The socio-religious beliefs and nature of the contemporary Vampire Subculture

The contemporary Vampire Subculture can be defined as a multi-faceted, socio-religious movement with its own distinct collective community and network of participants who share a similar belief system and customary lifestyle that reflect their concept of the vampire. The Vampire Subculture consists of individuals who profess to be 'real vampires', vampire communities of like-minded persons, 'blood-donors' who willingly allow vampires to partake of them, occult-based and mystical-orientated groups that appeal to their spirituality, the blood fetishists, and the live-action vampire role-players. In response, a Christian counter-movement of self-proclaimed 'vampire-slayers' has emerged that actively opposes the vampire subculture and its beliefs and practices. The socio-religious nature of the Vampire Subculture can be best described as a Segmented, Polycentric and Integrated Network of participants.

Pseudo-randomness of round-off errors in discretized linear maps on the plane

We analyze the sequences of round-off errors of the orbits of a discretized planar rotation, from a probabilistic angle. It was shown [Bosio & Vivaldi, 2000] that for a dense set of parameters, the discretized map can be embedded into an expanding p-adic dynamical system, which serves as a source of deterministic randomness. For each parameter value, these systems can generate infinitely many distinct pseudo-random sequences over a finite alphabet, whose average period is conjectured to grow exponentially with the bit-length of the initial condition (the seed). We study some properties of these symbolic sequences, deriving a central limit theorem for the deviations between round-off and exact orbits, and obtain bounds concerning repetitions of words. We also explore some asymptotic problems computationally, verifying, among other things, that the occurrence of words of a given length is consistent with that of an abstract Bernoulli sequence.

Envelhecimento ativo, capacidade funcional e atividade física: análise de fatores que contextualizam o processo de envelhecimento e sua percepção por parte de pessoas idosas

