Effect of tamoxifen on the enzymatic activity of human cytochrome CYP2B6

Tamoxifen is primarily used in the treatment of breast cancer. It has been approved as a chemopreventive agent for individuals at high risk for this disease. Tamoxifen is metabolized to a number of different products by cytochrome P450 enzymes. The effect of tamoxifen on the enzymatic activity of bacterially expressed human cytochrome CYP2B6 in a reconstituted system has been investigated. The 7-ethoxy-4-(trifluoromethyl) coumarin O-deethylation activity of purified CYP2B6 was inactivated by tamoxifen in a time- and concentration-dependent manner. Enzymatic activity was lost only in samples that were incubated with both tamoxifen and NADPH. The inactivation was characterized by a K-l of 0.9 muM, a k(inact) of 0.02 min(-1), and a t(1/2) of 34 min. The loss in the 7-ethoxy-4-(trifluoromethyl) coumarin O-deethylation activity did not result in a similar percentage loss in the reduced carbon monoxide spectrum, suggesting that the heme moiety was not the major site of modification. The activity of CYP2B6 was not recovered after removal of free tamoxifen using spin column gel filtration. The loss in activity seemed to be due to a modification of the CYP2B6 and not reductase because adding fresh reductase back to the inactivated samples did not restore enzymatic activity. A reconstituted system containing purified CYP2B6, NADPH-reductase, and NADPH-generating system was found to catalyze tamoxifen metabolism to 4-OH-tamoxifen, 4'-OH-tamoxifen, and N-desmethyl-tamoxifen as analyzed by high-performance liquid chromatography analysis. Preliminary studies showed that tamoxifen had no effect on the activities of CYP1B1 and CYP3A4, whereas CYP2D6 and CYP2C9 exhibited a 25% loss in enzymatic activity.

NEW Solutions: An Australian health promotion programme for people with mental illness

The prevalence of people who are overweight or obese is continuing to rise. This is a key risk indicator of preventable morbidity and mortality resulting from many diseases. The increase in the number of obese people is associated with dietary practices and a reduction in physical activity. There is a need to implement strategies for the reduction of obesity in at-risk groups. People with a mental illness are at high risk of many physical illnesses related to behavioural factors, which include poor diet and lack of exercise. Health promotion programmes need to be incorporated into mental-health services to improve the general health and wellbeing of people with a mental illness. An Australian psychiatric rehabilitation service developed and implemented a health promotion programme, NEW Solutions, which aimed to address issues related to weight gain, dietary practice and physical inactivity.

Clinical and economic impact of exercise electrocardiography and exercise echocardiography in clinical practice

Background Patients with known or suspected coronary disease are often investigated to facilitate risk assessment. We sought to examine the cost-effectiveness of strategies based on exercise echocardiography and exercise electrocardiography. Methods and results We studied 7656 patients undergoing exercise testing; of whom half underwent exercise echocardiography. Risk was defined with the Duke treadmill score for those undergoing exercise electrocardiography alone, and by the extent of ischaemia by exercise echocardiography. Cox proportional hazards models, risk adjusted for pretest likelihood of coronary artery disease, were used to estimate time to cardiac death or myocardial infarction. Costs (including diagnostic and revascularisation procedures, hospitalisations, and events) were calculated, inflation-corrected to year 2000 using Medicare trust fund rates and discounted at a rate of 5%. A decision model was employed to assess the marginal cost effectiveness (cost/life year saved) of exercise echo compared with exercise electrocardiography. Exercise echocardiography identified more patients as low-risk (51% vs 24%, p<0.001), and fewer as intermediate- (27% vs 51%, p<0.001) and high-risk (22% vs 4%); survival was greater in low- and intermediate- risk and less in high-risk patients. Although initial procedural costs and revascularisation costs (in intermediate- high risk patients) were greater, exercise echocardiography was associated with a greater incremental life expectancy (0.2 years) and a lower use of additional diagnostic procedures when compared with exercise electrocardiography (especially in lower risk patients). Using decision analysis, exercise echocardiography (Euro 2615/life year saved) was more cost effective than exercise electrocardiography. Conclusion Exercise echocardiography may enhance cost-effectiveness for the detection and management of at risk patients with known or suspected coronary disease. (C) 2003 Published by Elsevier Science Ltd on behalf of The European Society of Cardiology.

