This study was conducted to determine if alternative heating times and slower cooling times, other than those defined by FSIS, could be utilized and still comply with FSIS performance standards. Large (10.43 to 12.25 kg), cured bone-in hams (n = 190) and large (greater than or equal to 9.07 kg), uncured beef inside rounds (n = 180) were utilized in a two-phase study. Phase 1 of the study investigated the effect of alternative lethality parameters on toxin production of Staphylococcus aureus and log reduction of Salmonella Typhimurium and coliforms. Both the hams and roast beef were subjected to 1 of 10 treatments defined by varying final internal product temperatures (48.9 degrees C, 54.4 degrees C, 60.0 degrees C, 65.6 degrees C, or 71.1 degrees C) and smokehouse relative humidities (50% or 90%). Phase 2 investigated the effect of alternative stabilization parameters on log growth of Clostridium perfringens. Stabilization treatments extended the times taken to reduce internal product temperature from 54.4 degrees C to 26.7 degrees C and from 26.7 degrees C to 7.2 degrees C (ham) or 4.5 degrees C (beef), independently. Further, a control treatment following current FSIS, Appendix B guidelines was conducted for ham, and a "worst case" scenario was assessed for both products. The "worst case" treatment evaluated the effects of cooling products at room temperature (approximately 22.8 degrees C) in place of normal cooling procedures in a temperature controlled environment. Results of the study showed at least a 6.5-log10 reduction in S. Typhimurium across all lethality treatments for both products. Further, coliform counts also were reduced significantly, and S. aureus toxin kits returned negative results for toxin production for all treatments of ham and roast beef. Stabilization showed less than 1-log growth of C. perfringens for any treatment, with the exception of the "worst case" scenario for roast beef. As expected, > 1 log growth of C. perfringens was found for uncured roast beef maintained at room temperature for cooling. This study supports that there are multiple time and temperature combinations, other than those currently provided by FSIS, which may be utilized for cooking and cooling large roast beef and bone-in ham products while still meeting FSIS lethality and stabilization microbiological performance standards.

The peptidoglycan of many Gram-positive bacteria is densely functionalized with anionic glycopolymers called wall teichoic acids (WTAs). Recent studies have shown that these polymers play crucial roles in cell shape determination, regulation of cell division, and other fundamental aspects of Gram-positive bacterial physiology. Furthermore, in pathogens they are important in host infection and play key roles in antibiotic resistance. In many cases, precise mechanisms for WTA involvement in these processes have not been established. In order to better understand the roles of WTAs in the biology of the human pathogen Staphylococcus aureus, we sought to identify their interactions with other cellular pathways. By employing a transposon screen, we found that lipoteichoic acid (LTA) synthesis, D-alanylation of teichoic acids, cell wall stress sensors, CAAX-like proteases, and peptidoglycan biosynthesis were all synthetically lethal with depletion of WTAs in Staphylococcus aureus . Further investigations revealed that several genes required when WTAs were depleted were not essential when LTAs were removed. Unexpectedly, TA D-alanylation, became essential in the absence of WTAs, but not LTAs. Examination of terminal phenotypes following WTA depletion revealed that strains lacking LTA D-alanine esters died from envelope rupture during ongoing cell division whereas strains lacking LTAs were unable to form Z rings, stopped dividing, and had altered PG biosynthesis. Finally, we designed and implemented parallel, pathway-specific chemical screens to identify inhibitors that specifically kill mutants deficient in WTAs or D-alanylation of TAs. In addition to elucidating new interactions between cell envelope pathways, and establishing distinct roles LTAs and WTAs in the cell envelope of S. aureus, these experiments provide a list of potential targets and a strategy for identifying inhibitors for these targets, in compound combinations as therapeutics against antibiotic-resistant S. aureus infections.

