Indiana University-Purdue University Indianapolis (IUPUI) / Purpose: Obesity is a growing public health problem and the second most preventable cause of death in the US. Obesity has been linked as a risk factor for several cancers. However, there are limited studies that have examined the roles of metabolic syndrome (MetS) and C-reactive protein (CRP), as well as change in body composition from early adulthood to late adulthood on the risk of cancer. The overall objective of this dissertation was to determine the association of obesity and obesity-related markers with breast and colorectal cancer occurrence and mortality. Methods: Three datasets were used. The first study used 4,500 asymptomatic adults who were surveyed during a colorectal cancer screening study. The second study was based on the National Health and Nutrition Examination Survey (NHANES) 2005-2010. The dataset had 172 breast cancer survivors and 2,000 women without breast cancer. The last manuscript resulted from the NHANES follow-up study (NHANES III). A total of 120 cancer deaths from breast and colorectal deaths were identified from 10,103 women aged 18 years or older. Results: Overall, obesity and obesity related markers were associated with breast and colorectal cancer occurrence and mortality. BMI change and WC change were positively associated with increased risk of advanced colorectal neoplasia (AN). WC measures (both static and dynamic) were generally a better predictor of AN compared to BMI. In the second study involving breast cancer survivors, neither MetS nor CRP were associated with having a breast cancer diagnosis. Also, none of the individual components of MetS (WC, Triglycerides, HDL, fasting blood glucose and blood pressure) were associated with a breast cancer diagnosis. In the last study, MetS was associated with increased risk of mortality from obesity-related cancers. In addition, all components of MetS, except dyslipidemia, were associated with increased risk of mortality for the obesity-related cancers. Conclusion: Obesity expressed in terms of BMI and WC, or their change, MetS and CRP are important factors in regard to the occurrence, survivorship and mortality of breast and colorectal cancer. The results of this research underscore the importance of maintaining a healthy weight.

<p>This thesis examines the effect of surgical weight loss on gut and adipose tissue peptides involved in appetite regulation and energy homeostasis in morbidly obese humans. Roux-en-Y gastric bypass (RYGBP) is the gold standard operation used for effective long-term weight loss and improved health. The exact mechanisms for this outcome are under investigation.</p><p>We measured ghrelin, a recently discovered hunger hormone, insulin, adiponectin and leptin along with anthropometry measures in 66 morbidly obese patients prior to and 6 and 12 months after RYGBP. Impressive weight loss occurred postoperatively as did alterations in the peptides. Consistent correlations were found between weight, leptin, ghrelin and insulin. The main findings were low ghrelin concentrations in obesity and an increase after RYGBP.</p><p>We explored inflammatory proteins C-reactive protein (CRP), serum amyloid A and interleukin-6 before and during massive weight loss 6 and 12 months after RYGBP in morbidly obese subjects. The studied proteins declined after surgery and a correlation between CRP and homeostatic model of assessment for insulin resistance, independent of BMI, strongly linked insulin resistance and inflammation. CRP declined most in insulin-sensitive subjects.</p><p>We examined the excluded stomach mucosa and vagus nerve by measuring gastrin, pepsinogen I (PGI), pancreatic polypeptide (PP) and ghrelin levels during week 1 and year after RYGBP. Ghrelin levels rose with weight loss but declined 24-hours after surgery, like PP, indicating transient vagal nerve damage. Low levels of gastrin and PGI suggest a resting mucosa.</p><p>We evaluated gut peptides: peptide YY (PYY), glucaogon like peptide-1 (GLP-1), pro-neurotensin (pro-NT) and PP, in lean (young and middle-aged), obese and postoperative RYGBP subjects pre- and postprandially. RYGBP subjects had exaggerated levels of PYY and GLP-1 postprandially and higher basal proNT levels, implying a ‘satiety peptide tone’ that may contribute to the maintenance of weight loss.</p><p>In summary, RYGBP results in marked weight loss and alterations in gut and adipose tissue peptides involved in appetite regulation and energy homeostasis. These postoperative peptide changes may contribute to impressive weight loss observed after RYGBP.</p>