Everyday incivility: towards a benchmark

Commonplace incivility is a topic of longstanding interest within social theory, perhaps best exemplified by Goffman's studies of the interaction order. Nevertheless we know very little about its distribution and expression in everyday life. Current empirical work is dominated by criminological agendas. These tend to focus on more serious and illegal activities rather than minor deviant acts that are simply inconsiderate or rude. The paper reports findings from a focus group study conducted in Melbourne, Australia that set out to benchmark everyday incivilities. The results suggest that perpetrators of incivility have a surprisingly broad social distribution as does the range of locales that might be characterised as 'high risk'. Turning to the work of Putnam and Wolfe, we call for a research focus on low-level incivilities as key symptoms of the state of civic virtue and the strength of moral ties within civil society. Drawing on Virilio, Bauman and Durkheim, it is suggested that the experience of incivility is underpinned by the growth of freedom and movement in contemporary urban settings, and has ambivalent implications that not only invoke boundary maintenance and retreatism, but also offer the possibility for boundary expansion and tolerance of difference.

Reforming the law of medical negligence: Solutions in search of a problem

The Commonwealth Government's Principles Based Review of the Law of Negligence recently recommended reforms aimed at limiting liability and damages arising from personal injury and death, in response to the growing perception that the current system of compensating personal injury had become financially unsustainable. Recent increases in medical liability and damages have eroded the confidence of doctors and their professional bodies, with fears of unprecedented desertion from and reduced recruitment into high risk areas, and one of the primary foci of the review concerned medical negligence. The article analyses proposals to redefine the principles necessary for the finding of negligence, against the terms of reference of the review. The article assumes that for the foreseeable future, Australia will persist with tort-based compensation for personal injury rather than developing a no-fault scheme. If the suggested changes to the fundamental principles of negligence are unlikely to reduce medical liability, greater attention might be given to the processes which come into play after the finding of negligence, where reform is more likely to benefit both plaintiffs and defendants.

Caracterização molecular de papilomavírus humano (HPV) e vírus adeno-associado (AAV) em lesões intraepiteliais de colo uterino: um estudo de seguimento

O câncer de colo uterino (CCU), cujo agente etiológico é o papilomavírus humano (HPV), é um dos tipos de câncer mais frequentes em mulheres em todo o mundo, não só em incidência como também em mortalidade. Alguns genótipos de HPV, denominados de alto risco (HR-HPV), e suas variantes gênicas, estão mais associados à indução de lesões malignas, sendo HPV16 e 18 os mais frequentes. Algumas infecções do trato genital podem atuar como cofatores da progressão carcinogênica do CCU, porém a infecção por vírus adeno-associado (AAV) parece estar inversamente relacionada, o que pode refletir em um papel protetor no desenvolvimento do CCU induzido pelo HPV. Portanto, este estudo objetivou investigar o papel da infecção mista AAV-HPV e das variantes oncogênicas de HPV na progressão das lesões intraepiteliais de colo de útero e acompanhar a eliminação / persistência viral em relação à progressão / regressão das lesões cervicouterinas. Exames citológicos foram realizados em amostras de espécime cervical, coletadas em dois momentos, de mulheres atendidas no Hospital Universitário Cassiano Antonio Moraes – HUCAM e seguiram para tratamento conforme preconizado. DNA foi extraído pelo kit comercial QIAamp® DNA Mini Kit, seguindo instruções do fabricante. DNA de AAV foi investigado por PCR e nPCR e, de HPV, por PCR e Captura Híbrida® (CH). Genotipagem de AAV e HPV foram realizadas por RFLP e RLB, respectivamente. Dos casos encaminhados ao ambulatório de colposcopia, 57,3% tiveram citologia normal, 23,1% lesões de baixo grau e 19,6% lesões de alto grau. Dos casos com citologia normal, 78% permaneceram normais, enquanto 22% progrediram à lesão; dos casos com lesão de baixo grau, 74% regrediram para citologia normal, enquanto 78,6% dos casos com lesão de alto grau apresentaram lesão de baixo grau ou citologia normal na segunda coleta. Foram positivas para HPV, 56% e 36,5% das amostras da primeira e segunda coletas, respectivamente. Foi observada boa correlação (kappa= 0,66) entre os testes de PCR e CH para detecção de HPV. Os HR-HPV foram detectados em mais de 90% das amostras de ambas as coletas, sendo os mais frequentes os HPV16, 58, 51, 52 e 53. Variante não-europeia esteve associada ao desenvolvimento de lesão cervical de alto grau, enquanto a presença de AAV foi inversamente relacionada à progressão da lesão cervical induzida por HPV.

Há alternativas ao aumento de impostos? Sim, há.