<p>African medicinal plants are commonly used throughout Africa to treat a variety of ailments including wounds and ulcers, cough and chest complaints, gingivitis, fever and gonorrhoea, indication all related to infection and inflammation. In screening several plant species from an inventory of common medicinal plants from both South and West Africa for diverse medicinal purposes, 6 plants were selected because of their interesting and useful ethnomedicinal values.</p>

Orientador: Carlos Magno Castelo Branco Fortaleza / Resumo: A Leishmaniose Visceral (LV) é uma zoonose negligenciada e emergente na Região Sudeste do Brasil. Sua alta letalidade e as dificuldades para prevenção e controle fazem da LV um grave problema de saúde pública. Nós realizamos um estudo em casuística de um hospital de referência no município de Bauru, São Paulo. Foram realizadas: (I) descrição do quadro clínico e laboratorial; (II) estudo de preditores de óbito, recidiva e aquisição de infecções relacionadas à assistência à saúde (IRAS, anteriormente denominadas “infecções hospitalares”); (III) análise de preditores de incidência de LV e da coinfecção LV-HIV em setores censitários de Bauru. A coorte de base deste estudo foi composta de 683 sujeitos. O quadro clínico típico, com febre e hepatoesplenomegalia, foi mais frequente em monoinfectados que na coinfecção. Os preditores de óbito foram a idade e a soropositividade para HIV, sendo esta última também associada à recidiva. A carga de comorbidades e a inserção de cateteres venosos centrais foram fatores associados à aquisição de IRAS. Por fim, na análise espacial, observou-se maior incidência de LV e coinfecção LV-HIV em áreas periféricas de baixa renda e com urbanização precária. / Abstract: Visceral Leishmaniasis (VL) is a neglected and emerging zoonosis in the Southeastern Region of Brazil. Its high lethality and the difficulties for prevention and control make VL a serious public health problem. We studied VL cases attending a referral hospital in the city of Bauru, São Paulo State, Brazil. The following analyses were performed: (I) description of clinical and laboratory conditions; (II) study of predictors of death, recurrence and acquisition of healthcareassociated infections (HAIs, formerly referred to as "nosocomial infections"); (III) analysis of predictors of VL incidence and VL-HIV coinfection in Bauru census sectors. The baseline cohort of this study was composed of 683 subjects. The typical clinical picture, with fever and hepatosplenomegaly, was more frequent in monoinfected subjects than in coinfection. The predictors of death were age and HIV seropositivity, the latter being also associated with relapse. The burden of comorbidities and the insertion of central venous catheters were factors associated with the acquisition of HAIs. Finally, in the spatial analysis, we found higher incidence of VL and VL-HIV co-infection in peripheral areas of low income and with precarious urbanization. / Doutor

Magister Scientiae - MSc (Chemistry) / Plants have been widely used in traditional medicine for a number of ailments, among which may be included infectious diseases such as colds, influenza, chicken pox, TB, etc. as well as lifestyle diseases such as diabetes and cancer. Seaweeds have also been shown to contribute to the maintenance of health through their nutritional and medicinal properties and recently, a great deal of interest has developed towards the isolation of bioactive compounds from marine sources due to their numerous health benefits. Furthermore, marine algae are valuable sources of structurally diverse metabolites with scientifically proven therapeutic claims. Chemical constituents of red seaweed, Porphyra capensis was investigated in this present study along with subsequent brine shrimp lethality assay analysis of the crude extracts. The compounds isolated from the plant were from the hexane (6) and butanol (2) extracts. These compounds were all isolated and purified by various chromatographic techniques, namely silica gel chromatography, Sephadex LH-20 gel as well as C18 reversed phase silica gel. The structures of the isolated compounds were analysed and characterised by NMR, GC-MS, ESI MS and FTIR spectroscopy. Eight compounds were isolated and identified as phytol, desmosterol, 9-eicosenoic acid, 5,8,11,14,17-eicosapentanoic acid, palmitic acid, methyl (E)-hexadec-9-enoate, glycerol and compound 1 (novel compound). All the compounds were isolated from Porphyra capensis for the first time. The hexane, butanol and methanol extracts were found to be non-toxic with the brine shrimp test LC50 value at least two times greater than ?g/ml.

