Thirteen male adolescents, aged between 12 and 16 years, were selected and performed three protocols: exercise of moderate intensity (MI), high-intensity exercise (HI) and rest (RES). In MI, participants cycled for 45 minutes at 10% below 2nd ventilatory threshold, followed by 180 minutes of rest. In HI, participants cycled at 10% above the 2nd ventilatory threshold in order to achieve the same energy expenditure MI. RES, the participants remain at rest during the entire period. A high fat meal was provided after each protocol. Blood samples were collected at 0 (fasting), 45min (after exercise), 105min (1h after the meal), 135min, 165min, 195min and 225min in each protocol. Triglycerides (TG), total cholesterol (TC), HDL, LDL and glucose were measured. There were no differences between conditions in relation to the levels of TC, HDL, LDL and glucose. A significant reduction (p <0.05) was found in the levels of TG (mg / dL) in the condition MI when compared to the REP and HI at 105 minutes (70.1 ± 10.3 vs. 92.2 + 32.4 and 82.2 +10.4) and 135 (14.4 vs. 68.4 +. 97.3 + 15.6 + 24.9 and 91.54), respectively, and at 165 minutes between REP and MI (24.2 vs 103.14 +. 82.4 + 18.8). The area under the curve of TG (mg / dl / min) in MI was 17.19% significantly lower when compared to REP (16,437 vs 19,848) and 12.82% lower when compared to HI (16,437 vs 18,856). In conclusion, the MI exercise was effective in reducing the postprandial triglyceride levels in healthy adolescents, when compared at rest and during HI exercise.

Treatment of severe acute pancreatitis is considered to be conservative. The only generally accepted indication for surgery in severe acute pancreatitis patients is an established infection of the necrotic tissue and persisting or progressing symptoms of multiorgan failure despite the maximal intensive treatment. For surgical treatment are also indicated patients with complications of severe acute pancreatitis (erosive hemorrhage, perforation of GIT etc.). In the proposed work, attention is drawn to those cases, where the general condition of the patient deteriorates combined with a progression of ACS and where a decompressive laparotomy can improve the prognosis of the disease. In our group of 214 patients with severe acute pancreatitis, who were treated over the last six years, 70 patients were indicated for surgery. Out of this count, in 17 cases the indication for decompressive laparotomy was a raise of intraabdominal pressure up to the values of ACS together with the symptoms of organ dysfunction, 6 patients died and 11 younger patients survived.

Brain injury affects nearly 1.5 million people in the United States every year and estimated that 124,000 of those affected will have some form of long-term disability. Impaired Self Awareness (ISA) has been identified as one of the largest obstacles to successful brain injury rehabilitation and adaption to living with a brain injury. Research on the relationship between the awareness of individuals with acquired brain injury (IwABI) and their significant others has been inconsistent. This study examined the role IwABI and their significant others perception concordance&mdashagreement concerning functioning&mdashhas on maintenance of rehabilitation gains at a follow-up date after completion of adolescent brain injury rehabilitation services. Contrary to the hypotheses, the data showed a strong correlation (.872, p&le.01) and significant relationship (t=35, p&le.001) between IwABI and their significant others Functional Area Outcomes Menu (FAOM) scores at follow-up. There was no relationship between functioning at discharge and perception concordance at follow-up or time post-discharge and perception concordance at follow-up. Several explanations for the findings are provided along with suggestions for future investigation of the research subject.

Mitofusin 2 (MFN2), an outer mitochondrial membrane protein expressed in virtually all human tissues, is a multi-faceted protein known to affect mitochondrial morphology, metabolism, tethering, and movement as well as overall cell cycle progression. Most intriguing among its characteristics is its ability to bind to Ras and Raf, upstream effectors in the MAPK/ERK pathway. Conditional knockout (cKO) of renal proximal tubule MFN2 in vivo showed a post-ischemic protective effect. While the two day survival of control mice was only 28%, an unexpected 86% of the MFN2 cKO mice were alive at two days post-ischemia. This is likely explained by MFN2's ability to bind and sequester Ras at baseline. Because the MFN2 deficient mice did not sequester as much Ras, renal proximal tubule cells were able to proliferate at a greater rate and restore organ function more quickly. Immunoprecipitation studies confirm a strong interaction between Ras and MFN2 in resting cells but a weaker one immediately following ischemic insult, even in cells replete with MFN2. These results suggest that blocking the MFN2-Ras interaction may be a novel method to treat acute kidney injury. A small peptide mimicking Ras to block MFN2 could be feasible. This should grant ischemic tissue an increased propensity to regenerate healthy cells while leaving non-ischemic tissue completely unaffected. Such a therapeutic agent would be novel in the treatment of acute kidney injury and may have uses in other tissues as well due to MFN2's widespread expression profile.

