Orientador: André Luis Balbi / Banca: Jacqueline Teixeira Caramori / Banca: Pedro Alejandro Gordan / Resumo: A Insuficiência Renal Aguda apresenta uma alta incidência em pacientes internados em hospitais terciários, principalmente em Unidades de Terapia Intensiva, estando associada a elevada mortalidade. Este trabalho tem como objetivos descrever a população de pacientes internados no Hospital das Clínicas de Faculdade de Medicina de Botucatu - UNESP com diagnóstico de Insuficiência Renal Aguda atendidos pelo Grupo de Interconsultas do Serviço de Nefrologia e avaliar os fatores de risco associados ao óbito nestes pacientes. Foram acompanhados 946 pacientes no período de abril de 2002 a dezembro de 2006, todos maiores de 12 anos, com diagnóstico de Necrose Tubular Aguda e internados nas diferentes enfermarias e Unidades de Terapia Intensiva do Hospital das Clínicas, exceto na Pediatria e Nefrologia. Insuficiência Renal Aguda foi definida como um aumento de creatinina sérica de pelo menos 30% de seu valor basal em período mínimo de 48 horas. A média de idade foi de 61,8 ± 16,7 anos, com predomínio do sexo masculino (61,9%). Pacientes provenientes de enfermarias clínicas foram mais freqüentes (62,1%), sendo que 15,9% estavam internados na cardiologia e 15,2% na clínica médica geral, enquanto 13,3% estavam internados na enfermaria de gastroenterologia cirúrgica. 46,1% estavam internados em Unidades de Terapia Intensiva e a sepse esteve presente em 9,7% dos casos. Isquemia (51,2%) foi a etiologia mais freqüente e o tempo de acompanhamento nefrológico apresentou mediana de 7,5 dias, com intervalo interquartílico de 4 a 14 dias. / Abstract: Acute Renal Failure (ARF) present a high incidence in critically ill patients taken into tertiary care hospitais, mostly in the Intensive Care Unit (ICU) patients, were also associate with great mortality rate. The objective of this work was to describe the population of patients hospitalized in the School Medicine, Botucatu- UNESP with diagnosis of ARF, attended by Group of - Interconsults of Service Nephrology and to evaluate the risk factors associate with death in this patients. This was a cohort study which evaluated 946 patients with ARF, from April 2002 to December 2006, was included patients older than 12 years, with diagnosis of ARF due to Acute Tubular Necrosis (ATN) and hospitalized in wards and ICU of HC- FMBUNESP (except in the Pediatrics and Nephroloy wards). ARF was defined as serum creatinine at least 30% above basal value from 48 hours at minimum. The average of age was 61,8 ± 16,7 years, with predominantly masculine gender (61,9%). 15,9% were hospitalized in the cardiology and 15,2% in the clinical medical, while 13,3% were hospitalized in the gastroenterology surgical ward. 46,1% of patients were hospitalized in ICU and the sepsis was present in 9,7% of the cases. Ischemia was the etiology more frequent (51,2%) and the time of accompaniment nephrologic presented an median of 7,5 days (4 - 14). / Mestre