L’identification d’interactions synthétiques létales (SL) apparait aujourd’hui comme une approche prometteuse, qui permet de cibler directement les cellules cancéreuses. Dans cette étude, nous avons utilisé la levure Saccharomyces cerevisiae en tant qu’organisme modèle simple pour cribler des mutations SL avec une drogue, l’AICAR (5-Amino-4-Imidazole CArboxamide Ribonucleoside). L’AICAR est une molécule connue pour inhiber spécifiquement la prolifération de multiples lignées cancéreuses. Ici, nous montrons que la perte d’ubiquitination de l’histone H2B ou de méthylation de l’histone H3K4 est SL avec l’AICAR. Nos résultats pointent sur l’AICAR causant une accumulation de cellules en G1 due à ses effets sur la localisation subcellulaire de la cycline Cln3, tandis que la perte d’ubiquitination d’H2B ou de méthylation de H3K4 affectent l’expression des deux autres cyclines deG1, CLN1 et CLN2. Ainsi, l’AICAR et la perte d’ubiquitination de l’histone H2B ou de méthylation del’histone H3K4 affectent les trois cyclines simultanément, conduisant à une condition connue pourêtre SL. De plus, cette interaction chemo-genetique s’est révélée être conservée chez les cellules humaines HCT116. En effet, le knock down de RNF40, ASH2L ou MLL2 conduit à une sensibilité àl’AICAR exacerbée. Or, on sait que MLL2 est muté dans de nombreux cancers, ce qui rend cette interaction SL très intéressante dans le cadre d’une approche thérapeutique. / Identifying synthetic lethal interactions has emerged as a promising new therapeutic approach that aims to directly target the cancer cells. Here, we used the yeast Saccharomyces cerevisiae as a simple eukaryotic model to screen for mutations resulting in a synthetic lethality with 5-Amino-4-ImidazoleCArboxamide Ribonucleoside (AICAR) treatment. Indeed, AICAR has been reported to specifically inhibit the proliferation of multiple cancer cell lines. Here, we found that loss of two several histone modifying enzymes, including Bre1 (histone H2B ubiquitination) and Set1 (histone H3 lysine 4methylation), greatly enhanced AICAR inhibitory effects on growth. Our results point to AICAR causing a significant accumulation of G1 cells due to its impact on Cln3 subcellular localization, whilebre1 or set1 deletion impacts on the two other G1 cyclins, by affecting CLN1 and CLN2 expression .As a consequence, AICAR and bre1/set1 deletions jointly affect all three G1 cyclins, leading to a condition that is known to result in synthetic lethality. Most importantly, these chemo-genetic synthetic interactions were conserved in human HCT116 cells. Knock-down of RNF40, ASH2L orKMT2D induced a highly significant increased sensitivity to AICAR. As KMT2D is mutated at high frequency in a variety of cancers, this synthetic lethal interaction has an interesting therapeutic potential.