“Procuradoria aconselha levar swaps a tribunal”. Referindo-se com maior especificidade: “A Procuradoria-Geral da República manteve contactos informais com o Ministério das Finanças para avaliar a possibilidade de o Estado levar a tribunal os contratos de alto risco assinados por empresas públicas de transporte. E deu indicações ao Governo de que há condições para conseguir a anulação dos swaps, se o Estado optar pela via litigiosa – o que ainda não aconteceu. Para isso, o Executivo tem de dar essa indicação ao Ministério Público”. Abstract: "Attorney advises swaps take the court." Referring with greater specificity: "The Attorney General's Office had informal contacts with the Ministry of Finance to evaluate the possibility of the state to prosecute high-risk contracts signed by public transport companies. And has directed the Government that there are conditions to achieve the cancellation of swaps if the state chooses the remedy litigation - which has not happened yet. For this, the Executive must provide that information to the prosecutor. "

Heróis Nacionais dos Contratos-swap no Minho!

A Procuradoria-Geral da República manteve contactos informais com o Ministério das Finanças para avaliar a possibilidade de o Estado levar a tribunal os contratos de alto risco assinados por empresas públicas de transporte. E deu indicações ao Governo de que há condições para conseguir a anulação dos swaps, se o Estado optar pela via litigiosa – o que ainda não aconteceu. Para isso, o Executivo tem de dar essa indicação ao Ministério Público” § The Attorney General's Office had informal contacts with the Ministry of Finance to evaluate the possibility of the state to prosecute high-risk contracts signed by public transport companies. And the Government has indicated that there are conditions to achieve the cancellation of swaps, if the state chooses the remedy litigation - which has not happened yet. For this, the Executive must provide that information to the prosecutor ";

Increasing availability through maintainability growth using partial Multi Criteria Decision Making (pMCDM)

In the last decades considerations about equipments' availability became an important issue, as well as its dependence on components characteristics such as reliability and maintainability. This is particularly of outstanding importance if one is dealing with high risk industrial equipments, where these factors play an important and fundamental role in risk management when safety or huge economic values are in discussion. As availability is a function of reliability, maintainability, and maintenance support activities, the main goal is to improve one or more of these factors. This paper intends to show how maintainability can influence availability and present a methodology to select the most important attributes for maintainability using a partial Multi Criteria Decision Making (pMCDM). Improvements in maintainability can be analyzed assuming it as a probability related with a restore probability density function [g(t)].

A case-control study on the association of hepatitis B virus infection and hepatocellular carcinoma in Northeast Brazil

Hepatitis B virus (HBV) serological markers were investigated in 40 incident cases of hepatocellular carcinoma (HCC) and in two age and sex matched control groups, comprising 40 patients with other cancers and 80 healthy individuals, resident in Bahia, Brazil. Serologic tests were done by radioimmunoassay. The study observed high proportion of seropositivity to HBsAg (42.5%) and of those presenting HBsAg or antiHBc (65.0%) among HCC cases, higher in men than women and in those aged 17 to 30 years old. HBsAg seropositivity among HCC patients was greater than in the control group with other cancers (7.5%) and in healthy controls (2.5%), corresponding to odds ratio estimates of 15.0 (95% CI 3.29, 68.30) and 33.0 (95% CI 9.13, 119.28), both statistically significant. HBeAg was not observed and antiHBe was present in 41.2% of cases, suggesting the absence of viral replication, possibly with viral DNA intergration into the hepatocyte genome. The presence of cirrhosis was associated with HBsAg seropositivity among HCC cases. A history of chronic alcoholism is shown to be more frequently related to those cases with cirrhosis. This study highlights the relevant association between HCC and HBV in Northeast Brazil, particularly for young individuals, and the high risk of development of HCC for HBsAg carriers.

Avaliação do perfil hemodinâmico de válvulas aórticas percutâneas: análise comparativa entre os dois dispositivos disponíveis no mercado - válvula auto-expansível e válvula expansível por balão

Mestrado em Tecnologia de Diagnóstico e Intervenção Cardiovascular. Área de especialização: Intervenção Cardiovascular.

Intervenção coronária percutânea no enfarte agudo do miocárdio: influência no prognóstico dos doentes

Mestrado em Tecnologia de Diagnóstico e Intervenção Cardiovascular. Área de especialização: Intervenção Cardiovascular.

