GAD2 on chromosome 10p12 is a candidate gene for human obesity

The gene GAD2 encoding the glutamic acid decarboxylase enzyme (GAD65) is a positional candidate gene for obesity on Chromosome 10p11–12, a susceptibility locus for morbid obesity in four independent ethnic populations. GAD65 catalyzes the formation of γ-aminobutyric acid (GABA), which interacts with neuropeptide Y in the paraventricular nucleus to contribute to stimulate food intake. A case-control study (575 morbidly obese and 646 control subjects) analyzing GAD2 variants identified both a protective haplotype, including the most frequent alleles of single nucleotide polymorphisms (SNPs) +61450 C>A and +83897 T>A (OR = 0.81, 95% CI [0.681–0.972], p = 0.0049) and an at-risk SNP (−243 A>G) for morbid obesity (OR = 1.3, 95% CI [1.053–1.585], p = 0.014). Furthermore, familial-based analyses confirmed the association with the obesity of SNP +61450 C>A and +83897 T>A haplotype (χ2 = 7.637, p = 0.02). In the murine insulinoma cell line βTC3, the G at-risk allele of SNP −243 A>G increased six times GAD2 promoter activity (p < 0.0001) and induced a 6-fold higher affinity for nuclear extracts. The −243 A>G SNP was associated with higher hunger scores (p = 0.007) and disinhibition scores (p = 0.028), as assessed by the Stunkard Three-Factor Eating Questionnaire. As GAD2 is highly expressed in pancreatic β cells, we analyzed GAD65 antibody level as a marker of β-cell activity and of insulin secretion. In the control group, −243 A>G, +61450 C>A, and +83897 T>A SNPs were associated with lower GAD65 autoantibody levels (p values of 0.003, 0.047, and 0.006, respectively). SNP +83897 T>A was associated with lower fasting insulin and insulin secretion, as assessed by the HOMA-B% homeostasis model of β-cell function (p = 0.009 and 0.01, respectively). These data support the hypothesis of the orexigenic effect of GABA in humans and of a contribution of genes involved in GABA metabolism in the modulation of food intake and in the development of morbid obesity.

Fresh garlic : a possible vehicle for Salmonella Virchow

A sustained increase in Salmonella enterica serovar Virchow notifications in South Eastern Australia between September 1997 and May 1998 instigated a case-control study and environmental investigations. Cases were defined as having locally acquired culture-confirmed S. Virchow phage-type 8 infection and diarrhoeal disease. Matched controls were selected by progressive digit dialling based on cases telephone numbers. An exposure and food history questionnaire was administered by telephone. Phage typing and pulse field gel electrophoresis were performed on case and environmental isolates. Thirty-two notifications of S. Virchow infection met the case definition, 37% reported bloody diarrhoea and S. Virchow was isolated from blood in 13% of cases. Twelve patients were admitted to hospital and one died. Fresh garlic (OR 4·1, 95% CI 1·3-12·8) and semi-dried tomatoes (OR 12·6, 95% CI 1·5-103·1) were associated with these cases. The associations remained significant after adjusting for sex and age. S. Virchow (PT 8) was cultured from two brands of semi-dried tomatoes associated with cases in two different states. We provide sufficient evidence for semi-dried tomatoes and fresh garlic to be considered as potential risk foods in future Salmonella outbreak investigations.

Dietary fiber, potassium, magnesium and calcium in relation to the risk of preeclampsia

To explore the relation between preeclampsia risk and maternal intake of dietary fiber, potassium, magnesium and calcium. STUDY DESIGN: We conducted a case-control study of 172 preeclamptics and 339 normotensive controls. Maternal dietary intake was assessed using a food frequency questionnaire. Logistic regression procedures were used to estimate the association between each dietary factor and preeclampsia risk. RESULTS: Fiber intake was inversely associated with the risk of preeclampsia. When extreme quartiles of total fiber intake were compared, the odds ratio (OR) for preeclampsia was 0.46 (95% confidence interval [CI] 0.23-0.92). The multivariate OR for preeclampsia for women in the top quartile of potassium intake (>4.1 g/d) versus the lowest quartile (<2.4 g/d) was 0.49 (95% CI 0.24-0.99). There was some evidence of a reduced risk of preeclampsia with a high intake of magnesium and calcium, though these results were not statistically significant. Intake of fruits and vegetables, low-fat dairy products, total cereal and dark bread were each associated with a reduced risk of preeclampsia. CONCLUSION: Our results support previous reports that suggest that diets high in fiber and potassium are associated with a reduced risk of hypertension. Maternal intake of recommended amounts of foods rich in fiber, potassium and other nutrients may reduce the risk of preeclampsia.

