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Perinatal inflammation contributes to neurodevelopmental diseases, and animal models have revealed that the inflammatory response within the central nervous system is age dependent. It remains unclear what intrinsic and/or extrinsic factors are responsible for this variation. Here, my aim was to discover the mechanisms responsible for the age-dependent changes in the inflammatory response of the brain by injecting interleukin-1 (IL-1β) into the brain of mice at postnatal day (P)7, P14, P21 or into adult mice. A "window of susceptibility" was found at P14, which was associated with marked neutrophil recruitment and blood-brain barrier (BBB) breakdown, in response to a low dose of IL-1β. Evaluation of cytokine, chemokine, and adhesion molecule mRNA transcripts failed to reveal any specific increases in basal or reactive expression following the injection of IL-1β at P14. The extrinsic hepatic acute phase response (APR) was evaluated, but, once again, there was no evidence that an altered APR might account for the enhanced inflammatory response at P14. Indeed, an inverse relationship between the magnitude of the leukocyte recruitment to the brain and the APR was discovered. Enhancement of the APR with intravenous IL-1β after injection of a low dose of IL-1β into the brain was found to reduce the number of neutrophils and BBB permeability in the brain. While no molecular changes seem to account for the presence of the "window of susceptibility", a population of Iba-1⁺ large, flattened and irregular perivascular cells was discovered within the P14 brain, that may contribute to the increased leukocyte recruitment at P14. Although variations in the brain inflammatory response with development were not fully account for, my results highlight the importance of the systemic inflammatory response on the outcome of acute brain injury and suggest that the systemic APR might be manipulated therapeutically to protect the brain in the perinatal period.

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.

Pneumonia and sepsis are distinct but linked public health concerns. Each condition is the leading cause of the other; however, the responses controlling the susceptibility between the two disease processes remain speculative. The acute phase response (APR) is an important component of the host immune response during pneumonia and sepsis, and primarily driven by the activation of hepatocyte transcription factors NF-κB RelA and STAT3. While the NF-κB pathway is essential for inflammation and hepatocyte function, its inactivation has been associated with hepatotoxicity. Liver injury is an independent risk factor for sepsis morbidity and mortality, suggesting that pathways promoting liver homeostasis may limit the systemic consequences of pneumonia. To identify conditions in which NF-κB RelA is required for liver resilience, we challenged mice lacking hepatocyte RelA (hepRelAΔ/Δ) and wildtype (WT) controls with E. coli, K. pneumoniae, S. pneumoniae, LPS, or αGalCer to induce pneumonia, sepsis, and/or NKT cell activation. Severe hepatotoxicity was observed in hepRelAΔ/Δ mice in all conditions examined in association with apoptosis, which could be prevented by neutralization of TNFα. Lastly, these changes were associated with remodeling of the hepatic transcriptome, likely reflecting both the cause and consequence of hepatoxicity. We have previously shown that activation of STAT3 in hepatocytes limits pneumonia susceptibility during endotoxemia, but the mechanisms whereby this liver APR provides protection are unknown. Iron sequestration is a defense mechanism against bacterial infections, which require iron for growth. Based on previous observations that alveolar lining fluid is favorable for bacteria in the absence of liver STAT3, we investigated whether liver APR limits pneumonia susceptibility during sepsis by withholding iron to prevent bacterial outgrowth. WT mice or mice lacking hepatocyte STAT3 (hepSTAT3Δ/Δ) mice were challenged with endotoxemia followed by E. coli pneumonia, or cecal ligation and puncture (CLP). Induction of mRNA encoding several essential iron-regulating factors was ablated in hepSTAT3Δ/Δ mice after endotoxemia and pneumonia, and post CLP. Additionally, liver STAT3 activation significantly remodeled the pulmonary transcriptome during endotoxemia, which potentially represents other protective mechanisms. Taken together, these results suggest that hepatic APR is an important immunological interface modulating pneumonia and sepsis interaction and susceptibility.