p. 1-89 / Submitted by Santiago Fabio (fabio.ssantiago@hotmail.com) on 2013-05-09T18:43:01Z No. of bitstreams: 1 7777777777777777777.pdf: 508323 bytes, checksum: 9a5c1691ab294c0ff2616dd3c8bc39a4 (MD5) / Approved for entry into archive by Rodrigo Meirelles(rodrigomei@ufba.br) on 2013-05-11T15:34:34Z (GMT) No. of bitstreams: 1 7777777777777777777.pdf: 508323 bytes, checksum: 9a5c1691ab294c0ff2616dd3c8bc39a4 (MD5) / Made available in DSpace on 2013-05-11T15:34:34Z (GMT). No. of bitstreams: 1 7777777777777777777.pdf: 508323 bytes, checksum: 9a5c1691ab294c0ff2616dd3c8bc39a4 (MD5) Previous issue date: 2009 / Investiga-se a incidência, mortalidade e letalidade dos acidentes ofídicos e descrevem-se fatores associados à sua incidência no Nordeste Brasileiro de 2000 a 2006. Um estudo epidemiológico descritivo, observacional, individuado, do tipo série de casos, utilizou dados secundários e individuados do SINAN (Sistema de Informações de Agravos de Notificação). No período, ocorreram 40.222 casos, perfazendo incidência média anual de 11,8 casos/100.000 habitantes, letalidade de 0,6% e coeficiente anual de mortalidade de 0,07 óbitos/100.000 habitantes. Os acidentes predominaram na zona rural (82,4%), de fevereiro a julho (58,4%), em pacientes de 15 a 24 anos (34,3%), do sexo masculino (75,4%), com ocupação referida de "Trabalhadores agropecuários, florestais, pesca e assemelhados" (18,5%). A incidência correlacionouse positivamente ao percentual de área municipal agropecuária e negativamente ao índice municipal de desenvolvimento humano. O perfil clínico-epidemiológico do ofidismo no Nordeste Brasileiro apresentou mudanças importantes, de 2000 a 2006, distanciando-se do padrão outrora estabelecido pelo Ministério da Saúde, com a elevação do coeficiente de incidência e a redução na letalidade, o que sugere melhoras na qualidade das informações do sistema de informação. / Salvador

Submitted by Maria Creuza Silva (mariakreuza@yahoo.com.br) on 2015-04-20T14:02:11Z No. of bitstreams: 1 Dissertação Enny S. Paixão. 2013.pdf: 819378 bytes, checksum: a90381c9f008f3ce0d742397034a7710 (MD5) / Approved for entry into archive by Maria Creuza Silva (mariakreuza@yahoo.com.br) on 2015-04-20T14:26:08Z (GMT) No. of bitstreams: 1 Dissertação Enny S. Paixão. 2013.pdf: 819378 bytes, checksum: a90381c9f008f3ce0d742397034a7710 (MD5) / Made available in DSpace on 2015-04-20T14:26:08Z (GMT). No. of bitstreams: 1 Dissertação Enny S. Paixão. 2013.pdf: 819378 bytes, checksum: a90381c9f008f3ce0d742397034a7710 (MD5) / Com o objetivo de analisar a tendência temporal da mortalidade e letalidade por dengue e identificar fatores associados a esse desfecho no Brasil, realizou-se estudo de série temporal e agregados espaciais dos óbitos por dengue, registrados de 2000 a 2011, utilizando-se como fontes de dados Sistemas Oficiais de Informação. Ano-calendário e município foram unidades de análise. Curvas de tendência temporal das taxas de mortalidade e letalidade foram construídas para o Brasil, Regiões e faixa-etária. Avaliou-se associação entre essas taxas (média em 2008-2011) e indicadores sócio- econômicos e de atenção à saúde, mediante Regressão Binomial Negativa. De 2000 a 2011, a tendência da letalidade por FHD/SCD foi crescente no Brasil (β=0,67; p=0,036), na Região Sudeste (β=1,17; p=0,003) e nos grupos de 0-14 e 15 anos e mais (β=0,48; p=0,03 e β=1,1; p<0,001, respectivamente). A mortalidade também apresentou tendência crescente significante. Renda média per capita (RR=0,99; p=0,029), percentual da população em domicílios com coleta de lixo (RR=0,95; p=0,001) e número de Unidades Básicas de Saúde (RR= 0,85; p=0,015) mostraram-se associadas à letalidade por dengue. Para a taxa de mortalidade, somente as variáveis do grupo socioeconômico apresentaram associação significante: Índice de Gini (RR= 1,06; p<0,001); Renda média per capita (RR=0,99; p<0,001); Percentual da população com coleta de lixo (RR=0,92; p=0,044) e proporção de pessoas extremamente pobres (RR=0,96; p=0,001). A gravidade que a dengue vem exibindo no Brasil, principalmente em municípios mais pobres, é bastante preocupante. Embora parte dos óbitos por esta doença possa ser evitada, ainda não se dispõe de arsenal terapêutico capaz de evitar sua totalidade, o que torna imperativa a realização de pesquisas voltadas para aprimoramento do tratamento e, principalmente, desenvolvimento de novos instrumentos de controle para reduzir a circulação do agente da dengue.