Exposure estimation, uncertainty and variability in occupational hygiene retrospective assessment

This thesis reports on a quantitative exposure assessment and on an analysis of the attributes of the data used in the estimations, in particular distinguishing between its uncertainty and variability. A retrospective assessment of exposure to benzene was carried out for a case control study of leukaemia in the Australian petroleum industry. The study used the mean of personal task-based measurements (Base Estimates) in a deterministic algorithm and applied factors to model back to places, times etc for which no exposure measurements were available. Mean daily exposures were estimated, on an individual subject basis, by summing the task-based exposures. These mean exposures were multiplied by the years spent on each job to provide exposure estimates in ppm-years. These were summed to provide a Cumulative Estimate for each subject. Validation was completed for the model and key inputs. Exposures were low, most jobs were below TWA of 5 ppm benzene. Exposures in terminals were generally higher than at refineries. Cumulative Estimates ranged from 0.005 to 50.9 ppm-years, with 84 percent less than 10 ppm-years. Exposure probability distributions were developed for tanker drivers using Monte Carlo simulation of the exposure estimation algorithm. The outcome was a lognormal distribution of exposure for each driver. These provide the basis for alternative risk assessment metrics e.g. the frequency of short but intense exposures which provided only a minimal contribution to the long-term average exposure but may increase risk of leukaemia. The effect of different inputs to the model were examined and their significance assessed using Monte Carlo simulation. The Base Estimates were the most important determinant of exposure in the model. The sources of variability in the measured data were examined, including the effect of having censored data and the between and within-worker variability. The sources of uncertainty in the exposure estimates were analysed and consequential improvements in exposure assessment identified. Monte Carlo sampling was also used to examine the uncertainties and variability associated with the tanker drivers' exposure assessment, to derive an estimate of the range and to put confidence intervals on the daily mean exposures. The identified uncertainty was less than the variability associated with the estimates. The traditional approach to exposure estimation typically derives only point estimates of mean exposure. The approach developed here allows a range of exposure estimates to be made and provides a more flexible and improved basis for risk assessment.

Risk of prostate cancer associated with a family history in an era of rapid increase in prostate cancer diagnosis (Australia)

OBJECTIVE: We conducted a case-control study of prostate cancer and familial risk of the disease in Australia between 1994 and 1998, a period during which the incidence of prostate cancer increased dramatically with widespread use of prostate-specific antigen (PSA) testing. METHODS: 1475 cases and 1405 controls were asked about prostate cancer in their first-degree relatives. Odds ratios (OR) were calculated using logistic regression. RESULTS: Cases were more likely to report a family history of prostate cancer than controls (OR 3.0; 95% confidence interval (CI) 2.3-3.9) and cases reporting an affected relative were younger (58.8 versus 60.9 years, p < 0.0001). The OR for an affected first-degree relative increased with increasing number of affected relatives and decreased with increasing age of the case. The OR for more than one affected first-degree relative was 6.9 (95% CI 2.7-18). The OR for an affected brother was 3.9 (95% CI 2.5-6.1) and for an affected father was 2.9 (95% CI 2.1-3.9) but these were not significantly different (p = 0.2). When analyses were repeated including only diagnoses made in relatives prior to 1992, the risks were generally similar except that the OR for an affected brother decreased to 3.1 (95% CI 1.2-3.9). When only relatives' diagnoses made after 1991 were included results were again similar to those for all relatives, although the effect for brothers was greater and the attenuation with age at diagnosis dissipated. CONCLUSIONS: The recent introduction of PSA testing that has resulted in a greater prevalence of apparent prostate cancer, does not appear to have substantially altered familial risks of disease, although effects associated with brothers may be inflated.