A eficácia e segurança da fisioterapia respiratória no tratamento da bronquiolite aguda em crianças até 2 anos de idade: revisão sistemática

Contexto: a bronquiolite aguda é a principal patologia a afectar a criança nos primeiros 2 anos de vida, a fisioterapia respiratória é uma intervenção terapêutica utilizada com a intenção de melhorar o curso desta doença mantendo-se a incerteza sobre a sua eficácia. Objectivo: determinar a eficácia e segurança da fisioterapia respiratória em crianças com menos de 2 anos com bronquiolite aguda. Fontes de Informação: Medline (1966 a Agosto 2010), EMBASE(1990 a Agosto 2010), Pedro e Lilacs (1982 a Agosto 2010). Outra fonte de informação incluiu a bibliografia dos estudos obtidos. Selecção de estudos: estudos experimentais comparando a fisioterapia respiratória com cuidados habituais, em crianças com menos de 2 anos e bronquiolite aguda, em ventilação espontânea, em qualquer contexto. Estudos pré-experimentais ou observacionais com os mesmos participantes e intervenções foram admitidos complementarmente aos experimentais. Extracção de dados e análise: um investigador extraiu os dados dos artigos obtidos e avaliou o risco de viés. A eficácia e segurança da fisioterapia respiratória foram determinadas pelos seguintes outcomes: duração do internamento hospitalar ou do evento, variação de scores de severidade clínica, saturação periférica e suplementação de oxigénio, recidivas, recurso a antibióticos e efeitos deletérios ou deterioração clínica reportada. Síntese de dados: 6 estudos experimentais foram admitidos. As suas amostras provinham de criança internadas em hospital. As técnicas de fisioterapia respiratória foram comparadas com cuidados habituais. Nenhum estudo evidenciou melhoria dos outcomes de interesse na comparação entre grupos, excepto avaliações de curta duração da saturação periférica de oxigénio e scores de severidade clínica. 1 estudo reportou uma percentagem significativamente maior no grupo submetido a fisioterapia respiratória de crianças que vomitaram, tiveram uma desestabilização respiratória transitória, e na percepção de stress da criança pelos cuidadores. São relatadas ainda fracturas costais a causa de fisioterapia respiratória. Limitações: o risco de viés era alto em 2 estudos, baixo num estudo e indeterminado nos restantes. Conclusões: aparentemente a fisioterapia respiratória não é eficaz e pode produzir efeitos deletérios importantes, mas a evidência é pobre, carecendo de novos estudos.

Alcohol drinking patterns by gender, ethnicity, and social class in Bahia, Brazil

OBJECTIVE: To study patterns of alcohol consumption and prevalence of high-risk drinking. METHODS: A household survey was carried out in a sample of 2,302 adults in Salvador, Brazil. Cases of High-Risk Drinking (HRD) were defined as those subjects who referred daily or weekly binge drinking plus episodes of drunkenness and those who reported any use of alcoholic beverages but with frequent drunkenness (at least once a week). RESULTS: Fifty-six per cent of the sample acknowledged drinking alcoholic beverages. Overall consumption was significantly related with gender (male), marital status (single), migration (non-migrant), better educated (college level), and social class (upper). No significant differences were found regarding ethnicity, except for cachaça (Brazilian sugarcane liquor) and other distilled beverages. Overall 12-month prevalence of high-risk drinking was 7%, six times more prevalent among males than females (almost 13% compared to 2.4%). A positive association of HRD prevalence with education and social class was found. No overall relationship was found between ethnicity and HRD. Male gender and higher socioeconomic status were associated with increased odds of HRD. Two-way stratified analyses yielded consistent gender effects throughout all strata of independent variables. CONCLUSIONS: The findings suggest that social and cultural elements determine local patterns of alcohol-drinking behavior. Additional research on long-term and differential effects of gender, ethnicity, and social class on alcohol use and misuse is needed in order to explain their role as sources of social health inequities.

Entomological aspects of Chagas' disease transmission in the domestic habitat, Argentina

OBJECTIVE: To study the risk of Trypanosoma cruzi domestic transmission using an entomological index and to explore its relationship with household's characteristics and cultural aspects. METHODS: There were studied 158 households in an endemic area in Argentina. Each household was classified according to an entomological risk indicator (number of risky bites/human). A questionnaire was administered to evaluate risk factors among householders. RESULTS: Infested households showed a wide range of risk values (0 to 5 risky bites/human) with skewed distribution, a high frequency of lower values and few very high risk households. Of all collected Triatoma infestans, 44% had had human blood meals whereas 27% had had dogs or chickens blood meals. Having dogs and birds sharing room with humans increased the risk values. Tidy clean households had contributed significantly to lower risk values as a result of low vector density. The infested households showed a 24.3% correlation between time after insecticide application and the number of vectors. But there was no correlation between the time after insecticide application and T. infestans' infectivity. The statistical analysis showed a high correlation between current values of the entomological risk indicator and Trypanosoma cruzi seroprevalence in children. CONCLUSIONS: The risk of T. cruzi domestic transmission assessed using an entomological index show a correlation with children seroprevalence for Chagas' disease and householders' habits.