A leishmaniose é uma ameaça para cerca de 350 milhões de pessoas em 88 países no mundo. No município de Bandeirantes, estado do Paraná, Brasil, foram notificados 183 casos de leishmaniose tegumentar americana (LTA) entre 2000 a 2013. Objetivos: Descrever e analisar os casos de LTA ocorridos no município de Bandeirantes Paraná, entre 2007 e 2013 e investigar os fatores de risco associados à ocorrência da doença, considerando-se fatores socioeconômicos, condições habitacionais e do entorno das residências, atividades ocupacionais e de lazer, conhecimento sobre a LTA na população de estudo e algumas práticas; investigar a presença de anticorpos anti Leishmania sp. na população canina e descrever as características socioeconômicas, condições habitacionais e do entorno das residências, atividades ocupacionais, de lazer nos casos que evoluíram para óbitos bem como as características clínicas. Métodos: estudo caso-controle não pareado. A amostra constou de 104 casos autóctones de LTA notificados na Secretaria Municipal de Saúde de Bandeirantes e 90 controles, residentes selecionados aleatoriamente que apresentassem reação de imunofluorescência indireta (RIFI) negativa. A amostra da população canina foi composta por animais presentes nas residências dos casos e dos controles. Foram investigados os óbitos entre os indivíduos que tiveram LTA no período do estudo. Resultados: O sexo feminino prevaleceu entre os casos (62,50 por cento ) e controles (68,89 por cento ), bem como a faixa etária maior ou igual a 60 anos em ambos os grupos (46,15 por cento e 33,33 por cento , respectivamente). Todavia estas condições não se mostraram como fatores de risco significante. Mostraram-se como fatores de risco significantes (p < 0,05) as seguintes variáveis: ser analfabeto (OR = 10,09), aposentados (OR = 2,35), praticar atividades de lazer relacionadas à zona rural (OR = 4,47), frestas na casa (OR = 2,15), presença de matos próximos ao domicílio (OR = 6,92), presença de plantas frutíferas no peridomicílio (OR=2,02), anexos peridomicilares (OR = 4,30), galinheiro (OR=2,15) e canil (OR = 3,90), dormir fora do quarto (OR=4,97), 8 combate a animais sinantrópicos (OR = 2,69), uso de repelente corporal (5,43) e conhecer o mosquito transmissor (OR = 3,48), a relação com outros animais (OR =2,51) e prevenção (OR = 2,24). Como fatores de proteção: renda familiar > 3 salários mínimo (OR = 0,22), casa de alvenaria e reboco (OR = 0,41), abastecimento de água de rede (OR = 0,41), presença de rede de esgoto (OR = 0,33), coleta de lixo pública (OR = 0,35). Os exames sorológicos realizados nos cães do estudo demonstraram que 38,23 por cento foram reagentes para os casos e 2,12 por cento nos controles. Os cães dos casos possuem 28,47 vezes mais chance de contrair a LTA quando comparados com os cães dos controles (p<0,0001). Foram investigados 14 óbitos, 35,71 por cento estavam em tratamento da LTA e 42,86 por cento apresentavam lesões compatíveis com a LTA. Conclusões: A ocorrência da LTA em Bandeirantes mostrou-se associada estatisticamente às variáveis: idade, escolaridade, renda familiar, atividades de lazer relacionadas à zona rural, presença de anexos domiciliares e vegetação próximo ao domicílio, assim como o uso de repelente corporal, dormir fora do quarto e conhecer o mosquito vetor da LTA e a sua forma de prevenção. / The leishmaniasis threat around 350 million people in 88 countries around the world. In Bandeirantes - Parana from 2000 to 2013 183 cases of American tegumentary leishmaniasis (ATL) were reported. Objectives: to describe and analyze the occurrence of ATL in human population in Bandeirantes - Parana, between 2007 and 2013; to investigate the risk factors associated with the disease considering socioeconomic factors, housing conditions and the surrounding residences, occupational and leisure activities, knowledge of the LTA in the study population and some practical; investigate the presence of antibodies against Leishmania sp. the canine population and describe the socio-economic characteristics, housing conditions and the surrounding residences, occupational activities, leisure in cases that evolved to death and the clinical characteristics. Methods: A not paired case-control study was performed in with 104 cases, individuals who had autochthonous ATL notified in the Municipal Health Department of Bandeirantes and 90 controls were randomly selected out of those who presented negative reaction of indirect immunofluorescence (IIF). The canine population was selected from the cases and controls. The deaths among those individuals who had ATL during the study period were investigated. Results: Females were more abundant in case (62,5 per cent ) and control groups (68.89 per cent ) with predominance of age equal or greater than 60 years in both groups (46,15 and 33.33 per cent respectively). However, these conditions were not significant risk factors. The significant risk factors (p < 0,05) were: illiterate people (OR = 10,09), those who receive one to three minimum wages (OR =4,48), retired people (OR=2,35), to practice leisure activities related to rural area (OR=4,47), openings on the house (OR=2,15), presence of forests near the domicilie (OR = 6,92), presence of fruit plants near the house (OR=2,02), attachments to the house (OR = 4,30), chicken stay (OR=2,15), kennel (OR = 3,90), to sleep out of the bedroom (OR=4,97), to combat urban plagues (OR = 2,69), to use repellent (5,43) and to know the phlebotomine (OR = 3,48) and its relation with other animals (OR =2,51), and prevention (OR = 2,24). The protective factors were house of masonry and plaster (OR = 0.41), water supply network (OR = 0.41), 10 presence of sewage (OR = 0.33), public garbage collection (OR = 0.35). The serological tests performed in dogs of the study showed that 38.23 per cent were reactive to the cases and 2.12 per cent to the controls. The dogs of the cases have 28.47 times more chance of catching the ATL when compared with the dogs of the controls (p< 0.0001). Fourteen deaths were investigated, out of which 35.71 per cent were in treatment of ATL and 42.86 per cent had lesions compatible with the ATL. Conclusions: The occurrence of ATL in Bandeirantes proved to be statistically associated with the variables: age, education, family income, leisure activities related to rural area, presence of attachments to the house and vegetation near the domicile, as well as the use of repellent, sleeping outside of the room and knowing the disease vector of ATL and its prevention.

A Leishmaniose Visceral Canina é uma doença na qual o ciclo de transmissão envolve a interação de vetores, parasitas, reservatórios e hospedeiros além de componentes ambientais, sociais, e biológicos, que tornam complexa a compreensão da dinâmica desta doença nas regiões endêmicas. Este estudo epidemiológico transversal de tipo caso controle objetivou a identificação de fatores sociodemográficos, socioeconômicos, ambientais, da dinâmica populacional canina e do estilo de vida dos cães, associados à ocorrência de Leishmaniose Visceral Canina no município de Panorama, estado de São Paulo, Brasil. Para a identificação destes fatores foi realizada um inquérito epidemiológico nos domicílios com cães positivos e negativos a Leishmaniose Visceral diagnosticados por sorologia no anos 2012 e 2013. Mediante um modelo de regressão logística foram considerados como fatores de risco para a ocorrência de Leishmaniose Visceral Canina: cães não castrados, cães que dormem fora de casa, famílias com renda inferior a três salários mínimos, presença de vegetação próximo do domicilio, não ter vidro na janela, ter vasos com plantas, ter arvores no quintal e aquisição de um cão no último ano. O desenvolvimento deste trabalho auxilia no programa de prevenção e controle da Leishmaniose Visceral Canina do Município de Panorama, mediante a identificação dos principais fatores de risco determinantes para a manutenção da doença. Este estudo demonstrou a presença de fatores de risco sujeitos a modificações por parte da população e das autoridades sanitárias que poderiam contribuir para a redução do risco de transmissão da doença em Panorama, sendo elas: a ordenação do ambiente no peri-domicílio pela redução de matéria orgânica e entulho que poderiam servir como local para reprodução e abrigo da população vetora, a modificação da relação com os cães