Habitual physical activity and the risk for depressive and anxiety disorders among older men and women

Background: Regular physical activity is generally associated with psychological well-being, although there are relatively few prospective studies in older adults. We investigated habitual physical activity as a risk factor for de novo depressive and anxiety disorders in older men and women from the general population.
Methods: In this nested case-control study, subjects aged 60 years or more were identified from randomly selected cohorts being followed prospectively in the Geelong Osteoporosis Study. Cases were individuals with incident depressive or anxiety disorders, diagnosed using the Structured Clinical Interview for DSM-IV-TR (SCID-I/NP); controls had no history of these disorders.Habitual physical activity,measured using a validated questionnaire, and other exposures were documented at baseline, approximately four years prior to psychiatric interviews. Those with depressive or anxiety disorders that pre-dated baseline were excluded.
Results: Of 547 eligible subjects, 14 developed de novo depressive or anxiety disorders and were classified as cases; 533 controls remained free of disease. Physical activity was protective against the likelihood of depressive and anxiety disorders; OR = 0.55 (95% CI 0.32–0.94), p = 0.03; each standard deviation increase in the transformed physical activity score was associated with an approximate halving in the likelihood of developing depressive or anxiety disorders. Leisure-time physical activity contributed substantially to the overall physical activity score. Age, gender, smoking, alcohol consumption, weight and socioeconomic status did not substantially confound the association.
Conclusion: This study provides evidence consistent with the notion that higher levels of habitual physical activity are protective against the subsequent risk of development of de novo depressive and anxiety disorders.

The association between urban or rural locality and hip fracture in community-based adults : a systematic review

Urban or rural locality has been suggested to influence musculoskeletal health, with lower bone mineral density (BMD) and greater prevalence of fracture identified in urban residents. A computer-aided search of Medline, EMBASE, CINAHL and PsychINFO, January 1966 to November 2007 was conducted to identify studies investigating the relationship between urban or rural locality and the occurrence of hip fracture. The methodological quality of studies was assessed, and a best-evidence synthesis was used to summarise the results. Fourteen cohort studies and one case-control study were identified for inclusion in this review, indicating a lack of literature in the field. Best-evidence analysis identified moderate evidence for residents of rural regions to have lower risk of hip fracture compared to urban residents. Examining principal mechanisms for the observed relationship between urban/rural locality and hip fracture, such as factors at the person or area level, may help to identify modifiable risk factors and inform appropriate prevention strategies.

Application of epidemiology to change health policy : defining age-related thresholds of bone mineral density for primary prevention of fracture

In Australia, benefits for antifracture therapies have been available for patients with osteoporosis and a prior fracture. No benefits were available to those with no prior fracture. We aimed to define, in women with no prior fracture, age-related thresholds of bone mineral density (BMD) associated with fracture risk equivalent to that of women with prior fracture and osteoporosis. A case-control study of women (≥50 yr) was conducted, including 291 fracture cases and 823 controls. BMD was measured at the proximal femur and posterior anterior (PA) spine. A fracture risk score (FRS) for the group with no prior fracture was calculated with discriminant analysis. The thresholds for equivalent fracture risk between those with no prior fracture and those with prior fracture were assessed using logistic regression. Increasing the FRS to +0.98 in women with no prior fracture resulted in equivalent odds of sustaining a fracture to those with prior fracture and osteoporosis. The corresponding T-score thresholds at the spine were −4.6 at 50 yr, −3.9 at 60 yr, −3.1 at 70 yr, and −2.4 at 80 yr. The femoral neck T-score thresholds were lower by 0.5 standard deviation. The high-risk individuals defined by this study should be considered for primary fracture prevention therapy.

Risk factors for Mycobacterium ulcerans infection, southeastern Australia

Buruli/Bairnsdale ulcer (BU) is a severe skin and soft tissue disease caused by Mycobacterium ulcerans. To better understand how BU is acquired, we conducted a case-control study during a sustained outbreak in temperate southeastern Australia. We recruited 49 adult patients with BU and 609 control participants from a newly recognized BU-endemic area in southeastern Australia. Participants were asked about their lifestyle and insect exposure. Odds ratios were calculated by using logistic regression and were adjusted for age and location of residence. Odds of having BU were at least halved for those who frequently used insect repellent, wore long trousers outdoors, and immediately washed minor skin wounds; odds were at least doubled for those who received mosquito bites on the lower legs or lower arms. This study provides new circumstantial evidence that implicates mosquitoes in the transmission of M. ulcerans in southeastern Australia.