Motivation: Cardiovascular heart disease (CVD) is the leading cause of death worldwide. Risk markers for CVD include, amongst others, the haemostatic factors tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor type 1 (PAI-1), factor VII (FVII) and fibrinogen and more recently, C-reactive protein (CRP), a sensitive marker of inflammation. Epidemiological studies have demonstrated an inverse association between dietary fibre (DF) consumption and risk factors for CVD and CVD prevalence. Some research indicates that this protection may be related to favourable changes in the haemostatic profile and inflammatory markers. This is applicable for the consumption of total DF, as well as soluble and insoluble fibre. However, clinical intervention trials report conflicting data on the effects of DF on t-PA, PAI-1, FVII, fibrinogen and CRP. In addition, available literature is not clear on the mechanisms through which DF may have favourable effects. Objective: The main objective of this study was to review the results of randomised controlled trials systematically on the effects of DF on the above-mentioned selected haemostatic variables and CRP in healthy adults and subjects with hypertriglyceridaemia and the metabolic syndrome. Methods: Human adult intervention trials, at least two weeks in duration, with an increased and measurable consumption of DF were included. Electronic databases were searched from the earliest record to May/July 2006 and supplemented by crosschecking reference lists of relevant publications. From the literature search, two reviewers identified studies that were rated for quality based on the published methodology. No formal statistical analysis was performed due to the large differences in the study designs of the dietary intervention trials. The primary outcome measures were percentage changes between intervention and control groups, or baseline to end comparisons for t-PA, PAI-1, FVII, fibrinogen and CRP. Results t-PA activity increased significantly (14-167%) over the short and long-term following increased fibre intakes. PAI-1 activity decreased significantly between 15-57% over periods ranging from two to six weeks. These favourable changes in t-PA and PAI-1 occurred in healthy, hypertriglyceridaemic and metabolic syndrome subjects following consumption of diets containing ≥3.3 g/MJ DF and ≥4.5 g/MJ DF respectively. Mechanisms through which DF may affect t-PA and PAI-1 include its lowering effect on insulinaemic and glycaemic responses, decreasing triglycerides which are a precursor of very-low-density lipoproteins, fermentation of DF to short-chain fatty acids, which may reduce free fatty acid concentrations, as well as the role of DF in promoting weight loss. High DF intakes did not have a significant effect on fibrinogen concentrations possibly because of relatively little weight loss, too low DF dosages and maintaining a good nutritional status. Inadequate study designs deterred from meaningful conclusions. Significant decreases in FVll coagulant activity (6-16%) were observed with DF intakes of ≥3.3 g/MJ and concomitant decreased saturated fat intakes and weight loss in healthy and hypertriglyceridaemic subjects. Confounding factors include weight loss and a simultaneous decreased intake of saturated fats. The type of fibre seems to play a role as well. Mechanisms through which DF may reduce FVll concentrations include its effects on triglyceride-rich lipoproteins, insulin and weight loss. Increased DF consumption with dosages ranging between 3.3-7.8 g/MJ were followed by significantly lower CRP concentrations (25-54%), however, simultaneous weight loss and altered fatty acid intakes were also present in all the studies. Mechanisms are inconclusive but may involve the effect of DF on weight loss, insulin, glucose, adiponectin, interleukin-6, free fatty acids and triglycerides. Conclusions: Epidemiological evidence indicates an association between DF and the CVD risk factors t-PA, PAI-1, FVII, fibrinogen and CRP. In general, the risk of CVD may improve with high-fibre intakes as indicated by the favourable changes in some of the parameters. However, simultaneous reduced fat intakes and weight loss presented difficulties in separating out the effects of specific components. Furthermore, DF is consumed in a variety of different forms and different dosages that may have different effects. Overall, the study designs used in the intervention trials prevented significant conclusions. DF did, however, play a role in modifying t-PA, PAI-1, FVII and CRP. Potential effects on fibrinogen were not quantifiable. Recommendations: The results from this investigation provide the motivation for additional controlled clinical research to establish the effect and mechanisms of DF on haemostatic variables and CRP. A critical aspect of future studies would be to set up suitable protocols. The amount of subjects, duration of the trials, confounding factors such as weight loss and altered fat intakes and differentiation between types and dosage of DF are important. DF supplemental studies are recommended as they may be the most suitable method to reach meaningful conclusions. / Thesis (Ph.D. (Nutrition))--North-West University, Potchefstroom Campus, 2007