O processamento térmico contínuo usando trocadores de calor é uma forma muito comum de industrialização de alimentos líquidos. Atrelada à inativação de micro-organismos e enzimas pela alta temperatura, está a perda de qualidade do produto; portanto, o estudo e avaliação deste tipo de processo é fundamental para garantir a inocuidade e a melhora da qualidade do produto. Neste trabalho foi desenvolvida a modelagem matemática de um processo térmico contínuo em trocadores bitubulares para determinação da distribuição da temperatura média do produto e da letalidade sobre um atributo de segurança ou qualidade. No modelo, foram considerados os trocadores de aquecimento e de resfriamento, bem como o tubo de retenção. Admitiu-se regime permanente, escoamento pistonado e leva-se em conta a troca de energia com o ambiente. Para a aplicação do modelo, foi adotado um sistema em escala de laboratório com vazão de processamento entre 10 e 50 L/h, trocadores com quatro módulos de troca térmica e área total de 0,13 m² e sistema de indicação e aquisição de dados de temperatura. Como fluidos de trabalho foram usados: mistura de glicerina/água 80 % (Newtoniano) e solução 1 % de carboxi-metil-celulose (CMC, não-Newtoniano). Fluidos e utilidade foram água quente pressurizada e água gelada. Os parâmetros de troca térmica do modelo foram ajustados com sucesso através de ensaios experimentais. Foram ajustados: 1) coeficientes de convecção natural do ar sobre as seções de aquecimento e de resfriamento; 2) parâmetros da correlação de Nusselt x Reynolds para o coeficiente de convecção dos fluidos de trabalho; 3) coeficiente global de troca térmica com o ambiente no tubo de retenção. A validação do modelo ajustado foi realizada através da comparação das distribuições de temperatura experimental com a predição do modelo. A letalidade, levando em conta o tempo espacial no percurso do produto foi calculada e avaliada, indicando importante contribuição da seção de aquecimento e forte influência da elevação de temperatura na entrada do tubo de retenção para compensar as perdas para o ambiente. O modelo proposto mostra-se útil para a avaliação de processos térmicos em sistemas tubulares. / The continuous thermal processing using heat exchangers is a very usual form of industrialization of liquid foods. Linked to the inactivation of microorganisms and enzymes by high temperature is the loss of product quality; thus, the study and evaluation of this type of process is critical to ensure the safety and improve product quality. In this work, it was developed a mathematical model of a continuous process with tubular heat exchangers to determine the distribution of the average temperature of the product and the lethality considering a safety or quality attribute. In the model, are considered the exchangers for heating and cooling and the holding tube. It was assumed steady state plug-flow and it was taken into account the energy exchange with the ambient air. For the application of the model, it was adopted a laboratory system with processing flow rate between 10 and 50 L/h, exchangers with four heat transfer modules and total area of 0.13 m² and a temperature indication and acquisition system. The working fluids used were: a mixture of glycerol/water 80 % (Newtonian) and a 1 % solution of carboxymethylcellulose (CMC, non-Newtonian). Utility fluids were pressurized hot water and cold water. The heat transfer parameters of the model were adjusted successfully using the experimental data. Were adjusted: 1) the coefficients of natural convection of the air over the heating and cooling sections; 2) the parameters of the Nusselt x Reynolds correlation for the convective coefficient of the working fluid; 3) the overall heat exchange coefficient between the product and the ambient air in the holding tube. The validation of the fitted model was performed by comparing the experimental temperature distributions with the prediction from the model. Lethality, taking into account the space-time in the path of the product was calculated and evaluated, indicating a significant contribution of the heating section and a strong influence on the temperature rise in the entrance of the holding tube to compensate for losses to the surroundings. The model proves useful for the evaluation of thermal processes in tubular systems.