Acute rheumatic fever associated with household crowding in a developed country

Background: Acute rheumatic fever (ARF) and its sequelae, chronic rheumatic heart disease, remain important causes of morbidity and mortality worldwide, but there is little recent information about risk factors. The aim of this study was to examine the association between ARF and household crowding in New Zealand between 1996 and 2005.

Methods: This ecologic study used hospitalization data and census data to calculate incidence rates by census area unit (CAU). Rates of ARF were examined in relation to individual factors (age, ethnicity) and area factors based on the CAU of home address (household crowding, New Zealand deprivation index, household income, and proportion of children aged 5–14 years). The multivariate relationship between ARF incidence and CAU-based variables was assessed using a zero-inflated negative binomial model.

Results: This study included 1249 new cases of ARF between 1996 and 2005. At the univariate level, ARF rates were associated with household crowding across all age groups and ethnicities. ARF rates were significantly and positively related to household crowding after controlling for age, ethnicity, household income, and the density of children in the neighborhood. The incidence rate ratio was 1.065 (95% confidence interval, 1.052–1.079) for the total population.

Conclusions: In New Zealand, ARF rates are associated with household crowding at the CAU level. This finding supports action to reduce household crowding to improve health and reduce health inequalities. Our conclusion could be further investigated using a case-control study.

Targeting the mitochondrial electron transport chain in autism, a systematic review and synthesis of a novel therapeutic approach

Autism is a complex developmental disorder with an unknown etiology and without any curative treatment. The mitochondrial electron transfer chains play a major role in the production of ATP, and the generation and management of reactive oxidative stress (ROS). This paper is a systematic review of the role of the mitochondrial electron transport chain in autism, and a consequent hypothesis for treating autism is synthesized.

An electronic search with pre-specified inclusion criteria was conducted in order to retrieve all the published articles about the mitochondrial electron transport chain in autism. The two databases of PUBMED and Google Scholar were searched.

Statin and aspirin use and the risk of mood disorders among men

Background: There is a growing understanding that depression is associated with systemic inflammation. Statins and aspirin have anti-inflammatory properties. Given these agents have been shown to reduce the risk of a number of diseases characterized by inflammation, we aimed to determine whether a similar relationship exists for mood disorders (MD).

Methods: This study examined data collected from 961 men (24–98 years) participating in the Geelong Osteoporosis Study. MD were identified using a semistructured clinical interview (SCID-I/NP). Anthropometry was measured and information on medication use and lifestyle factors was obtained via questionnaire. Two study designs were utilized: a nested case-control and a retrospective cohort study.

Results: In the nested case-control study, exposure to statin and aspirin was documented for 9 of 142 (6.3%) cases and 234 of 795 (29.4%) controls (P < .001); after adjustment for age, exposure to these anti-inflammatory agents was associated with reduced likelihood of MD (OR 0.2, 95%CI 0.1–0.5). No effect modifiers or other confounders were identified. In the retrospective cohort study of 836 men, among the 210 exposed to statins or aspirin, 6 (2.9%) developed de novo MD during 1000 person-years of observation, whereas among 626 nonexposed, 34 (5.4%) developed de novo MD during 3071 person-years of observation. The hazard ratio for de novo MD associated with exposure to anti-inflammatory agents was 0.55 (95%CI 0.23–1.32).

Conclusions: This study provides both cross-sectional and longitudinal evidence consistent with the hypothesis that statin and aspirin use is associated with a reduced risk of MD.

Fatores de risco para óbito precoce em crianças e em adolescentes submetidos a tranplante hepático eletivo no Hospital de Clínicas de Porto Alegre