O linfoma é uma doença neoplásica comum em cães, requerendo quimioterapia para aumentar a sobrevida dos pacientes. Durante o tratamento, são freqüentes as recidivas, que motivam alteração do protocolo medicamentoso. Proteína C-reativa e amilóide A sérica são mediadores de fase aguda produzidos no fígado que apresentam elevações de concentrações séricas em condições inflamatórias, infecciosas e neoplásicas de maneira geral. O objetivo do trabalho foi avaliar o papel dessas proteínas na monitorização da remissão e recidiva do linfoma em cães, utilizando 2 protocolos de tratamento. O protocolo COP (ciclofosfamida, vincristina e prednisona) caracterizou-se por fase de indução de 1 mês e ciclos de manutenção a cada 21 dias e o protocolo VCM (vincristina, ciclofosfamida, metotrexato e L- asparaginase) foi empregado em um regime semanal contínuo. Constituíram-se 5 grupos de estudo: Normal (20 cães hígidos), Controle COP (4 cães hígidos submetidos a quimioterapia com o protocolo COP), Controle VCM (4 cães hígidos submetidos a quimioterapia com o protocolo VCM), Linfoma COP (10 cães com linfoma multicêntrico tratados com o protocolo COP) e Linfoma VCM (10 cães com linfoma multicêntrico tratados com o protocolo VCM). Proteína C-reativa e amilóide A sérica foram determinadas pela técnica de Elisa e a eletroforese foi feita em tiras de acetato de celulose. Nos cães do grupo Normal, o estabelecimento das concentrações de proteína C-reativa, amilóide A sérica e as rações eletroforéticas ocorreu uma única vez; nos cães dos grupos Controle COP e Controle VCM na 1ª, 2ª, 3ª, 4ª, 7ª, 10ª, 13ª e 16ª semanas de quimioterapia e, nos cães dos grupos Linfoma COP e Linfoma VCM, na 1ª, 2ª, 3ª e 4ª semanas, bem como na recidiva e num momento de estabilidade da doença imediatamente antes da recidiva. Os resultados foram interpretados por análise de variância com medidas repetidas, tendo como fatores de controle os grupos e as semanas de observação, seguida de comparações múltiplas de Tukey, ao nível de significância de 5 %. Concluiu-se que: o linfoma induz a resposta de fase aguda em cães, sendo a intensidade da resposta amenizada durante o tratamento bem-sucedido dos pacientes; incrementos de proteína C-reativa e amilóide A sérica não estão relacionados à recidiva do linfoma; a quimioterapia do linfoma com os protocolos COP e VCM não altera a resposta de fase aguda, avaliada por meio dessas proteínas, nem existe diferença na resposta de fase aguda entre tais protocolos; existe relação direta entre os níveis de proteína C-reativa e amilóide A sérica no curso do linfoma e da quimioterapia; aumentos das concentrações séricas de proteína C-reativa são acompanhados de elevações da fração de &beta;2-globulinas e aumentos de amilóide A sérica são acompanhados de elevações de &beta;1-globulinas. / Lymphoma is a common neoplasm in dogs and chemotherapy is indicated to achieve long-term survivals. During the treatment, frequent relapses require drug regimen modifications. C-reactive protein (CRP) and serum amyloid A (SAA) are hepatic acute-phase mediators and usually are increased in inflammatory, infectious and neoplastic conditions. The aim of this study was to evaluate the role of these proteins in remission and relapse monitoring of dogs with lymphoma, under 2 chemotherapy protocols. COP protocol (cyclophosphamide, vincristine and prednisone) included an one-month induction period and maintenance cycles each 21 days and VCM protocol (vincristine, cyclophosphamide, methotrexate and L-asparaginase) was administered in a continuous weekly schedule. Five groups were composed: Normal (20 healthy dogs), COP Control (4 healthy dogs submitted to chemotherapy with COP protocol), VCM Control (4 healthy dogs submitted to chemotherapy with VCM protocol), COP Lymphoma (10 dogs with multicentric lymphoma treated with COP protocol) and VCM Lymphoma (10 dogs with multicentric lymphoma treated with VCM protocol). CRP and SAA were determined by Elisa tests and the electrophoresis was performed in cellulose acetate strips. In Normal dogs, CRP and SAA levels, as well the electrophoretic fractions, were measured only one time; in COP Control and VCM Control groups of dogs at the chemotherapy weeks 1, 2, 3, 4, 7, 10, 13 and 16; in dogs from groups COP Lymphoma and VCM Lymphoma, at the weeks 1, 2, 3 and 4, beside the relapse and a called stability moment immediately before the relapse. Results were compared by means of repeated measures variancy analyses, considering the groups and the observation weeks as the control factors, followed by Tukey´s multiple comparisons, at 5 % of significance level. It was concluded that: lymphoma induces an acute phase response in dogs and the intensity of response declines along the disease remission; increases of CRP and SAA are not related to lymphoma relapse; neither COP nor VCM chemotherapy changes the acute-phase response, when CRP and SAA are taken in account, and there is not difference on acute-phase response between both regimens; there is a positive correlation between CRP and SAA levels during lymphoma assessment and chemotherapy; increases of CRP levels are followed by &beta;2-globulin elevations and increases of SAA levels are related to &beta;1-globulin elevations.