RESUMO: O envelhecimento populacional saudável ocupa parte da agenda do processo do envelhecimento humano, retratando uma preocupação social com repercussões nas economias societárias. O processo de envelhecimento, quando abordado fora do paradigma do envelhecimento saudável, desconsidera socialmente o potencial humano das pessoas idosas, promovendo a segregação e motivando atitudes de preconceito e discriminação, além de desperdiçar a experiência, o saber, a cultura e a capacidade de participação da pessoa idosa como contributo para a sociedade a que ela está inserida. O foco central da Política Nacional de Saúde do Idoso brasileira se inscreve na promoção de um envelhecimento saudável, nomeadamente por meio da manutenção da capacidade funcional ao valorizar a autonomia, a independência física e a integridade mental da pessoa idosa. O desafio para a viabilização do processo de envelhecimento ativo e bem-sucedido consiste na maximização das capacidades, potencialidades e recursos pessoais, comunitários e políticos. Pressupõe, também, uma concepção ampliada de viver, contextualizada no contínuo da vida, capaz de externar a preocupação com a saúde e o bem-estar, integrando as pessoas em fase de envelhecimento no contexto do ciclo de vida. Diante do exposto, a presente investigação objetivou conhecer os determinantes de envelhecimento ativo e bem-sucedido, numa população em processo de envelhecimento e relacioná-los com as ―práticas/conteúdos‖ e representações / significados‖ sobre o envelhecimento, as atividades físicas e a capacidade funcional. A investigação foi estruturada em três estudos: no primeiro foi criado e testado o instrumento ―Envelhecimento ativo, capacidade funcional e atividade física‖, na cidade de Lisboa, Portugal, e posteriormente realizada sua adaptação cultural e linguística do português de Portugal para o do Brasil. No segundo foi feita uma pesquisa observacional do tipo survey, descritiva e exploratória com o objetivo de conhecer as relações esteabelecidas entre o envelhecimento bem-sucedido, ativo, a atividade física e a capacidade funcional de uma população em processo de envelhecimento; e no terceiro momento foi realizado um estudo de cariz qualitativo com o objetivo de captar as percepções e comportamentos dos entrevistados diante do fato de se sentirem ou não pessoas idosas ou envelhecidas. Foram adotados os seguintes referenciais teóricos: envelhecimento ativo, envelhecimento bem sucedido, concepção muldidimensional do processual do envelhecimento (determinantes pessoais, familiares, sociais, psicocomunicacionais, econômicos e de saúde), atividade física e capacidade funcional e abordados à luz do perfil demográfico e da experiência das realidades européias, americana e brasileira. Foram triagulados métodos e técnicas (entrevista individual gravada, mensurações e questionário). Participaram pessoas com 60 anos de idade ou mais vinculadas que frequentam dois programas públicos destinados às pessoas idosas na cidade de Juiz de Fora, Minas Gerais, Brasil e foram excluidas as participações de pessoas com dependência para atividades da vida diária, para as atividades instrumentais da vida diária e com alteração do nível de consciência. Amostra aleatória estratificada composta por 326 participantes na qual foram realizadas mensurações e amostra por tipicidade construída a partir da base amostral composta de 87 participantes na qual foi realizada entrevista individual gravada. Atendidos todos os requisitos éticos e legais de pesquisa envolvendo seres humanos, segundo legislação brasileira. Aplicada Análise Fatorial e selecionados 11 fatores com 31 variáveis que contemplaram os determinantes do processo de envelhecimento ativo. Realizado reajustamento da análise fatorial,por questão de coerência conceptual, sendo selecionado oito fatores nomeados de acordo com o referencial teórico adotado que resultou em 25 variáveis que abordaram a participação em atividades e acesso aos serviços de saúde; à atividade física; à convivência, interação e avaliação do contato social; à escolaridade e renda; à saúde percebida e ao voluntariado. Utilizado como marcador para a atividade aeróbia o perfil da sobrecarga da atividade física semanal em consonância com diretrizes e recomendações de atividades aeróbias de intensidade moderada para as pessoas idosas. Identificado que 60,7% dos entrevistados realizam atividade física insuficiente. Os indicadores antropométricos utilizados evidenciaram índices de sobrepeso e de obesidade tanto entre os homens quanto entre as mulheres. Houve correlação do índice de massa corporal (IMC) com as medidas efetuadas segundo as faixas etárias. A análise inferencial possibilitou relacionar os determinantes do envelhecimento ativo, as medidas antropométricas e as variáveis sociodemográficas (escolaridade e idade), sendo obtidos os seguintes destaques: 1) à medida em que a idade aumenta, diminuem os níveis de prática da atividade física, dos contatos com as pessoas para conversar (das relações de convivência), dos trabalhos de voluntariado e das relações familiares e intergeracionais; 2) foi identificado um alinhamento conceptual dos diferentes determinantes concorrentes para um envelhecimento ativo à luz da prática da atividade física com a convivência e interação com os familiares e com auto-avaliação positiva da saúde percebida e atividade física; 3) quanto maior a idade menor os anos de escolaridade; 4) a diminuição da área transversa do braço e do IMC à medida que a idade aumenta, retratou diminuição da adiposidade corporal que está associada à perda da massa magra. A categorização do discurso dos 87 entrevistados permitiu captar a percepção do processo de envelhecimento por dois critérios antagônicos: preservação da autonomia e presença da deterioração. Foi caracterizado o sistema de crenças dos participantes com 1090 emissões de crenças. Houve tendência do sistema de crenças à centralidade com 638 (58,6%) crenças retratando concepções e situações difíceis de serem modificadas por processos educacionais. Os resultados obtidos diagnosticaram e reiteraram a tendência de incremento numérico de pessoas com 60 anos de idade ou mais na cidade brasileira de Juiz de Fora. Embora o estatuto do idoso esteja alicerçado em princípios do envelhecimento saudável e ativo ficou evidenciado a necessidade de estratégias para implementá-la com vistas a impactos sociais, econômicas e de saúde na perspectiva da prática de atividade física e da preservação da capacidade funcional. Constituem contribuição da presente investigação: 1) fundamentos teóricos e informação sobre juiz-foranos com 60 anos de idade ou mais segundo dimensões social, econômica, cultural e espiritual numa concepção ampliada de saúde; 2) abordagem do envelhecimento de forma processual e integrada, multidimensional e articulada com o ciclo da vida; 3) diagnóstico do grau de autonomia dos participantes permitindo subsidiar decisões para melhorar a capacidade funcional dos mesmos; 4) processo investigativo utilizando modelos teóricos que permitiram estabelecer um diagnóstico local e contextualizar o processo de envelhecimento para os participantes e 5) sobrecarga semanal de atividade física e os indicadores antropométricos dos participantes a ponto de subsidiar parâmetros de indicação terapêutica para manutenção da capacidade funcional.