de modo a aumentar a supervisão e a promoção do uso de medidas de proteção individual (coleira, repelentes, vacina) para a proteção da população canina nesta localidade. / Canine Visceral Leishmaniasis is a disease in which the transmission cycle involves the interaction of vectors, parasites, as well as reservoir hosts and environmental, social, and biological factors, making it very complex to understand the dynamic of this disease in endemic regions. This cross-sectional case-control epidemiological study aimed to identify risk factors for the occurrence of Canine Visceral Leishmaniasis in the city of Panorama, São Paulo, Brazil. An epidemiological survey was done to identify sociodemographic, socioeconomics, environmental, canine population dynamics and dogs life style factors, in households with positive and negative dogs diagnosed by serology in the years 2012 and 2013 in the city of Panorama. A logistic regression model was developed to take into account risk factors for the occurrence of Canine Visceral Leishmaniasis: intact dogs, dogs sleeping away from home, families with lower income, vegetation near the households, windows with no glass panels, potted plants, the presence of trees in the yard and the acquisition of a dog in the last year. The development of this work helps in the prevention and control program of Canine Visceral Leishmaniasis in the city of Panorama by the management of the determinant risk factors that maintain the disease. This study demonstrated the presence of some risk factors that are subject to modifications by the population and the health authorities and that could produce a reduction in the risk of disease transmission in Panorama: environmental ordination in areas around the houses with reduction of organic matter and rubbish that could serve as a place for the reproduction and shelter of the vector population, and the modification of the relationship with dogs promoting the use of individual protective measures (collar, repellents, vaccine etc.) to contribute to the protection of the dog population in this locality.

A diarreia ainda persiste como um problema de saúde pública, sendo uma das principais causas de mortalidade infantil nos países em desenvolvimento, principalmente em crianças abaixo de 5 anos. Este estudo teve por objetivo avaliar a etiologia das diarreias agudas em crianças de 0 a 5 anos atendidas no Hospital Universitário da USP em um estudo caso-controle. As fezes de 260 casos e 58 controles foram coletadas por suabe retal e conservadas em meio Cary-Blair até o momento da semeadura. As bactérias pesquisadas foram Escherichia coli diarreiogênicas (EPEC, EIEC, EAEC, EHEC, ETEC), Salmonella sp, Shigella sp, Yersinia enterocolitica e Campylobacter sp. Os meios de cultura utilizados para isolamento das bactérias foram Ágar SS e Ágar MacConkey. Após incubação por 24 horas a 37ºC, as bactérias foram identificadas fenotipicamente utilizando-se EPM-MILI-Citrato. Posteriormente, as bactérias enteropatogênicas foram aglutinadas com anti-soros específicos polivalentes. Para isolamento de Campylobacter sp foi utilizado Ágar Karmalli incubado a 42ºC por 48 horas em microaerofilia. Foram também pesquisados os fatores de virulência de Escherichia coli por colony-blot, utilizando sondas genéticas marcadas radioativamente. Os agentes virais pesquisados foram Rotavírus e Adenovírus em 134 crianças utilizando-se kit ROTA-VIKIA ADENO pelo método imunocromatográfico. Neste trabalho foi possível observar que a prevalência dos agentes foi: EPEC - casos: 34(13%), controles: 5(8,6%); EAEC - casos: 27(10,3%), controles: 8(13,7%); EIEC - casos: 5(1,9%); controles: 0, Shigella sonnei - casos: 7(2,7%); controles: 0, Shigella flexneri - casos: 4(1,5%), controles: 0; Salmonella - casos: 7(2,7%), controles: 1(1,7%); Campylobacter sp - casos: 4(1,5%), controles: 0; Rotavírus - casos: 21(17,3%), controles: 1(7,7%); Adenovírus - casos: 6(5%), controles: 1(7,7%) e Rotavírus + Adenovírus - casos: 2(1,7%), controles: 1(7,7%). O agente etiológico mais encontrado foi Rotavirus e se caracterizou como o único patógeno que apresentou significância estatística entre casos e controles (p<0,01). Ocorreu uma maior