A antibioticoterapia em cirurgias de terceiros molares inferiores inclusos e/ou impactados é um assunto controverso no meio odontológico. O objetivo do presente estudo foi elucidar a real necessidade de prescrição de antibióticos nestes tipos de cirurgias realizadas por três operadores com experiências clínicas distintas. Um especialista, uma doutoranda e um aluno do último ano da graduação realizaram 50 cirurgias cada um, todas com remoção de osso e alto grau de dificuldade. Antibióticos não foram prescritos nos períodos pré e pós-operatório. No período préoperatório, 2o e 7o dias pós-operatórios foram analisados os seguintes parâmetros: dor, edema, trismo, temperatura corpórea, níveis de proteína C-reativa e contagem de neutrófilos salivares. Durante a cirurgia foram analisados: pressão arterial sistólica, diastólica e média, oximetria, freqüência cardíaca, qualidade da anestesia, quantidade de anestésico local, sangramento, dificuldade e tempo de duração da cirurgia. No dia da retirada de pontos, 7o dia pós-cirúrgico, foi avaliada a qualidade de cicatrização e os voluntários relataram a avaliação global do período póscirúrgico. Não houve nenhum caso comprovado de alveolite ou outro tipo de infecção no local operado. O tempo de cirurgia do graduando e da doutoranda mostraram valores médios maiores que os do especialista (p<0,05). Houve diferença estatisticamente significativa entre o graduando e os outros dois operadores nos seguintes parâmetros: qualidade da anestesia, quantidade de tubetes utilizados, sangramento no momento da incisão, trismo e dor em vários momentos pósoperatórios (p<0,05). Não houve mudanças significativas nos parâmetros hemodinâmicos durante as cirurgias. Os voluntários operados pela doutoranda tiveram uma recuperação da abertura de boca melhor que os operados pelos outros dois operadores (95,88±1,67% para a doutoranda, 86,87±2,05% para o especialista e 79,51±3,05% para o graduando, p<0,05). Houve diferença estatisticamente significativa nos níveis de proteína C-reativa no 2o dia de pós-operatório entre o graduando e o especialista e entre o graduando e a doutoranda (20,39±2,77 mg/L, 18,83±3,94 mg/L e 9,31±0,68 mg/L, respectivamente, p<0,05) e na contagem de neutrófilos salivares no 2o dia de pós-operatório entre os voluntários operados pelo graduando e os operados pela doutoranda (248±41,01 e 78,40±14,51 respectivamente, p<0,05). Os voluntários operados pela doutoranda avaliaram mais positivamente o período pós-cirúrgico em relação àqueles operados pelos outros dois operadores, possivelmente pela menor força e maior delicadeza exercida no momento da cirurgia. A análise conjunta dos resultados obtidos nesta pesquisa permite concluir que a antibioticoterapia mostra-se desnecessária em cirurgias de terceiros molares com necessidade de osteotomia independentemente da experiência do operador. / The use of antibiotics in lower third molar surgeries with necessity of boné removal is controversial. The aim of this study was to elucidate the real necessity of antibiotics prescription in such types of surgeries performed by three different surgeons with distinct clinical experiences. A specialist, a PhD student and a senior dental student performed 50 surgeries each, all with osteotomy and high degree of difficulty. Antibiotics were not prescribed either before or after surgeries. In the preoperatory period and on the second and seventh postoperative days, the following parameters were analyzed: pain, swelling, trismus, body temperature, C-reactive protein levels and salivary neutrophil count. During the surgeries the following parameters were analyzed: systolic, diastolic and mean arterial pressure, oxymetry, heart rate, quality of anesthesia, amount of local anesthetic, bleeding, surgery difficulty and duration of surgery. At the suture removal, seventh postoperative day, quality of wound healing and global evaluation performed by the patient were recorded. There was no confirmed case of dry socket or another type of local infection in the study. The duration of surgeries performed by the senior student and the PhD student showed higher values as compared to the specialist (p<.05). There was statistically significant difference between the senior student compared to both surgeons in the following parameters: quality of anesthesia, amount of local anesthetic, bleeding at incision time, trismus and pain at several postoperative times (p<.05). There were no significant changes in hemodynamic parameters during the surgeries. The PhD students volunteers had better recovery of mouth opening in comparison with the volunteers of the other surgeons (95.88±1.67% for the PhD student, 86.87±2.05% for the specialist, and 79.51±3.05% for the senior student, p<.05). There was significant statistically difference in C-reactive protein levels between the senior student and the specialist, and between the senior student and the PhD student (20.39±2.77 mg/L, 18.83±3.94 mg/L and 9.31±0.68 mg/L, respectively, p<.05), and in salivary neutrophil counts on the second postoperative day between the senior students patients and the PhD students patients (248±41.01 and 78.40±14.51 respectively, p<.05). The PhD students volunteers evaluated the postoperative period more positively in comparison to the volunteers of the other surgeons. Taken together, the results of the present work allow to conclude that antibiotics prescription is not necessary in lower third molar removal with osteotomy regardless of the surgeons experience.