-------- ABSTRACT: The populational healthy aging holds part of the process of the human aging agenda, portraying a social concern with the repercussion in societary economies. The aging process when addressed out of the healthy aging paradigm socially disregard the human potential of the elderly, promoting segregation and motivating acts of prejudice and discrimination, in addition to the waste of experience, knowledge, culture and the participatory capacity of an older person in contributting to the society they are a part of. The Brazilian National Health Policy for the Elderly has its main focus in promoting the healthy aging, namely through the maintenance of the functional capacity by valuing the autonomy, physical independence and the mental integrity of the elderly person. The challenge of enabling the process of a successful and active aging lays in maximazing the capabilities, potencialities and personal, communitary and political resources. It infers additionaly a broad view of living, contextualized in the continuum of life, able to express concern with health and well-being, integrating the people in aging phase to the context of the life cycle. Hence, this research aimed to learn the determinants of active and successful aging in a population in aging process and relate them with the "practices/contents" and "representations/meanings" about aging, the physical activities and functional capacity. The investigation was structured in three studies: in the first it was developed and tested the instrument "Active Aging, Functional Capacity and Physical Activity" in the city of Lisboa, Portugal, and afterwards it was culturally and linguistically adapted from Portugal Portuguese to Brazilian Portuguese. The second study was an observational research with survey, descriptive and exploratory methods which aimed to learn the relations established between the successful aging, active aging, the physical activity and the functional capacity of a population in aging process; and the third comprised a qualitative study with the objective to collect the understanding and behavior of the interviewees based on the fact of either they saw themselves as elder or aged person or not. As theoretical framework were explored: active aging, successful aging, multidimensional concept of aging process (personal, familial, social, psycho-communicational, economic determinants), physical activity and functional capacity and explored based in demographic profile and in the European, American a Brazilian realities. Performed triangulation of methods and tecniques (recorded individual interviews, measurements and questionnaires). Participants were aged 60 or older included in two public services for the elderly population in the city of Juiz de Fora, Minas Gerais, Brazil and were excluded persons with dependency in both daily activities and instrumental daily activities and the persons with altered level of conciousness. Stratified ramdon sample of 326 participants in which were performed the measurements and typicality sample constructed from the sample basis of 87 participants whereupon the recorded individual interview was performed. Conforming to all the ethical and legal requirements of research with human beings according to the Brazilian legislation. Applied Factor Analysis and selected 11 factors and 31 variables that convey the determinants of the active aging process. Executed reajustment of factor analysis, for conceptual coherence, being selected eight factors named accordingly to the theoretical framework that resulted in 25 variables which approached the participation in activities and access to health care services; to physical activity; to coexistence, interaction and evaluation of social contact; to scholarity and income; to perceived health and volunteering. Used as marker to aerobic activity the profile of weekly physical activity overload in accordance with guidelines and reccomendations for moderate-intensity aerobic activities for older people. Identified that 60,7% of interviewees practice enough physical activity. Anthropometric markers evidence overweight and obesity levels both within men and women. There was correlation between body mass index (BMI) and measures carried out according to age ranges. The inferential analysis allowed relating the active aging determinants, the anthropometric measurements and sociodemographic variables (scholarity and age), obtaining the following highlights: 1) to the extent that age increases, lowers the levels of physical activity practice, of contact with people to talk to (social relationships), of volunteering work and familial and intergenerational relationships; 2) it was identified a conceptual alignment of diferent determinants concurrent to an active aging in light of the physical activity practice with the relationship and interaction of family and with positive self-assessment of perceived health and physical activity; 3) the older the person, lower are scholarity levels; 4) the decrease of the cross-sectional area of the arm and BMI as the age increases portrayed decreased adiposity of the body that is associated with loss of lean body mass. The categorization of the speech of 87 interviewees allowed to collect the understanding of the aging process by two opposite criteria: preservation of autonomy and existance of decline. It marked the belief system of participants with 1090 beliefs expressed. With tendency of the belief system to centrality with 638(58,6%) beliefs showing concepts and dificult situations to be changed through educational processes. The results diagnosed and reiterated the tendency of increase in the number of people aged 60 or older in the Brazilian city of Juiz de Fora. Although the elderly statute is built upon principles of healthy and active aging it was evident the need of strategies to implement it aiming at social, economic and health impacts in the perspective of physical education and preservation of the functional capacity. Constitute contributions of this study: 1) theoretical fundaments and data about Juiz de Fora citizens aged 60 or more according to social, economic, cultural and spiritual dimensions in a broad concept of health; 2) approach of aging in a procedural and integrative, multidimensional manner, articulated with the life cycle; 3) diagnosis of degree of autonomy of participants enabling decisions on how to improve their functional capacities; 4) investigative process using theoretical models which permit to stablish a local diagnosis and contextualize the aging process of participants and 5) weekly overload of physical activity and anthropometric indexes of participants as to subsidize parameters to therapeutic indication to the maintainence of functional capacity.