Alpha-tocopherol, the most abundant form of vitamin E in man, is transported in the circulation by plasma lipoproteins. It plays important roles, not only in preventing lipid peroxidation, but also in modulating several cell functions such as cell signaling and gene expression. While chylomicrons transport dietary alpha-tocopherol after intestinal absorption, LDL and HDL are the major carriers of alpha-tocopherol in fasting plasma and largely contribute to its delivery to cells and tissues. Exchanges of alpha-tocopherol occur between plasma lipoproteins. In addition, alpha-tocopherol transfers have also been observed, in both directions, between plasma lipoproteins and artificial chylomicrons such as intravenous lipid emulsion particles used in parenteral nutrition. In acute conditions, intravenous supply of vitamin E via lipid emulsions, which bypasses the intestinal tract, may offer some advantages over oral administration to rapidly increase alpha-tocopherol plasma concentration. However, many questions remain unanswered regarding kinetics and factors facilitating vitamin E exchanges between lipid emulsions and plasma lipoproteins. The first part of this work aimed at characterizing alpha-tocopherol transfers between alpha-tocopherol rich emulsion particles and plasma lipoproteins as well as the potential for plasma proteins to modulate such transfers. An in vitro model of incubation was used in which emulsion triglyceride concentration was relatively low and lipoprotein levels comparable to those commonly found in the circulation. Results indicate a high capacity for LDL and HDL to acquire extra-amounts of alpha-tocopherol by rapid mass transfers from alpha-tocopherol-rich emulsion particles. Data further shows that, at a fixed alpha-tocopherol concentration provided by emulsion particles, the limiting factor for alpha-tocopherol enrichment is not the capacity of plasma lipoproteins to accommodate extra-amounts of alpha-tocopherol but the facilitating effect of plasma proteins on alpha-tocopherol transfer, the duration of the incubation and possibly the competition between different acceptor particles. Two lipid transfer proteins, PLTP and CETP, appear to largely mediate facilitation of alpha-tocopherol transfer; however, other plasma proteins may be involved. Data further shows that alpha-tocopherol enriched LDL and HDL can readily transfer newly acquired alpha-tocopherol to cells, without any regulation by plasma proteins. Short-term prophylactic vitamin E supplementation has been suggested to be beneficial in some patients in acute conditions who present reduced plasma vitamin E concentrations in association with important changes in plasma lipids and severe oxidative stress. However, it was not clear whether low plasma vitamin E concentration in critically ill patients is related to changes in the composition of plasma lipoproteins or to a decrease in the number of alpha-tocopherol carriers. In the second part of this work, two clinical studies were conducted to analyze changes of lipoprotein concentration and composition in relation to inflammatory reaction and oxidative stress in selected subgroups of critically ill patients, namely patients undergoing cardiac surgery with different procedures. Important changes in LDL and HDL lipid content were observed, some of which contrast with previous observations made in critically ill septic patients. The reduced plasma level of alpha-tocopherol measured after cardiac surgery is entirely due to a reduced number of circulating LDL and HDL particles. Data suggests that such reduced number in alpha-tocopherol carriers post-surgery may impede the delivery of alpha-tocopherol to cells in conditions of increased requirements due to oxidative stress. Avoidance of extracorporeal circulation during cardiac surgery does not reduce inflammation-related changes in plasma lipids but largely prevents oxidative stress. This data on changes occurring in plasma lipoproteins may help to better define strategies against pro-inflammatory changes or oxidative stress. If further studies would confirm a clinical benefit with evidence-based rationale, alpha-tocopherol enriched lipid emulsions may be used to guarantee a sufficient alpha-tocopherol supply in acute conditions associated with fewer alpha-tocopherol transporters and increased requirements due to high risk of oxidative tissue injury.

Circadian rhythms are periodic physiological cycles that recur about every 24 hours, by means of which organisms integrate their physiology and behavior to the daily cycle of light and temperature imposed by the rotation of the earth. Circadian derives from the Latin word circa "about" and dies "day". Circadian rhythms have three noteworthy properties. They are endogenous, that is, they persist in the absence of external cues (in an environment of constant light intensity, temperature, etc.). Secondly, they are temperature compensated, that is, the nearly 24 hour period of the endogenous oscillator is remarkably independent of ambient temperature. Finally, they are phase shifted by light. The circadian rhythm can be either advanced or delayed by applying a pulse of light in constant darkness. Consequently, the circadian rhythm will synchronize to a periodic light-dark cycle, provided the period of the driving stimulus is not too far from the period of the endogenous rhythm. A window on the molecular mechanism of 24-hour rhythms was opened by the identification of circadian rhythm mutants and their cognate genes in Drosophila, Neurospora, and now in other organisms. Since Konopka and Benzer first discovered the period mutant in Drosophila in 1971 (Konopka and Benzer, 1971), there have been remarkable developments. Currently, the consensus opinion of molecular geneticists is that the 24-hour period arises from a negative feedback loop controlling the transcription of clock genes. However, a better understanding of this mechanism requires an approach that integrates both mathematical and molecular biology. From the recent discoveries in molecular biology and through a mathematical approach, we propose that the mechanism of circadian rhythm is based upon the combination of both negative and positive feedback. / Master of Science