Submitted by admin tede (tede@pucgoias.edu.br) on 2017-04-27T14:46:13Z No. of bitstreams: 1 JÉSSICA BARLETTO DE SOUSA BARROS.pdf: 1338303 bytes, checksum: f224cbe0cdd0f2bfa58ecbb4e530e87a (MD5) / Made available in DSpace on 2017-04-27T14:46:13Z (GMT). No. of bitstreams: 1 JÉSSICA BARLETTO DE SOUSA BARROS.pdf: 1338303 bytes, checksum: f224cbe0cdd0f2bfa58ecbb4e530e87a (MD5) Previous issue date: 2017-03-16 / The Zika virus (ZIKV) is a Flavivirus belonging to the family Flaviviridae, which was initially found and isolated on a Rhesus monkey in the Zika forest, Africa, in 1947. It is responsible for causing Zika fever, characterized mainly by symptoms such as fever, headache, Arthralgia, myalgia, and maculopapular rash. Currently, ZIKV infection has been considered an emerging and endemic infection and therefore several clinical aspects of the disease have been clarified, but there are still inflammatory features that need to be elucidated. The aim of the present study was to evaluate the inflammatory cytokines (IL-1β, IL-2, IL-5, IL-6, IL-7, IL-9, IL-12p70, IL-15 and IL-17A), anti-inflammatory (IL-4, IL-10, IL-13 and IL-1ra), and acute phase proteins (C-reactive protein and ferritin) in ZIKV-infected patients. We observed alterations in levels of C-reactive protein in ZIKV-infected patients when compared to healthy donors, and it was verified in the acute and convalescent phase. In relation to ferritin levels, they did not present significant changes at any point in the study. An increase in IL-5, IL-7 and IL-9 was also observed when compared to the acute and control groups. No changes were found in IL-4, IL-10 and IL-13 cytokines, however significant levels of IL-1ra were detected in ZIKV-infected individuals. Regarding the acute and convalescent phase, only IL-7 presented statistically significant values. All these molecules were correlated with the amount of signs and symptoms, and no statistical difference was observed. / O Zika vírus (ZIKV) é um Flavivírus pertencente à família Flaviviridae, que foi inicialmente encontrado e isolado em um macaco Rhesus na floresta Zika, África, em 1947. É responsável por ocasionar a febre Zika, caracterizada principalmente por sintomas como febre, cefaleia, artralgia, mialgia e exantema maculopapular. Atualmente, a infecção pelo ZIKV têm sido considerada uma infecção emergente e endêmica e por isso diversos aspectos clínicos da doença já foram esclarecidos, mas ainda existem características inflamatórias que precisam ser elucidadas. Assim, o presente trabalho objetivou avaliar as citocinas inflamatórias (IL-1β, IL-2, IL-5, IL-6, IL-7, IL-9, IL-12p70, IL-15 e IL-17A), anti-inflamatórias (IL- 4, IL-10, IL- 13 e IL-1ra), e proteínas de fase aguda (proteína C reativa e ferritina) em infectados pelo ZIKV. Observamos alterações nos níveis da Proteína C Reativa em infectados pelo ZIKV quando comparados aos doadores saudáveis, o mesmo foi verificado na fase aguda e convalescente. Em relação aos níveis de ferritina, esses não apresentaram alterações consideráveis em nenhum momento do estudo. Também foi constatado um aumento da IL-5, IL-7 e IL-9, quando comparado os níveis da fase aguda e grupo controle. Não foram encontradas alterações nos níveis das citocinas IL-4, IL-10 e IL-13, no entanto níveis significativos de IL-1ra foram detectados em infectados pelo ZIKV. Em relação a fase aguda e convalescente, apenas a IL-7 apresentou valores significativamente estatísticos. Todas essas moléculas foram correlacionadas com a quantidade de sinais e sintomas, e nenhuma diferença estatística foi observada.

Made available in DSpace on 2017-07-21T14:35:54Z (GMT). No. of bitstreams: 1 Daniel da Silveira.pdf: 4620671 bytes, checksum: 940d0c2a58ed2267604a5ec3cb5752ba (MD5) Previous issue date: 2016-02-16 / Intracranial hypertension causes several complications when installed, it can severely affect the individual afflicted with permanent sequelae, besides the risk of death. In the case of pregnant women, the risk is even greater due to the high complexity involved in physiological pregnancy period. In this context, the evaluation of intracranial pressure (ICP) could provide important information that can detect these problems and thereby prevent these complications. However, the invasive method that this procedure is performed makes the use of this methodology very limited. It’s necessary the use of a method that is capable of generating this information while providing security to the patient, not generating complications such as infections or injuries resulting from its invasive form. The aim of this study was to evaluate a new technology for noninvasively ICP measuring in pregnant women in a municipal health center in Ponta Grossa, relating it to the clinical and laboratory data obtained at the time of the procedure. It was observed that low and high-risk pregnant women showed a high in ICP. There were also significant differences between groups for laboratory parameters, such as serum levels of alkaline phosphatase and ultra-sensitive C-reactive protein (hs-CRP). The existence of changes in the ICP and its relationship with clinical and laboratory data in the population studied, introduces in the monitoring of pregnant women, a parameter with unknown data due to technical limitations, which allows to identify changes even in the absence of symptoms and to prevent complications related to elevation in intracranial pressure. / A hipertensão intracraniana promove diversas complicações quando instalada, podendo afetar gravemente o indivíduo acometido com sequelas permanentes, além do risco de óbito. Em se tratando de gestantes, o risco é maior ainda, devido à alta complexidade fisiológica envolvida no período gestacional. Nesse contexto, a avaliação da pressão intracraniana (PIC) pode fornecer informações importantes capazes de detectar esses problemas e com isso evitar essas complicações. No entanto, a forma invasiva como é realizado esse procedimento faz com que a utilização dessa metodologia seja bastante limitada. O uso de um método que seja capaz de gerar essas informações e ao mesmo tempo dar segurança ao paciente, não gerando complicações como infecções ou lesões decorrentes de sua forma invasiva, se faz necessário. O objetivo desse trabalho foi avaliar uma nova tecnologia para aferição da PIC de forma não invasiva em gestantes num centro municipal de saúde em Ponta Grossa, relacionando-a a dados clínicos e laboratoriais obtidos no momento da realização do procedimento. Observou-se que gestantes de baixo e alto risco apresentaram PIC elevada. Foram, ainda, encontradas diferenças significativas entre os grupos para os parâmetros laboratoriais, tais como nos níveis séricos de fosfatase alcalina e proteína C reativa -ultrassensível (PCR-us). A detecção da existência de alterações na PIC e sua relação com dados clínicos e laboratoriais, na população estudada, introduz no acompanhamento às gestantes, um parâmetro, com dados até então desconhecidos devido a limitações técnicas, que permite identificar alterações mesmo na ausência de sintomatologia e prevenir complicações relacionadas à elevação da pressão intracraniana.