The aim of these studies was to identify circulating miRNAs that can be used as biomarkers in patients with paracetamol-induced liver injury. Whether the miRNAs discovered in humans could be back-translated to zebrafish with the aim of developing a liver toxicity model to replace rodent use was also investigated. First, the miRNA signature of DILI induced by paracetamol was defined. Plasma miRNAs were quantified in paracetamol overdose patients. A signature of 16 miRNAs was discovered that best separated patients with liver injury from those without liver injury. This signature was tested in a second cohort and resulted in the detection of paracetamol-induced liver injury with high specificity and sensitivity. At first presentation to hospital miR-122-5p was the most sensitive single miRNA and superior to ALT activity in predicting liver injury. In order to further qualify miR-122-5p, three detailed studies relevant to possible clinical scenarios were performed. The effect of acute alcohol ingestion (commonly co-ingested with paracetamol overdose) on circulating concentrations of miR-122-5p in healthy volunteers was investigated. Alcohol ingestion induced a small, non-clinically relevant, increase in miR-122-5p. The effect of chronic kidney disease (CKD) and haemodialysis (HD) on circulating miR-122-5p concentrations was explored because kidney dysfunction has been associated with a reduction in the concentration of circulating miRNAs. HD patients had lower concentrations of miR- 122-5p compared to healthy volunteers and CKD patients. To facilitate miRNA measurement outwith hospitals, miR-122-5p was measured in a blood drop from a finger prick. miR-122-5p was readily measurable in finger prick samples and concentrations were significantly higher in the blood drop from DILI patients compared with healthy volunteers. To complement miR-122-5p as a marker of toxicity, circulating paracetamol metabolites were measured in plasma samples from paracetamol overdose patients. A higher percentage of circulating metabolites formed by cytochrome P450 enzymes were present in patients with liver injury and these metabolites were superior to both ALT and paracetamol concentration with regard to early patient stratification. To reduce need for rodent studies, miRNAs were back-translated into zebrafish. In order to study circulating miR-122-5p in adult zebrafish, a bloodletting method by collecting blood retro-orbitally was developed. After studying different dosing regimens of paracetamol in adult and larvae zebrafish the model was determined to be too variable with regard to liver injury. A new drug, triptolide, originating from traditional Chinese medicine and responsible for DILI in China, was tested as an alternative model for drug-induced liver injury in zebrafish larvae. miRNA-122-5p decreased in zebrafish larvae after triptolide treatment and triptolide-induced liver injury could be tracked by fluorescent microscopy. Selective plane illumination microscopy was able to track the decrease in liver volume during triptolide exposure. In order to identify the toxic pathways involved in triptolide-induced liver injury, RNA-sequencing was performed. This identified KEGG pathways including ribosome, spliceosome and notch signalling as pathways affected by triptolide. In summary, miRNAs can be used as highly sensitive biomarkers to detect acute liver injury in patients and zebrafish. Zebrafish may represent an alternative model species to study DILI, further work is needed.