Pharmacokinetic drug interaction potential of risperidone with cytochrome p450 isozymes as assessed by the dextromethorphan, the caffeine, and the mephenytoin test.

Two published case reports showed that addition of risperidone (1 and 2 mg/d) to a clozapine treatment resulted in a strong increase of clozapine plasma levels. As clozapine is metabolized by cytochrome P450 isozymes, a study was initiated to assess the in vivo interaction potential of risperidone on various cytochrome P450 isozymes. Eight patients were phenotyped with dextromethorphan (CYP2D6), mephenytoin (CYP2C19), and caffeine (CYP1A2) before and after the introduction of risperidone. Before risperidone, all eight patients were phenotyped as being extensive metabolizers of CYP2D6 and CYP2C19. Risperidone at dosages between 2 and 6 mg/d does not appear to significantly inhibit CYP1A2 and CYP2C19 in vivo (median plasma paraxanthine/caffeine ratios before and after risperidone: 0.65, 0.69; p = 0.89; median urinary (S)/(R) mephenytoin ratios before and after risperidone:0.11, 0.12; p = 0.75). Although dextromethorphan metabolic ratio is significantly increased by risperidone (median urinary dextromethorphan/dextrorphan ratios before and after risperidone: 0.010, 0.018; p = 0.042), risperidone can be considered a weak in vivo CYP2D6 inhibitor, as this increase is modest and none of the eight patients was changed from an extensive to a poor metabolizer. The reported increase of clozapine concentrations by risperidone can therefore not be explained by an inhibition of CYP1A2, CYP2D6, CYP2C19 or by any combination of the three.

CYP3A activity measured by the midazolam test is not related to 3435 C >T polymorphism in the multiple drug resistance transporter gene.

A recent study with 69 Japanese liver transplants treated with tacrolimus found that the MDR13435 C >T polymorphism, but not the MDR12677 G >T polymorphism, was associated with differences in the intestinal expression level of CYP3A4 mRNA. In the present study, over 6 h, we measured the kinetics of a 75 microg oral dose of midazolam, a CYP3A substrate, in 21 healthy subjects genotyped for the MDR13435 C >T and 2677 G >T polymorphism. No statistically significant differences were found in the calculated pharmacokinetic parameters between the three 3435 C >T genotypes (TT, CT and CC group, respectively: Cmax (mean +/- SD: 0.30 +/- 0.08 ng/ml, 0.31 +/- 0.09 ng/ml and 0.31 +/- 0.11 ng/ml; Apparent clearance: 122 +/- 29 l/h, 156 +/- 92 l/h and 111 +/- 35 l/h; t1/2: 1.9 +/- 1.1 h, 1.6 +/- 0.90 h and 1.7 +/- 0.7 h). In addition, the 30-min 1'OH midazolam to midazolam ratio, a marker of CYP3A activity, determined in 74 HIV-positive patients before the introduction of antiretroviral treatment, was not significantly different between the three 3435 C >T genotypes (mean ratio +/- SD: 3.65 +/- 2.24, 4.22 +/- 3.49 and 4.24 +/- 2.03, in the TT, CT and CC groups, respectively). Similarly, no association was found between the MDR12677 G >T polymorphism and CYP3A activity in the healthy subjects or in the HIV-positive patients. The existence of a strong association between the activity of CYP3A and MDR13435 C >T and 2677 G >T polymorphisms appears unlikely, at least in Caucasian populations and/or in the absence of specific environmental factors.