Introdução: Neutropenia febril é uma emergência médica que demanda um diagnóstico precoce e administração de antibióticos o mais breve possível. A procalcitonina (PCT) é um marcador inflamatório que vem sendo utilizado como um indicador de infecção bacteriana grave. A detecção precoce do quadro séptico é difícil, principalmente numa população heterogênea como no caso dos neutropênicos febris. A possibilidade de um único exame laboratorial poder identificar precocemente os quadros de sepse contribuiria de forma significativa para melhorar o prognóstico destes pacientes. Objetivo: Avaliar os níveis de PCT como marcador de infecção sistêmica comparados aos níveis de proteína C-reativa (PCR) em pacientes neutropênicos febris. Métodos: Foram estudadas amostras de 65 pacientes com a finalidade de determinar as concentrações séricas de PCT, PCR e outros parâmetros hematológicos em três momentos diferentes: antes da febre, no momento da febre e 72 após o término da febre. Os pacientes foram divididos inicialmente em quatro grupos: com infecção sistêmica comprovada laboratorial ou clinicamente (I), com febre de origem indeterminada - FOI- (II), com infecção localizada (III) e com infecção fúngica confirmada (IV). Posteriormente, os grupos I e IV foram denominados de 1 (com infecção sistêmica) e os grupos II e III de 2 (sem infecção sistêmica). Treze pacientes não apresentaram febre durante a internação sendo excluídos da comparação PCT/PCR. Resultados: A concentração de PCT mostrou estar associada com o diagnóstico de infecção grave e neutropenia febril. Não houve correlação entre os níveis de PCT e PCR. Conclusão: Fica evidente que a PCT demonstrou ser um marcador útil para o diagnóstico de infecção sistêmica em neutropenia febril, sendo provavelmente, superior à PCR. Pode-se caracterizar a PCT como um auxiliar de indicador de infecção sistêmica já no primeiro dia de apresentação da febre. A PCT, ao contrário da PCR, foi capaz de distinguir entre infecção sistêmica e infecção localizada ou febre de origem indeterminada, tendo boa capacidade diagnóstica. Entretanto, a PCT não se correlacionou com o prognóstico, possivelmente pelo pequeno tamanho da amostra, apesar da curva ROC da PCT do grupo com infecção sistêmica com evolução para óbito ter delimitado uma área estatisticamente diferente da esperada pelo acaso. / Introduction: Febrile neutropenia is a medical emergency that calls for a precocious diagnosis and the administration of antibiotics as soon as possible. The procalcitonin (PCT) is an inflammatory marker that has been used as an indicator of severe bacterial infection. Considering that neutropenic population is heterogeneous, an early and only reliable laboratory test that could identify septic patients would be of great value to improve its outcome. Objective: Assess the diagnostic value of PCT as a marker of systemic infection, comparing with C-reactive protein (CRP) levels in febrile neutropenia. Methods: Sixty-five adults patients were enrolled in the study. Blood sample was collected in order to determine the serum concentrations of PCT, CRP and other hematological parameters at three different moments: before the beginning of fever, at the onset of fever and 72 hours after cessation of it. Firstly, the patients were divided into four groups: with clinical or laboratorial proven systemic infection (I), with fever of undetermined origin (FUO) (II), with localized infection (III) and with proven fungal infection (IV). After that, the groups I and IV were named as 1:- with systemic infection. The groups II and III were named 2:- without systemic infection. Thirteen patients did not present fever during evolution and were excluded from the PCT/PCR comparison among febrile patients. Results: The PCT concentration showed it was associated with the diagnosis of severe infection in febrile neutropenia. No correlation could be found between the levels of PCT and CRP. Conclusion: PCT seems to be an useful marker for the diagnosis of systemic infection in febrile neutropenia, probably better than CRP. We could assume that PCT could indicate systemic infection at the very first day of the outcome of fever. Only PCT (and not CRP) could be able to distinguish between systemic infection and localized infection or FUO, with excellent diagnostic capacity. However none of the markers (PCT and CRP) could be correlated to prognosis, possibly due to the small size of the sample. Nevertheless, PCT ROC curve for evolution to death as a result of systemic infection limit an area under the curve statistically different that expected by chance.

