There is strong evidence which supports a physiological role for arginine vasopressin (AVP) in the negative modulation of the febrile process within the central nervous system (CNS). This evidence arises from a variety of experimental techniques employed in a number of different animal models. The CNS locus of action for AVP-mediated antipyresis is within a rostral diencephalic site called the ventral septal area (VSA). It has become evident that the mechanism by which AVP and aspirin-like drugs transduce changes in febrile body temperature are similar. Moreover, antipyretic drugs and AVP may share a common CNS locus of action. Therefore, investigations were conducted to determine whether antipyretic drugs are functionally linked to the endogenous antipyretic system of the brain. In addition, an examination of the role for centrally acting AVP and the natural suppression of fever during pyrogenic tolerance to endotoxin was conducted. AVP receptor antagonists of the peripheral V₁ and V₂ sub-type or saline control were microinjected into the VSA of rats rendered febrile by an intracerebroventricular (icv) injection of E. coli endotoxin, to assess the effects on the antipyresis elicited by indomethacin. Blockade of central V₁ but not V₂ receptors significantly attenuated the antipyretic effects of indomethacin given intraperitoneally. This effect was even more pronounced when the V₁ antagonist was infused for 30 min before and for 60 min after indomethacin administration. The V₁ analogue alone was without thermoregulatory effects. In order to determine whether the above effects were applicable to antipyretic drugs in general, central V₁ blockade was performed in the febrile rat subsequently treated with intraperitoneal sodium salicylate or acetaminophen. Salicylate-induced antipyresis was blocked, in a dose related manner, by VSA administration of the AVP V₁ antagonist. The fever reducing capacity of acetaminophen was unaffected by central V₁ blockade. Collectively these antipyretic drug studies, suggest that some but not all antipyretic drugs activate the endogenous AVP antipyretic pathway within the brain. Moreover, these data suggest that the mechanism of action of antipyretic drugs can no longer be simply explained as an action on prostaglandin biosynthesis. Endogenous release of AVP from VSA nerve terminals during endotoxin fever and drug-induced antipyresis was examined using the technique of push-pull perfusion. The release of AVP into the perfusion fluid remained unaltered by indomethacin injected into the non-febrile rat. However, during fever indomethacin prompted both an antipyresis as well as a significant increase in AVP release. Acetaminophen injected intraperitoneally also evoked an antipyresis but with no concomitant release of AVP within the VSA. These results are consistent with the antagonist studies. The effects on central AVP release by indomethacin appear to be related to the pyrogen employed because the drug did not evoke the release of AVP when administered prior to the hyperthermia produced by icv PGE₂. Indeed, PGE₂ itself stimulated AVP release which was inhibited by indomethacin treatment. These results are not consistent with an antipyretic role for AVP and await further clarification. Analysis of the release of AVP into the plasma and cerebrospinal fluid (CSF) were conducted during the fever evoked by intravenous endotoxin and subsequent to antipyretic intervention. Intravenous endotoxin was a provocative stimulus for plasma AVP release. Endotoxin-stimulated plasma AVP levels were unaffected by intraperitoneal injections of indomethacin, sodium salicylate or acetaminophen. In non-febrile controls, indomethacin, and to some extent acetaminophen, prompted increases in plasma AVP; although the temporal course of this release was different between the two drugs. Within the CSF, endotoxin treatment did not alter the normal diurnal rhythm of AVP release. Indomethacin treatment significantly suppressed CSF AVP release in non-febrile animals. A similar but non-significant trend was observed in febrile rats. Collectively, these studies demonstrate the independent regulation of AVP release within three separate biological compartments in response to febrogenic and antipyretic stimuli. The suppression of fever after repeated daily intravenous injections of bacterial endotoxins was thought to be exclusively a hepatic phenomenon. Experiments were conducted to determine whether a central mechanism involving AVP may also contribute to the antipyretic state observed during pyrogenic tolerance. In endotoxin tolerant animals, administration of a V₁ but not V₂ AVP receptor antagonist within the VSA, resulted in a significant reversal of the tolerant pyrogenic response. These data support the hypothesis that the central endogenous antipyretic system, involving AVP, plays a role in the mechanism of endotoxin tolerance. Tolerance does not develop following repeated central injections of pyrogens. Further experiments were performed to determine whether tolerance-induced activation of the antipyretic pathway would render an animal hyporesponsive to centrally administered pyrogens. When injected icv, during active endotoxin tolerance, the thermoregulatory responses to PGE₂ or endotoxin were not significantly suppressed from non-tolerant controls. However, analysis of VSA push-pull perfusates performed during a tolerant reaction to intravenous endotoxin revealed that increased AVP activity occurs within the first 30 min after the intravenous injection, well before the time PGE₂ or endotoxin were injected into the cerebral ventricles. This suggests that the antipyretic system is only activated briefly and may explain why centrally evoked fevers were unaffected during active endotoxin tolerance. In summary, this thesis research has demonstrated a direct functional link between the mechanism of action of antipyretic drugs and the endogenous antipyretic system within the brain. These results call into question the hypothesis whereby the fever reducing properties of antipyretic drugs can be explained exclusively as a result of the inhibition of prostaglandin biosynthesis. In addition, the differential effects on AVP release by antipyretic drugs suggests a number of biological pathways that can be activated by these drugs. Finally, a role for the AVP endogenous antiypretic system in the suppression of fever during endotoxin tolerance was established. / Medicine, Faculty of / Cellular and Physiological Sciences, Department of / Graduate