Basic biochemical investigations as rationale for the design of original antimalarial drugs. An example of phospholipid metabolism

The future of antimalarial chemotherapy is particulary alarming in view of the spread of parasite cross-resistances to drugs that are not even structurally related. Only the availability of new pharmacological models will make it possible to select molecules with novel mechanisms of action, thus delaving resistance and allowing the development of new chemotherapeutic strategies. We reached this objective in mice. Our approach is hunged on fundamental and applied research begun in 1980 to investigate to phospholipid (PL) metabolism of intraerythrocytic Plasmodium. This metabolism is abundant, specific and indispensable for the production of Plasmodium membranes. Any drug to interfere with this metabolism blocks parasitic development. The most effective interference yet found involves blockage of the choline transporter, which supplies Plasmodium with choline for the synthesis of phosphatidylcholine, its major PL, this is a limiting step in the pathway. The drug sensitivity thereshold is much lower for the parasite, which is more dependent on this metabolism than host cells. The compounds show in vitro activity against P. falciparum at 1 to 10 nM. They show a very low toxicity against a lymphblastoid cell line, demonstrating a total abscence of correlation between growth inhibition of parasites and lymphoblastoid cells. They show antimalarial activity in vivo, in the P. berghei or P. chabaudi/mouse system, at doses 20-to 100-fold lower than their in acute toxicity limit. The bioavailability of a radiolabeled form of the product seemed to be advantageous (slow blood clearance and no significant concentration in tissues). Lastly, the compounds are inexpensive to produce. They are stable and water-soluble.

Response to antiretroviral treatment in HIV-1-infected individuals with allelic variants of the multidrug resistance transporter 1: a pharmacogenetics study.

BACKGROUND:HIV-1-infected patients vary considerably by their response to antiretroviral treatment, drug concentrations in plasma, toxic events, and rate of immune recovery. This variability could have a genetic basis. We did a pharmacogenetics study to analyse the association between response to antiretroviral treatment and allelic variants of several genes. METHODS:In 123 patients, we did PCR analyses of the gene for the multidrug-resistance transporter (MDR1), which codes for P-glycoprotein, of genes coding for isoenzymes of cytochrome P450, CYP3A4, CYP3A5, CYP2D6, and CYP2C19, and of the gene for the chemokine receptor CCR5. We measured concentrations in plasma of the antiretroviral agents efavirenz and nelfinavir by high-performance liquid-chromatography, and measured levels of P-glycoprotein expression, CD4-cell count, and HIV-1 viraemia. FINDINGS: Median drug concentrations in patients with the MDR1 3435 TT, CT, and CC genotypes were at the 30th, 50th, and 75th percentiles, respectively (p=0.0001). In patients with CYP2D6 extensive-metaboliser or poor-metaboliser alleles, median drug concentrations were at percentiles 45 and 62.5, respectively (p=0.04). Patients with the MDR1 TT genotype 6 months after starting treatment had a greater rise in CD4-cell count (257 cells/microL) than patients with the CT (165 cells/microL) and CC (121 cells/microL) genotype (p=0.0048), and the best recovery of naïve CD4-cells. INTERPRETATION:The polymorphism MDR1 3435 C/T predicts immune recovery after initiation of antiretroviral treatment. This finding suggests that P-glycoprotein has an important role in admittance of antiretroviral drugs to restricted compartments in vivo.