No próximo ano, completam-se 40 anos desde a primeira tentativa de transplante hepático (TxH) em seres humanos. Há quase 20 anos, o transplante (Tx) tornou-se uma opção terapêutica real para os pacientes portadores de doença hepática terminal. Atualmente, o TxH é o tratamento de escolha para diversas enfermidades hepáticas, agudas ou crônicas. Dos transplantes realizados na Europa ou nos EUA, em torno de 12% dos pacientes são crianças e adolescentes. No Brasil, 20,9% dos pacientes transplantados de fígado em 2001 tinham até 18 anos de idade e, destes, 60,7% tinham 5 anos ou menos. O objetivo do TxH é a manutenção da vida dos pacientes com doença hepática irreversível, e a principal forma de avaliação de sucesso é a sobrevida após o Tx. A primeira semana que se segue ao TxH, apesar dos excelentes progressos dos últimos anos, continua sendo o período mais crítico. A maioria dos óbitos ou das perdas do enxerto ocorrem nas primeiras semanas, em particular, nos primeiros 7 dias de TxH. Diversos fatores de risco para o resultado do TxH podem ser identificados na literatura, porém há poucos estudos específicos do Tx pediátrico. As crianças pequenas apresentam características particulares que os diferenciam do Tx nos adultos e nas crianças maiores. Com o objetivo de identificar fatores de risco para o óbito nos 7 primeiros dias após os transplantes hepáticos eletivos realizados em 45 crianças e adolescentes no Hospital de Clínicas de Porto Alegre entre março de 1995 e agosto de 2001, foi realizado um estudo de caso-controle. Entre os 6 casos (13,3%) e os 39 controles foram comparadas características relacionadas ao receptor, ao doador e ao procedimento cirúrgico e modelos prognósticos. Das variáveis relacionadas ao receptor, o gênero, o escore Z do peso e da estatura para a idade, a atresia de vias biliares, a cirurgia abdominal prévia, a cirurgia de Kasai, a história de ascite, de peritonite bacteriana espontânea, de hemorragia digestiva e de síndrome hepatopulmonar, a albuminemia, o INR, o tempo de tromboplastina parcial ativada e o fator V não foram associados com o óbito na primeira semana. A mortalidade inicial foi maior nas crianças com menor idade (p=0,0035), peso (p=0,0062) e estatura (p<0,0001), bilirrubinemia total (BT) (p=0,0083) e bilirrubinemia não conjugada (BNC) (p=0,0024) elevadas, e colesterolemia reduzida (p=0,0385). Os receptores menores de 3 anos tiveram um risco 25,5 vezes maior de óbito que as crianças maiores (IC 95%: 1,3–487,7). A chance de óbito após o Tx dos pacientes com BT superior a 20 mg/dL e BNC maior que 6 mg/dL foi 7,8 (IC95%: 1,2–50,1) e 12,7 (IC95%: 1,3–121,7) vezes maior que daqueles com níveis inferiores, respectivamente. Das características relacionadas ao doador e ao Tx, as variáveis gênero, doador de gênero e grupo sangüíneo ABO não idênticos ao do receptor, razão peso do doador/receptor, causa do óbito do doador, enxerto reduzido, tempo em lista de espera e experiência do Programa não foram associados com o óbito nos primeiros 7 dias. Transplantes com enxertos de doadores de idade até 3 anos, ou de peso até 12 Kg representaram risco para o óbito dos receptores 6,8 (IC95%: 1,1–43,5) e 19,3 (IC95%: 1,3–281,6) vezes maior, respectivamente. O tempo de isquemia total foi em média de 2 horas maior nos transplantes dos receptores não sobreviventes (p=0,0316). Os modelos prognósticos Child-Pugh, Rodeck e UNOS não foram preditivos do óbito. Os pacientes classificados como alto risco no modelo de Malatack apresentaram razão de chances para o óbito 18,0 (IC95%: 1,2–262,7) vezes maior que aqueles com baixo risco. A mortalidade na primeira semana foi associada a valores elevados do escore PELD. O risco de óbito foi de 11,3 (IC95%: 1,2–107,0) nas crianças com valor do PELD maior que 10. As crianças pequenas e com maior disfunção hepática apresentaram maior risco de óbito precoce. Doador de pequeno porte e prolongamento do tempo de isquemia também foram associados à mortalidade. Somente os modelos de Malatack e PELD foram preditivos da sobrevida.