prevalência de EPEC atípica em relação à EPEC típica, dados concordantes com outros trabalhos. Houve predominância de Shigella sonnei em relação à Shigella flexneri, resultados divergentes encontrados em estudos anteriores. Rotavirus foi o enteropatógeno mais prevalente, sendo que nove crianças acometidas estavam desidratadas. Dez crianças tiveram infecção mista entre os agentes isolados. Em dezessete crianças do grupo controle (sem diarreia) foram encontrados agentes patogênicos, a saber: EPEC (5), EAEC (8), Salmonella (1) e Rotavirus + Adenovirus (1). / Diarrhea remains an important problem worldwide and has been characterized as one of the main causes of infant death in developing countries, especially in children under five years old. The aim of this study was to evaluate the etiology of acute diarrhea in children by case-control attended in São Paulo University Hospital. Fecal samples of 260 cases and 58 matched controls were collected by rectal swabs and conserved in Cary-Blair medium until the moment of seeding. Researched bacterial were diarrheiogenic Escherichia coli (EPEC, EIEC, EAEC, EHEC and ETEC), Salmonella sp, Shigella sp, Yersinia enterocolitica and thermophilic Campylobacter sp. Cultures for bacterium isolation were made in SS agar and MacConkey agar. After incubation at 37ºC by 24 h, bacteria were tested using biochemical tests (EPM-MILI-Citrato). For Campylobacter isolation was used Karmali agar at 42ºC by 48 h in 5% CO2. Colony-blot hybridization using specific radiolabelled DNA probes was used to identify diarrheiogenic E. coli. Rotavirus and Adenovirus were sought in 121 cases and 13 controls by ROTA-VIKIA ADENO by immunochromatographic assay. The prevalence of the pathogens were as follows: EPEC - cases: 34 (13%), controls: 5 (1,9%); EAEC - cases: 27 (10,3%), controls: 8 (13,7%); EIEC - cases: 5 (1,9%), controls: 0; Shigella sonnei - cases: 7 (2,7%), controls: 0; Shigella flexneri - cases: 4 (1,5%), controls: 0; Salmonella - cases: 7 (2,7%), controls: 1 (1,7%); Campylobacter sp - cases: 4 (1,5%), controls: 0; Rotavirus - cases: 21 (17,3%), controls - 1 (7,7%); Adenovirus - cases: 6 (5%), controls: 1 (7,7%) and Rotavirus + Adenovirus - cases: 2 (1,7%), controls: 1 (7,7%). The main etiologic agent found was Rotavirus, which was the only pathogen significant between cases and controls (p<0,01). Atypical EPEC had major prevalence comparing to typical EPEC. Shigella sonnei was more isolated than Shigella flexneri, a different result found in other studies. Ten children had mixed infection between the isolated agents. In seventeen children of the control group (without diarrhea) were found pathogens, that is: EPEC (5), EAEC (8), Salmonella (1) and Rotavirus + Adenovirus (1).

The present study was designed to assess the risk factors associated with carpal tunnel syndrome (CTS). Toward this end, a wide range of putative occupational, biological , and psychosocial correlates of CTS was investigated using a case-control methodology. Cases were 87 patients from an orthopedic clinic with clinical symptoms and electrodiagnostic testing results suggestive of CTS. Controls were 74 gender-matched patients from the same orthopedic clinic, without clinical symptoms of CTS and normal electrodiagnostic testing results. Participants completed a self-report questionnaire that included eight potential occupational correlates (i.e., repetition, force, vibration, typing, lifting heavy loads, and standing on feet), 10 potential personological correlates (i.e., obesity, advocational exercise levels, diabetes, thyroid problems, arthritis, gynecological surgery, and menstrual complications), and 11 potential psychosocial correlates (i.e., depression, anxiety, somatization, health locus of control job satisfaction, and physical and mental health indices). Results of multiple logistic regression analyses revealed that occupational repetition , vigorous exercise, physical activities with wrist strain, physical health, and job satisfaction were significant predictors of CTS. In addition, obesity was a borderline significant predictor of CTS. Plausible explanations for the current findings, along with implications, are discussed .