BACKGROUND: Acute pancreatitis (AP) is a sterile initiator of systemic inflammation that can trigger multiple organ dysfunction syndrome (MODS). In the acute phase of AP, the kynurenine pathway of tryptophan metabolism plays an important role in the genesis of AP-MODS in experimental animal models, but it is unknown whether the pathway is activated in human AP. Human data are required to support the rationale for kynurenine 3- monooxygenase (KMO) inhibition as a treatment for AP-MODS and reinforce the translational potential. Additionally, as respiratory dysfunction is frequent in severe AP, the role of lung ultrasonography in severity stratification deserves investigation. Furthermore, the effect of AP-MODS on long-term survival is unknown. OBJECTIVES: My objectives were to: 1) Define the temporal and quantitative relationship of kynurenine metabolites with the onset and severity of APMODS, 2) Investigate the value of lung ultrasonography in the early diagnosis of respiratory dysfunction in human AP-MODS, and 3) Examine whether early AP-MODS impacts on long-term survival. METHODS: 1) A prospective, observational, clinical experimental medicine study titled “Inflammation, Metabolism, and Organ Failure in Acute Pancreatitis” (IMOFAP) was performed. For 90 days, consecutive patients with a potential diagnosis of AP were recruited and venous blood was sampled at 0, 3, 6, 12, 24, 48, 72 and 168 hours post-recruitment. Kynurenine metabolite concentrations were measured by liquid chromatography–tandem mass spectrometry (LC-MS/MS) and analysed in the context of clinical data, disease severity indices, and cytokine profiles. 2) In a nested cohort within IMOFAP, 41 participants underwent lung ultrasonography to evaluate whether this imaging modality can detect respiratory dysfunction in AP. 3) Survival data for a prospectively maintained database of patients with AP was analysed after accounting for in-hospital deaths. RESULTS: 1) During the IMOFAP study, 79 patients were recruited with an elevated serum amylase, of which 57 patients met the diagnostic criteria for AP; 9 had severe disease. Temporal profiling revealed early tryptophan depletion and contemporaneous elevation of plasma concentrations of 3- hydroxykynurenine, which paralleled systemic inflammation and AP severity. 2) Lung ultrasonography findings correlated with respiratory dysfunction. 3) 694 patients were followed up for a median of 8.8 years. AP-MODS conferred a deleterious effect on overall survival which persisted after the exclusion of inhospital deaths (10.0 years, 95% C.I. = 9.4-10.6 years) compared to AP without MODS (11.6 years, 95% C.I. = 11.2-11.9 years; P = 0.001). This effect was independent of age. CONCLUSIONS: In the acute phase of AP, metabolic flux through KMO is elevated and proportionate to AP severity. Lung ultrasonography may be a useful technique for evaluating AP-MODS. AP-MODS is an independent predictor of long-term mortality. Together, this work reinforces the rationale for investigating early phase KMO inhibition as a therapeutic strategy in humans.

Orientador: André Luís Balbi / Banca: Daniela Ponce / Banca: Denice Mafra / Resumo: É consenso na literatura que a desnutrição é freqüente em pacientes hospitalizados, devido principalmente a patologias que aumentam o risco nutricional, tais como a Injúria Renal Aguda (IRA). Sendo assim, a avaliação do estado nutricional nessa condição clínica torna-se uma ferramenta fundamental para a identificação de possíveis distúrbios nutricionais. Os objetivos deste trabalho foram realizar avaliação nutricional inicial e identificar, a partir desta, marcadores clínicos e nutricionais associados ao óbito em pacientes com IRA. Tratou-se de estudo prospectivo transversal realizado no Hospital das Clínicas da Faculdade de Medicina de Botucatu - UNESP no período de março de 2008 até março de 2010. Logo após a primeira avaliação nefrológica, foi realizada uma avaliação nutricional composta por dados clínicos, inquérito alimentar, balanço nitrogenado, antropometria, bioimpedância, Avaliação Subjetiva Global (ASG) e exames laboratoriais, tendo como desfecho o óbito. Foram avaliados 278 pacientes, com predomínio do sexo masculino e maiores de 60 anos, com mortalidade de 39,9%. Na análise multivariada, sepse, oligúria e necessidade de diálise estiveram associados a maior mortalidade. Quanto às características nutricionais e antropométricas, maior metabolismo basal, uso de dieta oral comparada ao jejum e maior ângulo de fase foram variáveis associadas a menor mortalidade, enquanto o uso de dieta parenteral comparada ao jejum, maiores valores de uréia e fósforo e menores valores de creatinina e albumina estiveram associados a maior mortalidade. Em conclusão, a partir da avaliação nutricional inicial, este estudo identificou variáveis associadas ao óbito que podem ser úteis no acompanhamento nefrológico de pacientes com IRA / Abstract: There is consensus in the literature that malnutrition is frequent in hospitalized patients, mainly due to the presence of pathologies that increase the nutritional risk, such as Acute Kidney Injury (AKI), and thus the assessment of nutritional status in that clinical condition makes a fundamental tool for the identification of possible nutritional disorders. The objectives of this research were to realize initial nutritional assessment and identify, from this, clinical and nutritional markers associated with death in these patients. This was a transversal prospective study with patients with AKI, admitted to the HC-FMBUNESP of March 2008 until March 2010. Immediately after the first nephrology evaluation, was applied a nutritional assessment composed of clinical data, food investigation, nitrogen balance (NB), anthropometry, bioelectrical impedance, Subjective Global Assessment (SGA) and laboratory values, taking death as outcome. Were evaluated 278 patients, with predominance of males with a mortality of 39.9%. In the multivariate analysis, sepsis, oliguria and requirement dialysis were associated with greater mortality. As regards the nutritional and anthropometric characteristics, negative NB was present in 69.2% of the population. The other multivariate analyzes showed that greater basal metabolism, use of oral diet compared to fasting and greater phase angle were variables associated with lower mortality, while the use of diet parenteral compared to fasting, higher values of urea and phosphorus and lower creatinine and albumin were associated with greater mortality. In conclusion, from the initial nutritional assessment of patients with AKI, this study identified nutritional variables related to death, which must be assessed together with clinical variables, by nephrologist / Mestre