Veterinarians in Tucson and Phoenix were surveyed by mail, requesting information about their patients recently diagnosed or treated for Valley Fever. Information obtained included risk factors and outcome.

La fièvre Q dans sa forme aiguë induit des pneumonies et des hépatites et plus rarement, dans sa forme persistante, des infections cardio-vasculaires. Sur la base des données du Centre National de Référence de la fièvre Q, de 1991 jusqu’à 2016, nous avons observé qu’à la phase aiguë, l’augmentation des anticorps anticardiolipines était associée à des complications cardiaques, neurologiques et des voies biliaires. Par ailleurs, nous avons décrit des cas de pneumopathies interstitielles associées et des cas d’endocardites aiguës. Nous avons montré l’existence d’une association entre l’infection persistante à C. burnetii, l’atteinte ganglionnaire et la survenue de cancer des ganglions, les lymphomes. L’étude comparative de la virulence de différentes souches de C. burnetii chez la souris a montré que la souche endémique et épidémique de Guyane Française était la plus virulente. / Q fever can be responsible of acute Q fever (pneumonia or hepatitis) and the infection could persist causing cardio-valvular infection. Based on the database of the national reference center for Q fever, from 1991 to 2016, we observed that the elevation of anticardiolipin antibodies was associated with acute Q fever cardiac, neurological and biliary tract complication. We described cases of interstitial lung diseases and report cases of acute Q fever endocarditis. We showed an association between persistent C. burnetii infection, lymph node involvement and lymphoma. The in silico, in vitro and in vivo comparison of 3 strains of C. burnetii have shown that the Guiana strain, which is endemic in French Guiana, was the most virulent strain.

El texto completo de este trabajo no está disponible en el Repositorio Académico UPC por restricciones de la casa editorial donde ha sido publicado. / Serum samples collected from 88 Peruvians with unexplained fever were analyzed for viral sequences using metagenomics. Nucleic acids of anelloviruses, pegivirus A (GBV-C), HIV, Dengue virus, and Oropouche virus were detected. We also characterized from two sera the RNA genomes of new species of partitivirus and dicistrovirus belonging to viral families known to infect fungi or arthropod, respectively. Genomic DNA of a putative fungal cellular host could be PCR amplified from the partitivirus-containing serum sample. The detection in human serum of nucleic acids from viral families not known to infect vertebrates may indicate contamination during sample collection and aliquoting or human infection by their presumed cellular host, here a fungus. The role, if any, of the non-vertebrate infecting viruses detected in serum in inducing fever is unknown. / Revisión por pares