Kidney disease remains a public health problem worldwide, where there is an increase in the number of incidence of Acute Kidney Injury (AKI) in hospitalized patients. The AKI is characterized by an abrupt decrease in renal function, resulting in the inability of the kidneys to perform itÂs basics functions. The Ischemia/Reperfusion (I/R) injury can be defined as all changes resulting from the deprivation and the re-establishment of the oxygen supply to tissues and organs. It is a complex process that results in the production of reactive oxygen species (ROS) and oxidative stress damage. The Brazilian Red Propolis is a complex mixture collected and produced by Apis mellifera bees, and seems to be promising in this context, attenuating the oxidative and nephrotoxic effect in the kidney. This experimental study aims to replicate and standardize a framework of AKI by Ischemia/reperfusion (I/R) in rats, and analyze the possible protective renal effects of Red Propolis Alcohol Extract (RPAE) at a dose of 150mg/kg on markers and pathological variables. Wistar rats, adult males, were divided into 4 groups, using an induction and treatment regimen. We evaluated biochemical parameters indicative of renal function (creatinine, urea, creatinine clearance) tubular function (FENa+ and FEK+), oxidative profile through MDA (malondialdehyde) and activity of antioxidant enzyme GSH, in addition to histological analysis and immunohistochemistry. The RPAE significantly altered almost all parameters investigated. The results demonstrated the protective effect of the extract in the dose used against the nephrotoxicity: decreased serum levels of creatinine (1.8  0.5 vs 2,7Â0,9) and urea (181.1  65.6 vs 274,3Â91,81), reversed the increase in FENa+ (0,58Â0,30 vs 1,03Â0,39) and FEK+ (64,74Â52,44 vs 134,4Â54,94), reversed the decrease of creatinine clearance (0,41Â0,14 vs 0,073Â0,048), decreased MDA levels (90,22Â20,82 vs 133,9Â23,36) and increased GSH (1784Â297,4 vs 1267Â229,5), decreased the rate of acute tubular necrosis (2,0Â0,7 vs 3,6Â0,5), increased the expression of eNOS (2,20,4 vs 0,60,5) and Heme-oxygenase (2,60,5 vs 1,40,5). Therefore, occurred protection of renal function, protection of the tubular damage and oxidative stress. These results describe for the first time the effect of Red Propolis on a model of AKI induced by I/R, suggesting the protective effect of the extract against this type of injury. / As doenÃas renais apresentam um problema de saÃde pÃblica mundial, aonde hà um aumento nos nÃmeros de incidÃncia de LesÃo Renal Aguda (LRA) em pacientes hospitalizados. A LRA caracteriza-se por uma reduÃÃo abrupta da funÃÃo renal, resultando na incapacidade dos rins em exercer suas funÃÃes bÃsicas. A lesÃo por isquemia/reperfusÃo (I/R) pode ser definida como as alteraÃÃes resultantes da privaÃÃo seguida do re-estabelecimento do fornecimento de oxigÃnio para tecidos e ÃrgÃos. à um processo complexo, que resulta na produÃÃo espÃcies reativas de oxigÃnio (EROs) e dano por estresse oxidativo. A PrÃpolis Vermelha brasileira à uma mistura complexa coletada e produzida pelas abelhas Apis mellifera, e parece ser promissor nesse contexto, atenuando assim o efeito oxidativo e nefrotÃxico no rim. Este estudo experimental tem como objetivo reproduzir e padronizar um quadro de LRA por Isquemia/ReperfusÃo (I/R) em ratos, e analisar os possÃveis efeitos protetores renais do Extrato AlcoÃlico de PrÃpolis Vermelha (EAPV) na dose de 150mg/kg, sobre os marcadores e variÃveis desse quadro patolÃgico. Foram utilizados ratos Wistar, adultos machos, divididos em 4 grupos, utilizado um esquema de induÃÃo e de tratamento. Foram avaliados os parÃmetros bioquÃmicos indicativos da funÃÃo renal (creatinina, ureia, Clearence de creatinina) funÃÃo tubular (FENa+ e FEK+), o perfil oxidativo atravÃs do MDA (Malonaldeido) e atividade da enzima antioxidante GSH, alÃm da anÃlise histolÃgica e imunohistoquÃmica. O EAPV alterou significativamente quase todos os parÃmetros investigados. Os resultados demonstraram efeito protetor do extrato na dose de utilizada diante dos parÃmetros de nefrotoxicidade: diminuiu os nÃveis sÃricos creatinina (1,8Â0,5 vs 2,7Â0,9) e urÃia (181,1Â65,6 vs 274,3Â91,81), reverteu o aumento da FENa+ (0,58Â0,30 vs 1,03Â0,39) e da FEK+(64,74Â52,44 vs 134,4Â54,94), reverteu a diminuiÃÃo do clearence de creatinina (0,41Â0,14 vs 0,073Â0,048), diminuiu os nÃveis de MDA (90,22Â20,82 vs 133,9Â23,36) e aumentou o de GSH (1784Â297,4 vs 1267Â229,5), diminuiu o Ãndice de necrose tubular aguda (2,0Â0,7 vs 3,6Â0,5) a aumentou a expressÃo de eNOS (2,20,4 vs 0,60,5) e Heme-oxigenase (2,60,5 vs 1,40,5). Portanto, ocorreu proteÃÃo da funÃÃo renal, do dano tubular e do estresse oxidativo. Estes resultados relatam pela primeira vez o efeito da PrÃpolis Vermelha sobre um modelo de LRA induzido por I/R, demonstrando o efeito protetor do extrato na LRA.