Os trocadores de calor tubulares são muito utilizados para o processamento térmico de alimentos líquidos viscosos por possuírem um maior diâmetro hidráulico em comparação aos trocadores de calor a placas. O cálculo da letalidade neste tipo de trocador está diretamente relacionado ao perfil de velocidade e à distribuição do tempo de residência (DTR). Para escoamento laminar de fluidos viscosos, Newtonianos e não-Newtonianos, geralmente adota-se um perfil de velocidade laminar e de lei de potência, respectivamente. No entanto, algumas características do equipamento como irregularidades na tubulação, a corrugação do tubo ou as curvas podem modificar o perfil de velocidade ideal. Esse desvio da idealidade pode ser caracterizado através da determinação experimental da distribuição do tempo de residência do processo. Este trabalho teve como objetivo a determinação experimental da DTR de fluidos viscosos em um equipamento bitubular de processamento térmico e o ajuste do perfil de velocidade associado. Modelos clássicos de DTR foram ajustados aos dados, assim como foram propostos e testados novos modelos generalizados de DTR, a fim de caracterizar o escoamento laminar não ideal em tubos. A determinação da DTR experimental foi realizada para vazões entre 10 e 50 L/h utilizando água, solução de carboximeticelulose 1,0% (pseudoplástico) e mistura glicerina/água 80%. Os dados de DTR foram obtidos através de duas técnicas: condutimétrica e colorimétrica. A primeira técnica baseia-se na injeção de solução saturada de cloreto de sódio e detecção online por um condutivímetro, porém, não apresentou resultados satisfatórios mostrando que o método não é adequado para fluidos viscosos. Já a segunda técnica utilizada se baseia na injeção de corante e posterior detecção em espectrofotômetro. Os modelos que melhor se ajustaram aos dados experimentais para os três fluidos estudados foram os modelos generalizados y-laminar e exponencial. A letalidade foi calculada a partir da distribuição de temperatura no trocador de calor em estado estacionário e do tempo médio de residência obtido experimentalmente e permitiu detectar o sobreprocessamento no processo estudado. / Tubular heat exchangers are widely used for thermal processing of viscous liquid foods because they have larger hydraulic diameters than the plate heat exchangers. The calculation of lethality in this type of exchanger is directly related to velocity profile and the residence time distribution (RTD). For the laminar flow of viscous fluids, Newtonian and non-Newtonian, generally laminar and power law velocity profiles are used, respectively. However, some features of the equipment as irregularities in the pipe, the corrugation of the pipe or the presence of curves can change the ideal velocity profile. This ideality deviation can be characterized through the experimental determination of the residence time distribution of the process. The aim of this work was the experimental determination of the RTD of a viscous fluid in a bitubular thermal processing equipment and the determination of the associated velocity profile. Classic models of RTD were fitted to the data, as well as were proposed and tested new generalized models of RTD, in order to characterize the non ideal laminar flow in tubes. The experimental determination of RTD was performed to volumetric flow rates between 10 and 50 L/h using water, carboximeticelulose solution 1,0% (pseudoplastic) and glycerin/water mixture 80%. The RTD data were obtained through two techniques: conductimetric and colorimetric. The first technique is based on injection of saturated solution of sodium chloride and online detection with a conductivimeter however, unsatisfactory results showed that the method was not suitable for viscous fluids. The second technique is based on the injection of dye and subsequent detection with a spectrophotometer. The best fitted models to the experimental data for the three studied fluids were: ylaminar and exponential generalized models. The lethality was calculated from the temperature distribution in the heat exchanger at steady state and average residence time obtained experimentally and allowed the evaluation of the overprocessing of this process.