Effects of grapefruit juice on the pharmacokinetics of the enantiomers of methadone

BACKGROUND AND OBJECTIVES: Cytochrome P450 (CYP) 3A4 is the main CYP isozyme involved in methadone metabolism. We investigated the influence of grapefruit juice, which contains inhibitors of intestinal CYP3A, on the steady-state pharmacokinetics of methadone. METHODS: For 5 days, 8 patients undergoing methadone maintenance treatment received 200 mL water or grapefruit juice 30 minutes before and again together with their daily dose of methadone. Blood sampling for R-, S-, and R,S-methadone plasma determination was performed over a 24-hour period. CYP3A activity was determined by measuring the plasma 1'-hydroxymidazolam/midazolam ratio. RESULTS: A decrease in the midazolam ratio was measured in all patients after grapefruit juice (mean +/- SD before grapefruit juice, 9.3 +/- 5.9; mean +/- SD after grapefruit juice, 3.9 +/- 1.2; P <.05). Grapefruit juice led to a mean 17% increase in the area under the curve extrapolated to 24 hours for both enantiomers of methadone (range, 3% to 29% [P <.005]; range, -4% to 37% [P <.05]; and range, 1% to 32% [P <.01]; for R-, S-, and R,S-methadone, respectively). A similar increase in peak level and decrease in apparent clearance were measured with grapefruit juice, whereas time to peak level, terminal half-life, and apparent volume during the terminal phase of R-, S-, and R,S-methadone were not affected by grapefruit juice. No symptom of overmedication was either detected by the clinical staff or reported by the patients. CONCLUSIONS: Grapefruit juice administration is associated with a modest increase in methadone bioavailability, which is not expected to endanger patients. However, it cannot be excluded that a much stronger effect may occur in some patients, and thus grapefruit juice intake is not recommended during methadone maintenance treatment, in particular in patients initiating such a treatment.

Association of CYP3A5 genotypes with blood pressure and renal function in African families.

OBJECTIVE: Renal cytochrome P450 3A5 (CYP3A5) activity has been associated with blood pressure and salt sensitivity in humans. We determined whether CYP3A5 polymorphisms are associated with ambulatory blood pressure (ABP) and with glomerular filtration rate (GFR) in African families. METHODS: Using a cross-sectional design, 375 individuals from 72 families, each with at least two hypertensive siblings, were recruited through a hypertension register in the Seychelles (Indian Ocean). We analyzed the association between the CYP3A5 alleles (*1, *3, *6 and *7) and ABP, GFR and renal sodium handling (fractional excretion of lithium), from pedigree data, allowing for other covariates and familial correlations. RESULTS: CYP3A5*1 carriers increased their daytime systolic and diastolic ABP with age (0.55 and 0.23 mmHg/year) more than non-carriers (0.21 and 0.04 mmHg/year). CYP3A5*1 had a significant main effect on daytime systolic/diastolic ABP [regression coefficient (SE): -29.6 (10.0)/-8.2 (4.1) mmHg, P = 0.003/0.045, respectively] and this effect was modified by age (CYP3A5*1 x age interactions, P = 0.017/0.018). For night-time ABP, the effect of CYP3A5*1 was modified by urinary sodium excretion, not by age. For renal function, CYP3A5*1 carriers had a 7.6(3.8) ml/min lower GFR (P = 0.045) than non-carriers. Proximal sodium reabsorption decreased with age in non-carriers, but not in CYP3A5*1 carriers (P for interaction = 0.02). CONCLUSIONS: These data demonstrate that CYP3A5 polymorphisms are associated with ambulatory BP, CYP3A5*1 carriers showing a higher age- and sodium- related increase in ABP than non-carriers. The age effect may be due, in part, to the action of CYP3A5 on renal sodium handling.

Plasma levels of the enantiomers of thioridazine, thioridazine 2-sulfoxide, thioridazine 2-sulfone, and thioridazine 5-sulfoxide in poor and extensive metabolizers of dextromethorphan and mephenytoin.