Abstract The effects of perioperative filgrastim (rhG-CSF) and surgery per se on the postoperative acute phase reaction were studied by assessing leukocyte functions, cytokine levels and tenascin-C (Tn-C) and procollagen propeptide (PINP, PIIINP) concentrations in different body fluid compartments in patients undergoing gastrointestinal surgery. Thirty consecutive patients were randomized to receive either filgrastim or placebo for five days, starting 12 hours before colorectal surgery. Filgrastim treatment led to marked neutrophilia with decreased neutrophil migration in peripheral blood but not in peritoneal fluid 48 hours postoperatively. Neutrophil phagocytosis and bacterial killing did not differ between the groups. Filgrastim caused increased postoperative expression of neutrophil CD11b/CD18 in blood but not in peritoneal fluid or wound fluid. CD11b/CD18 expression was higher in both wound fluid and peritoneal fluid than in blood in the placebo group. The expression of neutrophil CD62L was higher in blood than in peritoneal fluid or wound fluid in both groups. The serum concentration of interleukin (IL)-8 was lower in the filgrastim group 5 hours postoperatively. The concentrations of IL-1β, IL-6, transforming growth factor (TGF)-β and IL-10 did not differ between the groups. The cytokine levels were markedly higher locally in the wound and in the peritoneal cavity compared to circulating blood. No adverse events attributable to filgrastim were seen. Leukocyte counts, neutrophil and monocyte functions and the levels of IL-6, IL-8 and granulocyte colony-stimulating factor (G-CSF) were measured from 18 patients before and after colorectal surgery. Surgery caused an increase in neutrophil and monocyte counts along with lymphocytopenia. Neutrophil phagocytosis was decreased 4 and 24 hours postoperatively, but normalized after that. A distinct systemic cytokine response was seen postoperatively. In a study with 24 patients, Tn-C concentration increased in wound fluid during the first postoperative week after abdominal surgery. The Tn-C level was markedly higher in wound fluid than in serum.

Class of 2014 Abstract / Specific Aims: Evaluate serum posaconazole concentrations following dose adjustment in response to subtherapeutic serum concentrations. Determine optimal dose adjustment schema and identify toxicity with doses above 600 mg daily (e.g.: 200 mg per os three times daily). Methods: The health records were reviewed for 29 patients ≥ 18 years with acute myeloid leukemia over a four-year period. Participants initially received posaconazole 200 mg per os three times daily as prophylaxis and required at least one dose adjustment secondary to a subtherapeutic posaconazole serum concentration. Patients were stratified by posaconazole dosing following dose adjustment (A=200mg QID, B=300mg TID, C=400 mg TID, D=400 QID). Main Results: There was a statistically significant increase in posaconazole serum concentration in each group compared to baseline serum concentration, aside from group C (group A and B P<0.001, group C P=0.236, and group D P=0.0076). The majority of participants in 3 of the 4 groups reached therapeutic serum concentration (A=0.87, B=0.76, D=0.80) whereas group C had a serum posaconazole concentration on average below therapeutic range (0.51). There was no significant difference between the four groups in regards to renal function (p=0.35) or hepatic function (AST p=0.676, ALT p=0.877, total bilirubin p=0.097). Conclusion: A dose increase led to an increase in posaconazole serum concentration except for the dosing regimen of 400 mg three times daily. However, the study is limited by a small patient population, an unequal number of patients in each group, and potentially by poor absorption of posaconazole suspension. Further research is required to expand on these findings.