<p>Tularemia is a zoonosis caused by the small, fastidious, gram-negative rod Francisella tularensis that appears over almost the entire Northern Hemisphere. In Sweden, tularemia has appeared mainly in restricted areas in northern parts of central Sweden.</p><p> The disease can be transmitted through several routes: direct contact with infected animals, by vectors, through contaminated food or water or through inhalation of aerosolized bacteria. Distinct clinical forms of the disease are seen, depending on the route of transmission. During the last years, tularemia has emerged in new areas in central Sweden, south of the endemic area. The emergence of tularemia in the County of Örebro prompted the investigations presented in this thesis.</p><p> We performed a case-control study, using a mailed questionnaire, to identify risk factors for acquiring tularemia in Sweden (Paper I). After multivariate analysis, mosquito bites and cat ownership could be associated with tularemia in all studied areas while farming appeared as a risk factor only in endemic areas.</p><p> In Paper II, we evaluated a PCR analysis, targeting the tul4 gene, used on samples from primary lesions in patients with ulceroglandular tularemia. The method performed well, with a sensitivity of 78% and a specifi city of 96%. The clinical characteristics of tularemia in an emergent area in Sweden were studied Paper III), using case fi les and a questionnaire. Of 278 cases of tularemia reported during the years 2000 to 2004, 234 had been in contact with a doctor from the Department of Infectious Diseases at Örebro University Hospital, and were thus included. The ulceroglandular form of the disease was seen in 89% of the cases, with the primary lesion, in most cases, on the lower leg. An overwhelming majority of cases occurred during late summer and early autumn, further supporting transmission by mosquitoes. Erythemas overlying the affected lymph node areas were seen in 19% of patients with forms of tularemia affecting peripheral lymph nodes. Late skin manifestations, of various appearances, were seen in 30% of the cases, predominantly in women. A raised awareness of tularemia among physicians in the county during the course of the outbreak was found, as documented by the development of shorter doctor’s delay and less prescription of antibiotics inappropriate in tularemia.</p><p> Finally, we developed a simplifi ed whole-blood lymphocyte stimulation test, as a diagnostic tool in tularemia (Paper IV). The level of IFN-γ, as a proxy for lymphocyte proliferation, was measured after 24-h stimulation. Additionally, a tularemia ELISA with ultra-purifi ed LPS as the antigen was evaluated, showing a high sensitivity. The lymphocyte stimulation test, when performed on consecutive samples from subjects with ongoing tularemia was able to detect the disease earlier in the course of the disease than both the new ELISA and the tube agglutination test. Furthermore, all tularemia cases became positive in the lymphocyte stimulation test within 12 days of disease. In conclusion, this thesis describes risk factors for acquiring tularemia as well as the clinical characteristics of the disease in Sweden. Additionally, a Francisella PCR analysis and a tularemia ELISA based on highly purifi ed LPS is evaluated, and a simplified lymphocyte stimulation test, for early confirmation of the disease, is developed.</p><p>Henrik Eliasson, Department of Infectious Diseases,</p><p>Örebro University Hospital, SE-701 85 Örebro, Sweden,</p><p>henrik.eliasson@orebroll.se</p>

The purpose of this thesis was to assess the possible risk of myocardial infarction in work entailing exposure to vibration, and to study whether there is any relation between short-term exposure to vibration and cardiac regulation. Epidemiological methods were applied to investigate a possible association between occupational exposure to vibration and myocardial infarction. Two study populations were used; one case-control study (n=475) and one cohort of iron-ore miners in Kiruna and Malmberget, Sweden (n=13621). In the former, the cases were first-time myocardial infarction patients and the controls were selected to match for sex, age and hospital catchment area. Job-exposure matrixes for vibration were established for both the case-control study and the cohort study. In order to study acute effects on cardiac regulation, an experimental study was conducted on healthy subjects (n=20) who were exposed to hand-arm vibration exclusively and in combination with exposure to noise. The effect on the autonomic balance was measured by heart rate-variability. In the case-control study, an increased risk of contracting myocardial infarction was found among occupations entailing vibration exposure. The results from the cohort show an increased risk of myocardial infarction mortality compared to a reference population. The increment was higher for those younger than 60 years. Relative risks for myocardial infarction mortality increased with increasing exposure to vibration in the group at working-age and the increased risk remained after adjusting for exposure to dust. In the experimental study, exposure to hand-arm vibration was found to acutely affect the autonomic nervous system as the total heart-rate variability decreased during exposure to hand-arm vibration. To conclude: work entailing exposure to vibration is a risk factor for myocardial infarction, increased myocardial infarction mortality attributed to exposure to vibration seems to be mainly observed at working-age, and exposure to hand-arm vibration acutely decreases heart-rate variability and thus affects heart-rate regulation.