Orientador: José Jurandir Fagliari / Banca: Daniela Gomes da Silva / Banca: Luiz Paulo Martins Filho / Resumo: Foi avaliada a importância de proteínas de fase aguda (PFA) como biomarcadores de enfermidades em ruminantes domésticos. Para tal se determinou o proteinograma sérico e leucograma de 15 bovinos sadios e 15 doentes, 15 ovinos sadios e 15 doentes, e 15 caprinos sadios e 15 doentes. Todos foram submetidos a colheitas diárias de sangue durante sete dias, enquanto permaneciam internados no Hospital Veterinário da FCAV-UNESP, Câmpus de Jaboticabal. Em bovinos a haptoglobina teve destaque como biomarcador precoce e confiável de foco inflamatório/infeccioso. Em ovinos ceruloplasmina, haptoglobina, 1-glicoproteína ácida mostraram moderada atividade frente às enfermidades avaliadas. Caprinos acometidos por ectima contagioso não apresentaram boa responsividade das PFAs. No entanto, ceruloplasmina, haptoglobina, 1-glicoproteína ácida destacaram-se como biomarcadores de foco inflamatório/infeccioso em caprinos acometidos por mastite e artrite secundária à infecção pelo vírus da artrite encefalite caprina. Transferrina, embora tenha se mostrado biologicamente como uma PFA negativa em todos os grupos estudados, apenas apresentou comportamento estatisticamente diferenciado em bovinos acometidos por mastite. Por fim, o proteinograma sérico obtido por meio da técnica eletroforética SDS-PAGE, mostrou-se mais útil como exame complementar ao diagnóstico das enfermidades avaliadas que o leucograma / Abstract: The importance of acute phase proteins (APP) as biomarkers of disease was evaluated in domestic ruminants. It was determined the serum proteinogram and leucocyte count of 15 healthy and 15 clinically ill cattle; 15 healthy and 15 clinically ill sheep and 15 healthy and 15 clinically ill goats. All animals were submitted to daily blood sampling during 7 days, while kept interned in the Veterinarian Hospital from FCAV-UNESP, Jaboticabal campus. In cattle, haptoglobin was a very reliable inflamatory/infeccious early biomarker. In sheep ceruloplasmin, haptogobin and 1-acid glycoprotein showed moderate activity to the diseases studied. Goats with contagious ectima did not show a good response in APP serum concentrations. However, ceruloplasmin, haptoglobin and 1-acid glycoprotein showed to be reliable soon biomarkers in goats with mastitis and arthritis due to caprine arthritis encephalitis. Alhtough transferrin biologically behaved as a negative APP in all diseases and species studied, it only showed a statistically significant behaviour as such in cows with mastitis. Moreover, the assessment of APP profile through the electrophoretic SDS-PAGE technique was more useful as a complementary tool to the establishment of diagnosis than the leucocyte count / Mestre