Class of 2016 Abstract / Objectives: To determine if prescribers took into consideration patients’ metabolic risk factors when prescribing a low, medium or high risk second generation antipsychotic and if non-metabolic risk factors influenced prescribing. Methods: Adults 18 years or older who were admitted to an acute inpatient psychiatry unit and ordered at least one SGA were included in the study. Each patient’s metabolic syndrome risk score was determined using retrospective chart review and they were subsequently divided into low or high-risk groups. Clozapine and olanzapine were categorized as high risk for causing weight gain and diabetes, risperidone and quetiapine were moderate risk, and all others were considered low risk. A chi square test compared the two groups in regard to type of SGA selected, gender, and race, while an independent t-test analyzed the differences in age. Results: 300 patients were analyzed and divided into high (n=57) and low (n=253) risk groups. For the low risk group, 10.7%, 55.1%, and 34.2% were prescribed a low, moderate, or high risk SGA, respectively. For the high-risk group 17.5%, 56.1%, and 26.3% were prescribed a low, moderate, or high risk SGA, respectively. The type of SGA selected was not significantly different between the groups (p=0.262). Equivalence was shown between the two groups in terms of gender and race (p=0.68, p=0.65 respectively). Age was significantly different (p< 0.01). Conclusions: Prescribers may not consider metabolic risk factors when prescribing high risk SGAs such as clozapine and olanzapine.

Background: Due to the growing number of individuals suffering from dementia, many will require acute hospital care as other indirectly related conditions appear throughout the course of the disorder. Significant concerns have been raised about the provision of quality care. Understanding their experiences is essential. Method: Semi-structured interviews were conducted with caregivers and people with dementia after acute hospitalization. Data was analyzed using qualitative content analysis. Results: Twenty-nine participants experienced hospitalization and commented primarily on the negative experience. Despite the importance of caregiver involvement, and evidence of caregiver burden, they commented they were rarely included in care plans and lacked support. Continuity of care was said to be affected by absent communication amongst health care team members. The acute hospital process and environment was perceived as not supportive of dementia person-centred care principles, with reports of poor staff knowledge and recognition of the disorder. Conclusion: Reports of acute care hospital experiences of people with dementia and their caregivers provide insights for potential gaps in care delivery.

Globally, policy recommendations on vaccines as provided by the Strategic Group of Experts on Immunization (SAGE) rely on a number of factors including burden of disease. In the scope of this thesis, two studies were conducted in order to inform the World Health Organization Hepatitis E Virus (HEV) working group and ultimately the SAGE: 1) a systematic review and meta-analysis of the global incidence, prevalence and mortality associated with all genotypes of HEV; and 2) a global subgroup analysis of incidence, prevalence and mortality on special populations and high risk populations. Circulation of HEV was documented in all global regions. Severe disease was observed among pregnant women and fulminant hepatic failure patients in both studies conducted. Poor data quality was observed in both studies, this poses a serious challenge for estimating the burden of disease. Countries should consider the implementation of an HEV surveillance system to improve data quality and ultimately to inform decision-making.

Acute Myeloid Leukemia (AML) is a type of cancer that affects the process of hematopoiesis. In individuals affected with AML, normal blood cells do not develop into red blood cells, white blood cells, and platelets, leading to symptoms such as anemia, neutropenia, and thrombocytopenia. The prognosis of AML is affected by multiple factors including: the genetic make-up of the leukemic cells, age of the affected individual, and underlying blood disorders such as myelodysplastic syndrome (MDS). MDS affects the development of stem cells into red blood cells, white blood cells, and platelets. Due to their clinical heterogeneity, AML and MDS continue to be a challenge that should be investigated in the community hospital setting. Remission rates between patients diagnosed with de-novo AML and patients diagnosed with AML with MDS were compared in a community hospital setting following induction therapy using a retrospective study design. Length of stay between patients diagnosed with de-novo AML and patients diagnosed with AML with MDS was compared during induction therapy. The association of age at diagnosis and number of chromosomal abnormalities to remission status was evaluated in each disease group. The association of blood transfusion requirements and neutropenic fever to length of stay was evaluated in each disease group. There were no statistically significant differences found between disease groups with respect to remission rates and length of stay. There were no statistically significant associations found between blood transfusion requirements and neutropenic fever in each disease group. There was an association found between age at diagnosis and remission status in patients diagnosed with AML with MDS. This indicates that older patients with AML with MDS are less likely to benefit from therapy and achieve complete remission. It is important to consider the small sample size, rare nature of the disease, and other variables that could have contributed to trends seen in the study population. The impact of predictors such as growth factor use and incidence of fungal infections should be investigated in future studies with AML patients. Considering these factors will allow for the development of targeted therapies and mechanisms against drug resistance for affected individuals.