Cadmium and lead accumulate in humans and can have toxic effects. Exposure to cadmium is well known to cause kidney damage. Cadmium binds to metallothioneins, proteins that play a role in cadmium transport. Lead exposure’s main effect is on the central nervous system, but associations with kidney disease have also been found, although it is unknown if the latter is a causal association. The main source of both metals within the non-smoking population is from the diet. This thesis aims to 1) compare the biomarkers lead and cadmium concentration in whole-blood, plasma and urine with regard to their ability to discriminate between individuals with different mean concentrations, and to describe the effect of urinary dilution, 2) estimate the association between end-stage renal disease and blood concentrations of cadmium, lead and mercury, using prospectively collected samples for exposure evaluation, 3) use longitudinal data on kidney function makers to evaluate kidney recovery after a substantial decrease in cadmium exposure, and 4) assess the influence of metallothionein polymorphisms (MT1A rs11076161, MT2A rs10636 and MT2A rs28366003) on cadmium-associated kidney toxicity and recovery due to a reduction in Cd exposure. Repeated sampling of whole-blood, plasma and urine was conducted on 48 occupationally lead-exposed men and 20 individuals under normal environmental lead exposure, for estimation of the day-to-day and between individual-variation. Prospective samples were obtained for 118 cases that later in life developed end-stage renal disease, and 378 matched controls. Erythrocyte cadmium, lead, and mercury concentrations were determined and the risk of developing end-stage renal disease associated with metal concentrations was estimated. For evaluation of kidney recovery after a reduction in cadmium exposure and to test for gene-environment interactions, follow-up data on N-acetyl-β‑d-glucosaminidase, β2‑microglobulin, albumin, and gene polymorphisms were obtained for 412 individuals within the Chinese population and the relation to blood and urinary cadmium was assessed. The concentration of lead in blood was found to be the biomarker with the largest fraction of the total variance attributable to between-individual variation, and was therefore the biomarker with the best ability to discriminate between individuals with different mean concentrations, both for individuals under occupational and normal environmental exposure (91 and 95%, respectively). Adjusting for urinary dilution had a great effect on the fraction of the total variance attributable to between-individual variation among individuals with normal lead exposure but only a minor effect among those who were occupationally exposed. Variance analysis showed that blood concentrations were also the best discriminating biomarker for cadmium. Erythrocyte lead was, in a univariate model, associated with an increased risk of developing end-stage renal disease [odds ratio (OR) = 1.54 for an interquartile range increase, with a 95% confidence interval (CI) = 1.18-2.00], while erythrocyte mercury was negatively associated (OR = 0.75 for an interquartile range increase, with a 95% CI = 0.56-0.99). For erythrocyte cadmium, the OR was 1.15 with a 95% CI of 0.99-1.34. Associations with lead and cadmium were only seen among men. In the study on kidney recovery, the proportion of individuals with albumin level above the 95th percentile decreased between baseline and follow up, but no decrease was found for the tubular markers N-acetyl-β‑d-glucosaminidase and β2-microglobulin. Metallothionein polymorphisms modified cadmium-associated effects on N-acetyl-β‑d-glucosaminidase and β2-microglobulin levels but did not modify cadmium-associated change in any of the kidney function markers between baseline and follow up after a substantial decrease in exposure. Blood concentrations of lead and cadmium are the biomarkers with the best ability to discriminate between individuals with different mean concentrations. Adjustment for urinary dilution has great influence on the fraction of the total variance attributed to between individual variation among urine samples with low lead concentrations, but only a small influence on samples with high lead concentrations. This suggests a difference in excretion. The association between end-stage renal disease and low-level lead exposure, as assessed through prospective erythrocyte samples, gives reason for concern, although