Evidências sugerem o envolvimento de um estado de inflamação crônica de baixo grau na fisiopatologia do transtorno bipolar (TB). Os estudos apresentados nesta tese tiveram como objetivo explorar o papel da inflamação crônica nos mecanismos fisiopatológicos do TB através da avaliação dos níveis séricos de proteína C-reativa (PCR). A PCR é um marcador de inflamação sistêmica comumente utilizado na prática clínica, sendo considerado fator de risco para várias patologias, incluindo câncer e doença cardiovascular. O primeiro artigo, através de um estudo de meta-análise, teve como objetivo avaliar o tamanho de efeito da associação entre níveis de PCR em pacientes bipolares nas diferentes fases de humor (n=730) comparado a indivíduos controles (n=888). Pacientes bipolares apresentaram níveis de PCR significativamente elevados em comparação ao grupo controle, com moderado tamanho de efeito (effect size, ES = 0.39; 95% IC, 0.24 – 0.55; P < 0.0001). Níveis de PCR foram significativamente maiores em pacientes maníacos (ES = 0.73; 95% IC, 0.44 – 1.02; P < 0.001) e em eutímicos (ES = 0.26; 95% IC, 0.01 – 0.51; P = 0.04). O segundo artigo se propôs a revisar dados da literatura relacionados a biomarcadores periféricos potencialmente implicados na progressão do TB. Pacientes em diferentes estágios do TB apresentaram níveis alterados de marcadores de estresse oxidativo, neurotrofinas e de inflamação, incluindo a PCR, o que reforça a hipótese da inflamação crônica exercer um papel importante na fisiopatologia do TB. Em seguida, considerando a abordagem multidimensional no TB, o terceiro artigo avaliou a reatividade emocional como uma dimensão relevante para caracterizar pacientes bipolares apresentando sintomas subclínicos de humor durante a fase de remissão (N=613). Apesar de todos pacientes estarem em remissão, a maioria deles (68%) apresentou reatividade emocional anormal (hipo ou hiper-reatividade emocional). Esse estudo avaliou, também, o funcionamento psicossocial nesses pacientes e os níveis de PCR ultra-sensível como um possível marcador objetivo de hiper-reatividade emocional no TB. Os pacientes com hiper-reatividade emocional, em comparação aos pacientes com hipo- ou normal reatividade emocional, apresentaram prejuízo cognitivo e níveis de PCR significativamente mais elevados (P < 0.001). Esses resultados provêm de um estudo transversal e, portanto, conclusões sobre causalidade dessas associações não podem ser inferidas, já que outros fatores, além dos níveis de PCR, podem também contribuir para o estado inflamatório crônico observado nesses pacientes. Em suma, os resultados desta tese sugerem que a inflamação crônica de baixo grau, evidenciada pelas alterações nos níveis de PCR, parece estar implicada na fisiopatologia e na progressão do TB. Novas intervenções terapêuticas com alvo em mecanismos inflamatórios e na modulação dos níveis de PCR devem ser priorizados em estudos futuros. / Evidence suggests that chronic low-grade inflammation appears to be involved in the pathophysiology of bipolar disorder (BD). The studies presented in this thesis aimed at exploring the role of chronic inflammation in the BD pathophysiological mechanisms by assessing serum levels of C-reactive protein (CRP). CRP is a marker of low-grade inflammation widely used in clinical practice, and a risk factor for cardiovascular and malignant diseases. The first article, a meta-analysis, aimed at evaluating the effect size of the association between CRP levels in bipolar patients (n=730) compared to healthy subjects (n=888). Overall, CRP levels were significantly elevated in patients with BD versus controls (effect size, ES = 0.39; 95% CI, 0.24 to 0.55; P < .0001). CRP levels were significantly higher in manic (ES = 0.73; 95% CI, 0.44 to 1.02; P < 0.001) and euthymic (ES = 0.26; 95% CI, 0.01 to 0.51; P = 0.04). The second paper aimed at reviewing the scientific literature regarding peripheral biomarkers potentially implicated in the progression of BD. Bipolar patients within different disease’s stages presented altered levels of oxidative stress, neurotrophins and inflammatory markers, including PCR. These findings reinforce the hypothesis of the potential role of the chronic inflammation in BD pathophysiology. Regarding the multidimensional approach in BD, the third article assessed emotional reactivity as a major dimension for better characterizing remitted bipolar patients with subthreshold mood symptoms (N=613). Although all patients were in remission, most of them (68%) showed abnormal emotional reactivity (hipo- or hyper-reactivity). In addition, this study assessed the psychosocial functioning in these patients as well as the levels of high-sensitivty PCR (hsCRP) as an objective marker of emotional hyper-reactivity in BD. Patients with emotional hyper-reactivity had higher levels of PCR and cognitive impairment compared to patients with emotional hypo or normal emotional reactivity (P < 0.001). This was a crosssectional study of emotional reactivity, hsCRP levels and functional status in remitted bipolar patients, and no conclusions regarding the causality of these associations can be substantiated. Others factors could also be contributing to the chronic inflammatory state in these patients. In conclusion, the results of this thesis suggest that low-grade chronic inflammation, as evidenced by alteration in CRP levels, may be implicated in the pathophysiology as well as in the BD progression. Novel therapeutic interventions targeting inflammatory mechanisms and the modulation of CRP levels should be prioritized in future studies.