Acute kidney injury (AKI) is a major health burden associated with a 50% mortality rate. Of particular concern, the incidence of AKI has increased dramatically over the last decade. Yet, there is a paucity of available treatments to prevent AKI or to reduce the high rate of AKI-associated mortality. A common cause of AKI, especially in hospital settings, is prolonged decreases in renal blood flow (i.e., renal ischemia). Recent studies have demonstrated that activating the cholinergic anti-inflammatory pathway via vagal stimulation can mitigate AKI severity in rodent models of renal ischemia-reperfusion (IR) injury. While vagal stimulation is not a practical approach to prevent AKI in patients due its invasive nature and numerous side effects, recent studies have identified non-neuronal cholinergic cells within the kidney that could be targeted to reduce the severity of AKI. The overarching goal of this project is to examine the potential role of the renal cholinergic system in modulating the severity of and recovery from AKI in transgenic mice expressing green fluorescent protein (GFP) under control of the choline acetyl-transferase (ChAT) promoter, a protein involved in the synthesis of acetylcholine. The objectives of this study were to develop a clinically relevant model of renal IR-induced AKI in mice by identifying the duration of ischemia required for manifestation of the effects of AKI and to determine whether differences in susceptibility to AKI exists between male and female mice. Initially, male mice underwent 20 (n=3), 22 (n=3), or 25 (n=4) minutes of bilateral renal IR under isoflurane anesthesia with body temperature controlled at 37°C. Ischemia was achieved by careful placement of vascular clamps on the renal artery and vein supplying each kidney. The severity of AKI was determined by measuring serum creatinine (SCr) at 3 days post-AKI. Compared to SCr of mice that were 3 days post-sham AKI (SCr = 0.47 mg/dl, n=2), SCr of male mice from all three ischemia time categories was substantially elevated (SCr > 3 mg/dl, n=10). However, mortality associated with 22 and 25 minutes IR was striking (>90%) making studies of long-term AKI effects difficult. In contrast, 20 minutes IR resulted in AKI manifest by elevated SCr (3.43±0.7 mg/dl, n=3), widespread acute tubular necrosis and a clinically relevant mortality rate of 50%. Next, male (n=10) and female (n=5) mice were subjected to 20 minutes of IR. The mortality rate in male mice (n=10) was 50% (n=10) through 7 days post-AKI; however, all female mice survived. Additional studies showed that female mice had lower SCr 3 days post-AKI (0.63±0.1 mg/dl, n=2) with very modest levels of acute tubular necrosis as compared to the higher SCr (1.92±0.1 mg/dl, n=2) and extensive acute tubular necrosis observed in male mice. The differences observed in AKI severity and mortality rates suggest that female mice are protected against AKI as compared to male mice and future studies will explore the potential role of the renal cholinergic system in contributing to these sex differences in AKI.

Lung biopsy is neither widely known nor practiced and it was only in 1949 that i first came across a paper on this subject. The title was: "Cellular analysis of the aspiration lung biopsy from normal and some pathological conditions by Z. Godlowski" (1949). The very term "lung biopsy" conjures up the picture of a needle being introduced into an air filled, very vascular structure where the bleeding of an injured vessel cannot readily be stopped, where the stage is set for air embolisms and where tension pneumothorax may occur. it was with great surprise but also an apparently innocuous procedure. Unfortunately, at that time, there was no opportunity to use the method. In 1950 I became the University Assistant at the New Somerset Hospital in Cape Town. Many of the cases admitted to the wards presented with chest pathology. Patients with pneumococcal lobar pneumonia were not infrequent and occasional cases did not resolve as expected but went on to become so-called chronic pneumonia. What happened when an acute lobar pneumonia went on to the chronic stage and why did this occur? it was suggested that investigae this problem.