further studies are needed to determine causality. A cadmium-associated increase in albumin is reversible after a substantial reduction in exposure, but this is not the case for the observed tubular effects. The tubular kidney effects of cadmium might be modified by the MT1A rs11076161 polymorphism. / För att bedöma exponering för kadmium och bly mäts ofta deras koncentrationer i blod eller urin. Dessa studerades i longitudinella data för 48 blyarbetare och 20 individer med normal miljömässig exponering. Blod- och urinprover togs var annan till var tredje månad. Kadmium- och blykoncentrationer mättes sedan i helblod, plasma och urin. Koncentrationer av bly i blod var den biomarkör som hade den största andelen av den totala variationen som kunde förklaras av skillnader mellan individer, och var därför den biomarkör med den bästa förmågan att särskilja på individer med olika medelkoncentration, både för individer med yrkesexponering och normal miljömässig exponering (91 respektive 95% av variansen berodde på vilken individ blodprovet kom ifrån). Justering för urinens utspädning av bly i urin förbättrar oftast urins användbarhet som biomarkör. För bly stämde detta bara hos dem som inte var blyarbetare. Blodkoncentrationer var också den biomarkör med störst andel av den totala variation som kunde förklaras med skillnader mellan individer för kadmium. Kadmium och bly ackumuleras i njure respektive ben och kan ha toxikologiska effekter. Det är välkänt att höga exponeringsnivåer av kadmium orsakar njurskada och även vid lägre exponeringsnivåer har studier funnit samband med markörer för njurfunktion. Exponering för bly påverkar i första hand det centrala nervsystemet. Studier har dock funnit samband mellan koncentrationer av bly i blod och njurens glomerulära filtrationshastighet. Det är oklart både om dessa associationer, vid låga exponeringsnivåer, är viktiga för hälsan och om de verkligen beror på att kadmium och bly orsakar njurskada. För att studera end-stage renal disease användes prospektiva kohorter där personer lämnat blodprov för forskning: Västerbottens interventionsprogram med prover som tagits vid Västerbottens hälsoundersökningar, MONICA-undersökningar i Norr- och Västerbotten, mammografiundersökningarna i Västerbotten och Malmö kost cancer. Sammanlagt ingick över ett hundra tusen individer i dessa kohorter. Med hjälp av det Svenska njurregistret identifierades sedan 118 personer som senare i livet fått end-stage renal disease. Dessa jämfördes med 378 kontroller. För dessa 496 personer tinades blodprovet (närmare bestämt röda blodkroppar) upp och analyserades för kadmium och bly. För att undersöka njurens förmåga till återhämtning studerades tre områden i Kina varav ett tidigare varit kraftigt kadmiumexponerat. Erytrocytkoncentrationer av bly var, utan att ta hänsyn till några andra variabler, associerat med en ökad risk för att utveckla end-stage renal disease (med oddskvoten 1.54 för en interquartile range ökning av erytrocytbly, med ett 95% konfidensintervall 1.18-2.00). Sambanden kvarstod också efter att ha tagit hänsyn till övriga variabler. För erytrocytkadmium var oddskvoten 1.15 med 95% konfidensintervall 0.99-1.34, och sambandet försvagades när hänsyn togs till andra variabler. Associationerna sågs bland män men inte bland kvinnor. Eftersom kadmium vid höga nivåer orsakar njurskada är det också av intresse att studera om påverkan på njuren går över om exponeringen minskas. Totalt följdes 412 individer upp med mätningar av markörer för njurfunktion och kadmiumkoncentrationer i blod och urin. Första undersökningen gjordes 1998, då man just hade slutat äta kadmiumförorenat ris. En andra undersökning gjordes 2006. Andelen individer med avvikande albuminvärde i urin var lägre vid uppföljningen jämfört med vid baslinjen, men ingen minskning sågs för markörer för tubulär förmåga att återta proteiner. Åttioprocent av kadmium i celler är bundet till proteinet metallotheonin, vilket skyddar mot cellskada, men har också en roll i transporten av kadmium från levern till njurarna. En tidigare studie har visat att njurens känslighet för kadmiumexponering var associerad med genetiska skillnader i detta protein. För att studera genetiska associationer studerades de 412 personerna i den kinesiska studien [då också individernas genotyper av metallotheonin-polymorfierna MT1A rs11076161 (G/A), MT2A rs10636 (G/C) och MT2A rs28366003 (A/G) bestämdes]. Genetiken spelade roll för sambandet mellan