Background: Acute heart failure and chronic obstructive pulmonary disease (COPD) exacerbation are common, and are sometimes difficult to differentiate in the emergency department (ED). Objectives: To determine the clinical impact of Point-of-Care Ultrasonography (POCUS) in ED patients with suspected acute heart failure or COPD. Methods: We conducted a prospective health records review with 1:3 matching, and analyzed time to events using time-dependent Cox regression analyses, classification performance, and adverse events. Results: There were 81 patients with lung POCUS and 243 matched patients. No differences were found in ED length of stay or length of care, nor adverse events. Significance was found for time to treatment (P=0.03). Lung POCUS had high sensitivity (92.5%) and specificity (85.7%) for identifying acute heart failure. Conclusions: Lung POCUS could result in faster treatments for patients with suspected acute heart failure and COPD, and has high accuracy in identifying acute heart failure.

The published literature indicates that large information system implementations are often expensive failures with costs to human safety largely because of missing or corrupt information. This has generated the overall research question of “What do Key Informants think about Information Quality in Acute Care?” This dissertation research examined information quality using a Grounded Theory analytic method for coding and analyzing semi structured interview responses from ten clinical (nurses, physicians, pharmacist) and ten non-clinical (IT support) interviewees in several public sector health organizations across Canada. The semi structured interview questions focused on five key areas: information quality, acute care setting, information systems, risk (as a function of poor information quality) and patient safety. A key finding from the interview data is that information is missing and unstable within the two key health care information systems: the paper chart, the main repository of narrative unstructured data, and the electronic health record system, of structured data. The interviewees mentioned pressure to information standardization such as fixed patient identity information anchoring patient data in the rest of the patient record. However, there is resistance to standardizing other information because the users, nurses and physicians, resist fettering in order to be able to tell the patient’s story in narrative unstructured data form. A descriptive socio-technical model, the Systems Engineering Initiative for Patient Safety (SEIPS) Model that organizes elements for analysis under the headings of person, task, technology and tools, organization, external environment and patient outcomes, was considered for further discussion in the context of the study. The SEIPS Model analysis also helps to identify gaps in the Model including what missing and uncertain information might mean. Key points from this discussion include how the information system maps to the real world, the patient, and to the user’s perception of the real world. This mapping can never be totally accurate and complete so gaps exist. The discussion of information and information flow lead to enhancements of the SEIPS Model, placing information and information quality in its rightful place as a “glue” for the acute care system. This is an important contribution to knowledge that can lead to future research so there can be a better fit between the real world, information, information systems and people to provide safer care. / Graduate

In recent years, self-myofascial release has gained popularity as a post-exercise therapeutic technique in regards to alleviating pain or muscle soreness. New developments have led many researchers and practitioners to examine self-myofascial release, in the form of foam rolling, pre-exercise. The effects of foam rolling, in combination with a dynamic warm-up, is not quite understood. Minimal research has been published on this topic. To date, there has been one article that examines how a dynamic warm-up and foam rolling can improve performance. Therefore, the purpose of this study is to determine if an acute bout of foam rolling in the form of self-myofascial release in addition to a dynamic warm-up could improve performance. Fourteen active male and female participants (N = 14; age: 20.931.44; height: 68.043.21, weight: 80.0922.82, BMI: 26.47 5.89) with no prior experience foam rolling volunteered to engage in this counterbalanced, within-subjects design. Participants engaged in experimental condition groups: a general warm-up (GW) group, a dynamic warm-up (DYN) group, and a foam rolling (FM) group. Following each condition, participants performed a series of performance tests. One-way repeated measures ANOVA was conducted to compare the effect of the independent variable (group: general warm-up, dynamic warm-up, and foam rolling group) on the dependent variable (scores: flexibility, vertical jump, standing long jump, and sprint scores) to determine if significant differences exist. When the omnibus F-test statistic was significant, pairwise comparisons using Sidak comparisons were performed. The data indicated that the foam rolling group showed significant differences in flexibility and power (specifically in the standing long jump) when compared to a general or dynamic warm-up. Furthermore, no significant differences were found in the vertical jump or the speed test among the three groups. The results suggest that total-body foam rolling session may be valuable for improvements in certain aspects of performance. Implications from this study suggest foam rolling can be used before a workout routine.