Orientadora: Mirela Tinucci Costa / Banca: Suely Nunes Esteves Beloni / Banca: José Jurandir Fagliari / Resumo: A erliquiose canina é uma doença de alta incidência na região nordeste do Estado de São Paulo, sendo responsável pela morte de muitos cães. O diagnóstico precoce favorece a pronta instituição do tratamento e melhora o prognóstico do animal. Estudos têm apontado que a determinação da concentração de proteínas de fase aguda (PFA) pode contribuir para detecção precoce de doenças e auxiliar na predição do prognóstico. O presente estudo objetivou avaliar o perfil de proteínas de fase aguda (PFA) em cães experimentalmente infectados com Ehrlichia canis, amostra Jaboticabal, no início da infecção e após o tratamento. Para tanto, foram utilizados 10 cães sem contato prévio com hemoparasitas. Deste, cinco foram infectados e cinco serviram de controle da infecção. Hemogramas, nested PCR, detecção de anticorpos anti-E. canis e eletroforetograma de proteínas séricas foram realizados em períodos pré-determinados. Os resultados mostraram que a proteína-C reativa, ceruplasmina e a α1-glicoproteína ácida tiveram suas concentrações aumentadas antes do aparecimento dos sinais clínicos e das alterações de hemograma nos cães infectados. Os sinais clínicos da doença tornaram-se evidentes por volta do 17º dia de infecção. Trombocitopenia foi registrada a partir do 3º dia de infecção. Mórulas intracitoplasmáticas foram detectadas a partir do 15º dia. Títulos sorológicos anti-E. canis, variando de 1:2560 a 1:5120, e nPCR positiva foram evidenciados no 18º dia. Nas avaliações após o tratamento os cães infectados estavam assintomáticos, com nPCR negativo e acentuada redução dos títulos de anticorpos específicos em quatro dos cinco cães. Todas as PFA estudadas reduziram suas concentrações a títulos próximos aos iniciais. Este estudo mostrou que as mensurações das PFA contribuem para o diagnóstico precoce e predição de cura... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Canine ehrlichiosis is an endemic disease, with high incidence in the Northwest area of Sao Paulo State - Brazil and it is responsible for the death of numerous dogs. The rapid and accurate diagnosis helps the prompt establishment of treatment and improves the prognosis of the animal. Evidence has shown that the measurement of acute phase proteins (APP) can contribute for the early detection of the disease and help to predict its prognosis. This study evaluated the profile of APP in dogs experimentally infected with Ehrlichia canis, Jaboticabal - SP - Brazil sample, at the onset of the infection and after its treatment. Ten dogs, with no previous hemoparasitosis, were randomly assigned in either the infected group (5 animals), which received the bacteria, or the control group (5 animals). In pre-determined intervals, their blood was colected and hemogram, nested PCR, anti-E. canis antibodies detection and tritation and eletrophoresis of serum proteins were performed. We showed that, in infected dogs, the concentration of C-reactive protein, ceruplasmin and α-1 acid glycoprotein were increased previous to the clinical signs forthcoming and hemogram alterations. The clinical signs were evident around the 17th day of infection. Thrombocytopenia was found on the 3th day of infection. Intra-cytosolic morules were detected on the 15th day of infection. Sorologic tritation of anti-E. canis, ranging from 1:2560 to 1:5120, and positive nPCR were found on the 18th day of infection. In the post-treatment evaluation, the infected dogs were asymptomatic with negative nPCR and decreased tritation of specific antibodies in four out of five dogs. All APP analyzed were similar to basal levels. This study showed that the measurement of APP can, indeed, contribute for the early diagnosis and prediction of cure, after treatment, of the experimental acute phase of canine Ehrlichiosis. / Mestre