förmåga att återta proteiner och kadmium men påverkade inte förändring av njurfunktion efter att man slutat äta kadmiumförorenat ris. Kadmium- och blykoncentrationer i blod är de biomarkörer, av koncentrationer i blod, plasma och urin, med den bästa förmågan att skilja på individer med olika medelkoncentrationer. Justering för urinutspädning påverkade andelen av den totala variationen som kunde förklaras av skillnader mellan individer i stor utsträckning för individer med normal miljömässig exponering men inte bland yrkesexponerade, vilket tyder på en skillnad i hur utsöndringen går till. Associationen mellan end-stage renal disease och låg exponering för bly, uppmätta i prospektiva erytrocytprover, ger orsak till oro, men ytterligare studier behövs för att kunna utvärdera om detta är ett kausalt samband. En kadmiumrelaterad skada av den glomerulära filtrationen är reversibel efter en kraftig reducering i exponering, men detta är inte fallet för tubulär skada. De tubulära njureffekterna av kadmiumexponering kan påverkas av metallotheonin-polymorfier.

Accessibility of high-throughput genotyping technology makes possible genome-wide association studies for common complex diseases. When dealing with common diseases, it is necessary to search and analyze multiple independent causes resulted from interactions of multiple genes scattered over the entire genome. The optimization formulations for searching disease-associated risk/resistant factors and predicting disease susceptibility for given case-control study have been introduced. Several discrete methods for disease association search exploiting greedy strategy and topological properties of case-control studies have been developed. New disease susceptibility prediction methods based on the developed search methods have been validated on datasets from case-control studies for several common diseases. Our experiments compare favorably the proposed algorithms with the existing association search and susceptibility prediction methods.

In 2004, lung cancer has been the leading cause of cancer death in Taiwan. Many studies demonstrate that vitamin A plays a crucial role in the prevention of lung cancer. However, few epidemiologic studies have examined the association of dietary vitamin A/precursors and lung cancer in Taiwan. Therefore, a case-control study was conducted to investigate the relationship between the consumption of local common foods that are rich in vitamin A/precursors and the risk of lung cancer. The cases were 301 newly diagnosed patients with histopathologically confirmed primary lung cancer. Two control groups were recruited: 602 hospital controls and 602 neighborhood controls. The consumption of 13 food items and vitamin supplements was estimated with the use of a structured food-frequency questionnaire in face-to-face interviews. Adjusted odds ratios (AOR) and the corresponding 95% confidence intervals (CI) were evaluated with controlling for potential confounders, using the conditional logistic regression model. It was found that reduced risk for lung cancer was associated with increased intakes of vitamin A, a-carotene, or b-carotene from various food groups except fruits. However, inverse associations were not observed for vitamin A, a-carotene, or b-carotene intake from various food items, except garland chrysanthemum and sweet potato leaves. On the other hand, retinol intake from food groups or items was not correlated with lung cancer development. Additionally, more servings of vegetables (AOR for the highest versus the lowest quartile = 0.67-0.70, 95% CI = 0.42-1.08, plinear trend = 0.04), garland chrysanthemum (AOR for the highest versus the lowest tertile = 0.58-0.74, 95% CI = 0.37-1.14, plinear trend = 0.01-0.04) and sweet potato leaves (AOR for the highest versus the lowest tertile = 0.43-0.65, 95% CI = 0.28-0.96, plinear trend &#x00A3; 0.03) were associated with the reduced risk for lung cancer. In conclusion, there were protective effects of dietary intake of vitamin A, a-carotene and b-carotene. The vegetables provided higher potential protection against development of lung cancer than the fruits, especially for garland chrysanthemum and sweet potato leaves. Therefore, our findings suggest that more consumption of garland chrysanthemum and sweet potato leaves might reduce the risk of lung cancer in Taiwan.

Thesis (Ph. D.)--University of Washington, 2002. / Vita. Includes bibliographical references (leaves 65-69).