Background The World Health Organisation currently recommends the use of artemisinin-based combination drugs for treatment of uncomplicated malaria in high malaria endemic regions. However, comprehensive understanding of factors affecting treatment of malaria with antimalarials is lacking in many rural communities in Africa. This study seeks to test the following hypothesise: 1. That socio-economic and demographic factors at the household level affect treatment of self reported malaria/fever with antimalarials in the Kilombero/Ulanga and Rufiji valleys in Tanzania 2. Distance of a household to a health facility affects treatment of malaria/fever with antimalarials in the Kilombero/Ulanga and Rufiji valleys in Tanzania. Methods: Secondary data analysis of a cross- sectional household survey on antimalarials carried out in 2005 in the Kilombero/Ulanga and Rufiji valleys in Tanzania. Georeferenced health facilities and households’ datasets from the Rufiji and Ifakara demographic surveillance systems sites were also used to estimate distance variables. Results: Out of a total of 1433 participants who reported malaria/fever, 32% (95% CI: 29.29, 34.89) obtained treatment with antimalarials. Among them, 36% obtained treatment with Sulfadoxine Pyreminthamine (SP) as a monotherapy and 44% treated malaria/fever with SP and Artesunate as a combination therapy.8% used quinine while 11 % used Amodiaquine and Artesunate. The remaining 1% used chloroquine. After adjusting for all confounding variables in a multivariate survey logistic regression model, age group, education level of the household head and district of residence were found, with statistical evidence, to be associated with treatment of reported malaria/fever with antimalarials. Background The World Health Organisation currently recommends the use of artemisinin-based combination drugs for treatment of uncomplicated malaria in high malaria endemic regions. However, comprehensive understanding of factors affecting treatment of malaria with antimalarials is lacking in many rural communities in Africa. This study seeks to test the following hypothesise: 1. That socio-economic and demographic factors at the household level affect treatment of self reported malaria/fever with antimalarials in the Kilombero/Ulanga and Rufiji valleys in Tanzania 2. Distance of a household to a health facility affects treatment of malaria/fever with antimalarials in the Kilombero/Ulanga and Rufiji valleys in Tanzania. Methods: Secondary data analysis of a cross- sectional household survey on antimalarials carried out in 2005 in the Kilombero/Ulanga and Rufiji valleys in Tanzania. Georeferenced health facilities and households’ datasets from the Rufiji and Ifakara demographic surveillance systems sites were also used to estimate distance variables. Results: Out of a total of 1433 participants who reported malaria/fever, 32% (95% CI: 29.29, 34.89) obtained treatment with antimalarials. Among them, 36% obtained treatment with Sulfadoxine Pyreminthamine (SP) as a monotherapy and 44% treated malaria/fever with SP and Artesunate as a combination therapy.8% used quinine while 11 % used Amodiaquine and Artesunate. The remaining 1% used chloroquine. After adjusting for all confounding variables in a multivariate survey logistic regression model, age group, education level of the household head and district of residence were found, with statistical evidence, to be associated with treatment of reported malaria/fever with antimalarials. Conclusion: The results suggest that participant’s age, education level of household head and location of district are important predictors of treatment of malaria with antimalarials in rural Tanzania. The implementation of any antimalarials policy in Tanzania would therefore, require a careful consideration of these factors.

No description available.

published_or_final_version / Microbiology / Doctoral / Doctor of Philosophy

Incidence of dengue fever (DF) has been estimated a 30 fold increase in the past 50 years. Clinical manifestations of DF range from a simple febrile illness with physical soreness to life-threatening dengue hemorrhagic fever (DHF). The need for a better classification of the severity in DEN infections has been proposed to clarify the immunopathogenesis for the prevention and management of serious DEN infections. We attempted to investigate whether different mechanisms involved in the varied manifestations of bleeding tendency and vascular leakage in DF. In a hospital-based study, we first compared clinical features as well as laboratory data including virus load, T helper (Th1/Th2) cytokines, and vascular leakage-related mediators between patients with DHF and DF. Moreover, we defined another class of patients associated with bleeding tendency but not fulfilled with DHF criteria, called DF w/B, for a further comparison. The virus load in blood was not significantly different among DF, DHF and DF w/B. DF patients had a higher Th1 cytokine, IFNr, expression (70.0 ¡Ó 10.7 vs. 33.1 ¡Ó 8.0 vs. 33.0 ¡Ó 7.1 pg/ml; DF vs. DF w/B, p = 0.009; DF vs. DHF, p = 0.002), and both DHF and DF w/B patients had a significantly higher IL-10 levels (14.3 ¡Ó 4.1 vs. 26.2 ¡Ó 3.3 vs. 26.0 ¡Ó 3.5 pg/ml; DF vs. DF w/B, p = 0.023; DF vs. DHF, p = 0.016) than DF patients. Both DHF and DF w/B patients also had a higher rate of secondary dengue infection (DF w/B vs. DHF vs. DF: 50.0%, 74.4% and 14.3%¡A p < 0.001). By contrast, DHF but not DF w/B patients had significantly higher vascular leakage-related mediators: sVCAM-1, PGE2 and TNF£\ levels than DF patients. Patients with DF w/B had a higher platelet counts (DF w/B vs. DHF: 66.0 ¡Ó 8.3 vs. 20.7 ¡Ó 2.1 x109/L, p < 0.001) but lower ALT levels than those with DHF (DF w/B vs. DHF: 56.3 ¡Ó 7.7 and 144.7 ¡Ó 20.5 IU/L). This study provides new insight to different immune mechanisms involved in patients with DF, DF w/B, and DHF. DF involves augmented Th1 reaction, and DF w/B involves altered Th2 reaction, but DHF involves both altered Th2 reaction and augmented vascular insult. Clarification of the immune mechanisms among DF, DFw/B and DHF will facilitate certain specific treatment and prevention of DF patients from varied bleeding tendency and vascular leakage manifestations.

Thesis (M.D.)--Dublin.

No description available.