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mso-ascii-font-family:Calibri / mso-ascii-theme-font:minor-latin / mso-hansi-font-family:Calibri / mso-hansi-theme-font:minor-latin / mso-bidi-font-family:"Times New Roman" / mso-bidi-theme-font:minor-bidi / mso-ansi-language:EN-US / mso-fareast-language:EN-US / } </style> <![endif]--><b style="mso-bidi-font-weight: normal"><span lang="EN-GB">Background</span></b><span lang="EN-GB">: Malnutrition is a risk factor for the development of pulmonary tuberculosis (TB) and may be responsible for the premature deaths of patients with active disease. An adequate nutritional status may therefore be protective in delaying the onset from latent infection to active disease. In South Africa, very little data is available on the nutritional status of adults who present with tuberculosis. This study therefore aims to compare the nutritional status of newly diagnosed pulmonary tuberculosis patients with TB-free controls.</span> <b style="mso-bidi-font-weight: normal"><span lang="EN-GB">Study population &amp / Design</span></b><span lang="EN-GB">: This is a community based case-control study. Forty-three newly diagnosed pulmonary tuberculosis patients were recruited as cases and matched according to age, gender and race to 43 TB-free close contacts. HIV positive subjects were excluded from the study.</span> <b style="mso-bidi-font-weight: normal"><span lang="EN-GB">Methods</span></b><span lang="EN-GB">: Each participant was interviewed and completed a structured questionnaire to obtain demographic information. Weight was measured to the nearest 0.1kg and height to the nearest 1mm. A 24-hr dietary recall method was used to obtain dietary information. Biochemical analysis was carried out to measure&nbsp / concentrations of transferrin, albumin, CRP, ferritin, zinc, copper, vitamin A and E.</span> <b style="mso-bidi-font-weight: normal"><span lang="EN-GB">Results</span></b><span lang="EN-GB">: The median Body Mass Index (BMI) for cases was 18.80kg/m&sup2 / (IQR 14.35, 32.11) and TB-free contacts 21.17 kg/m&sup2 / (IQR 16.75, 34.98) with a significant difference between the groups of p=0.001. There was significant difference in weight (p=0.002) and MUAC (p=0.000) between groups. No significant difference in dietary intake of energy (KJ) (p=0.695), protein (p=0.804), CHO (p=0.801) and fat ( p=0.796) was found between groups. There was a statistically significant increase in ferritin (p=0.000) and C-reactive protein (CRP) (p=0.000) in TB patients, while albumin (p=0.000), serum zinc (p=0.000) and serum vitamin A (p=0.000) were statistically significantly lower among cases.</span> <b style="mso-bidi-font-weight:normal"><span lang="EN-GB">Conclusion</span></b><span lang="EN-GB">: There was no significant difference in the macronutrient intake of TB cases and TB-free contacts, although a significant difference was seen in BMI, MUAC and weight between groups, with all these parameters being lower in TB patients. Ferritin and CRP levels were markedly increased in TB cases while serum zinc, vitamin A and albumin are all significantly lower in&nbsp / TB patients than TB free contacts.</span> <b style="mso-bidi-font-weight:normal"><span lang="EN-GB">&nbsp / </span></b></p> <p>&nbsp / </p>

The overarching aim of the thesis research was to investigate mechanisms altered by protein-energy malnutrition (PEM), a common stroke co-morbidity factor that could affect the extent of brain damage and recovery following stroke. To model stroke, the rat 2-vessel occlusion model of global brain ischemia was employed. To characterize the effects of PEM, three states of malnutrition were assessed: PEM co-existing with brain ischemia (Study 1), effects of PEM independent of brain ischemia (Study 2), and PEM developing after brain ischemia (Study 3). The first hypothesis tested was co-existing PEM triggers an exacerbated glial response to global brain ischemia. The failure to achieve a consistent model of global ischemia prevented us from drawing conclusions on whether co-existing PEM exacerbates reactive gliosis. Nonetheless, this study demonstrated that mean temperature and temperature fluctuation are increased within the first 24hr of exposure to a low protein diet. The second hypothesis tested was PEM causes sustained changes in core temperature that are associated with an inflammatory response. Exposure to a low protein diet caused an immediate small and transient increase in mean temperature and a larger sustained increase in temperature amplitude. As malnutrition evolved, mean temperature declined. PEM stimulated an acute-phase response, characterized by an increase in the positive acute-phase protein, alpha-2-macroglobulin (A2M), and a decrease in the negative acute-phase protein, albumin. This response appeared to be aberrant, since the positive acute-phase protein, alpha-1-acid glycoprotein (AGP), was decreased with PEM. The final hypothesis tested was PEM developing after global brain ischemia exacerbates systemic and hippocampal inflammation, which is associated with diminished neuroplasticity. The effects of PEM on the acute-phase response are persistent following brain ischemia, as demonstrated by decreased serum albumin and increased serum A2M. A decrease in the positive acute-phase protein, haptoglobin, strengthened the evidence that PEM triggers an atypical reaction. The strong glial response elicited by global ischemia was unaltered by PEM. However, PEM influenced hippocampal neuroplasticity mechanisms, as GAP-43 and synaptophysin were significantly lower at d21. In summary, it has been demonstrated that PEM affects core temperature, the systemic acute-phase reaction and the neuroplasticity response to global brain ischemia.