Acidentes de trânsito fatais e sua associação com indicadores sociais e adolescência

Introdução - Os acidentes de trânsito são um grave problema de saúde pública universal, em países desenvolvidos e subdesenvolvidos, estando entre as primeiras causas de morte em quase todos os países do mundo (DEL CIAMPO & RICCO, 1996). No Brasil, assu-mem grande relevância, especialmente pela alta morbidade e mortalidade, predominância em populações jovens e/ou economicamente ativas, maior perda de anos de vida produtiva e ele-vado custo direto e indireto para a sociedade. Objetivo - Os objetivos deste trabalho foram descrever a magnitude da mortali-dade por acidentes de trânsito, avaliar sua correlação com indicadores sociais e proporção de jovens na população e testar a sua associação com adolescência, sexo masculino e consumo de álcool. Material e Métodos - Foi realizado, inicialmente, um estudo ecológico envolven-do todas as capitais das unidades da federação e Distrito Federal (exceto o município do Rio de Janeiro), com coleta de dados sobre acidentes de trânsito com vítimas no Departamento Nacional de Trânsito. Foram descritos os índices de acidentes de trânsito com vítimas p/ 1.000 veículos (IAT-V) e de feridos p/ 1.000 veículos (IF-V) referentes aos anos de 1995, 1997 e 1998 e o índice de mortos p/ 10.000 veículos (IM-V) referente ao período de 1995 a 1998. Em seguida, avaliou-se a existência de correlação entre o IM-V e taxa de mortalidade infantil (TMI), índice municipal de desenvolvimento humano (IDH-M), índice de condições de vida (ICV), proporção de condutores adolescentes envolvidos em acidentes de trânsito com vítimas (PCJ-ATV) e proporção de residentes jovens (PRJ) nas diferentes capitais. Em um segundo momento, realizou-se um estudo de caso controle, onde foram estudados 863 condu-tores envolvidos em acidentes de trânsito com vítimas atendidos no Departamento Médico Legal de Porto Alegre, no período de 1998 a 1999. Os condutores foram divididos em dois grupos: condutores envolvidos em acidentes de trânsito com vítima fatal (casos) e com vítima não fatal (controles). Os grupos foram comparados com relação a adolescência, sexo mascu-lino e consumo de álcool, através da razão de chances e seu intervalo de confiança, com signi-ficância determinada pelo teste de qui-quadrado. Resultados - No estudo ecológico, observou-se, no Brasil, uma tendência decres-cente quanto aos indicadores de eventos relacionados ao trânsito no período de 1995 a 1998. Nas capitais das unidades da federação e Distrito Federal, apesar da ampla variação apresenta-da, a maioria manteve a mesma tendência decrescente observada para o país como um todo. Na análise das correlações entre o IM-V e os indicadores sociais, observou-se forte correlação positiva com a TMI (r = 0,57; P = 0,002), ou seja, quanto maior a TMI, maior a mortalidade no trânsito, além de correlação negativa com o IDH-M (r = - 0,41; P = 0,038) e com o ICV (r = - 0,58; P = 0,02). Quando se avaliaram o IDH-M e o ICV separados em suas dimensões, a dimensão renda de ambos indicadores foi a única que não demonstrou correlação com o IM- -V. As demais dimensões do IDH-M e ICV demonstraram correlação negativa, sendo que a dimensão infância (r = - 0,62; P = 0,001) apresentou a maior correlação. A análise da asso-ciação entre o IM-V e a PCJ-ATV não demonstrou correlação, mas, quando avaliada a asso-ciação com a PRJ nas capitais, houve forte correlação positiva (r = 0,59; P = 0,002). No estudo de caso controle, quando avaliada a relação entre condutores envolvidos em acidentes com vítima fatal e adolescência, sexo masculino e consumo de álcool, não foi observada asso-ciação importante em nenhum dos fatores em estudo. Conclusões - Apesar de os indicadores de eventos relacionados ao trânsito (IAT- -V, IF-V e IM-V) terem apresentado uma tendência decrescente durante o período de estudo, acidentes de trânsito continuam sendo um grave problema de saúde pública. O estudo ecológico evidenciou a existência de relação entre o IM-V e os indicadores sociais (TMI, IDH-M e ICV), sendo que a dimensão renda não demonstrou correlação e a dimensão infância apresen-tou a correlação negativa de maior valor. Quanto à PCJ-ATV, não foi encontrada associação relevante entre este indicador e o IM-V. Entretanto, observou-se forte associação entre a PRJ e o IM-V. O estudo de caso controle não evidenciou associação entre adolescência e os de-mais fatores estudados e maior risco para acidente de trânsito fatal.