Concentrations of total (R) + (S) and of the enantiomers (R) and (S) of thioridazine and metabolites were measured in 21 patients who were receiving 100 mg thioridazine for 14 days and who were comedicated with moclobemide (450 mg/day). Two patients were poor metabolizers of dextromethorphan and one was a poor metabolizer of mephenytoin. Cytochrome P450IID6 (CYP2D6) is involved in the formation of thioridazine 2-sulfoxide (2-SO) from thioridazine and also probably partially in the formation of thioridazine 5-sulfoxide (5-SO), but not in the formation of thioridazine 2-sulfone (2-SO2) from thioridazine 2-SO. Significant correlations between the mephenytoin enantiomeric ratio and concentrations of thioridazine and metabolites suggest that cytochrome P450IIC19 could contribute to the biotransformation of thioridazine into yet-unknown metabolites, other than thioridazine 2-SO, thioridazine 2-SO2, or thioridazine 5-SO. An enantioselectivity and a large interindividual variability in the metabolism of thioridazine have been shown: measured (R)/(S) ratios of thioridazine, thioridazine 2-SO fast eluting (FE), thioridazine 2-SO slow eluting (SE), thioridazine 2-SO (FE+SE), thioridazine 2-SO2, thioridazine 5-SO(FE), and thioridazine 5-SO(SE) were (mean +/- SD) 3.48 +/- 0 .93 (range, 2.30 to 5.80), 0.45 +/- 0.22 (range, 0.21 to 1.20), 2.27 +/- 8.1 (range, 6.1 to 40.1), 4.64 +/- 0.68 (range, 2.85 to 5.70), 3.26 +/- 0.58 (range, 2.30 to 4.30), 0.049 +/- 0.019 (range, (0.021 to 0.087), and 67.2 +/- 66.2 (range, 16.8 to 248), respectively. CYP2D6 is apparently involved in the formation of (S)-thioridazine 2-SO(FE), (R)-thioridazine 2-SO(SE), and also probably (S)-thioridazine 5-SO(FE) and (R)-thioridazine 5-SO(SE).

CYP3A5 and ABCB1 genes influence blood pressure and response to treatment, and their effect is modified by salt.

The permeability-glycoprotein efflux-transporter encoded by the multidrug resistance 1 (ABCB1) gene and the cytochromes P450 3A4/5 encoded by the CYP3A4/5 genes are known to interact in the transport and metabolism of many drugs. Recent data have shown that the CYP3A5 genotypes influence blood pressure and that permeability-glycoprotein activity might influence the activity of the renin-angiotensin system. Hence, these 2 genes may contribute to blood pressure regulation in humans. We analyzed the association of variants of the ABCB1 and CYP3A5 genes with ambulatory blood pressure, plasma renin activity, plasma aldosterone, endogenous lithium clearance, and blood pressure response to treatment in 72 families (373 individuals; 55% women; mean age: 46 years) of East African descent. The ABCB1 and CYP3A5 genes interact with urinary sodium excretion in their effect on ambulatory blood pressure (daytime systolic: P=0.05; nighttime systolic and diastolic: P<0.01), suggesting a gene-gene-environment interaction. The combined action of these genes is also associated with postproximal tubular sodium reabsorption, plasma renin activity, plasma aldosterone, and with an altered blood pressure response to the angiotensin-converting enzyme inhibitor lisinopril (P<0.05). This is the first reported association of the ABCB1 gene with blood pressure in humans and demonstration that genes encoding for proteins metabolizing and transporting drugs and endogenous substrates contribute to blood pressure regulation.

Effects of caffeine on energy metabolism, heart rate, and methylxanthine metabolism in lean and obese women.

The magnitude of coffee-induced thermogenesis and the influence of coffee ingestion on substrate oxidation were investigated in 10 lean and 10 obese women, over two 24-h periods in a respiratory chamber. On one occasion the subjects consumed caffeinated coffee and on the other occasion, decaffeinated coffee. The magnitude of thermogenesis was smaller in obese (4.9 +/- 2.0%) than in lean subjects (7.6 +/- 1.3%). The thermogeneic response to caffeine was prolonged during the night in lean women only. The coffee-induced stimulation of energy expenditure was mediated by a concomitant increase in lipid and carbohydrate oxidation. During the next day, in postabsorptive basal conditions, the thermogenic effect of coffee had vanished, but a significant increase in lipid oxidation was observed in both groups. The magnitude of this effect was, however, blunted in obese women (lipid oxidation increased by 29 and 10% in lean and obese women, respectively). Caffeine increased urinary epinephrine excretion. Whereas urinary caffeine excretion was similar in both groups, obese women excreted more theobromine, theophylline, and paraxanthine than lean women. Despite the high levels of urinary methylxanthine excretion, thermogenesis and lipid oxidation were less stimulated in obese than in lean subjects.

The Forum on Patronage and Pluralism in the Primary Sector - Report of the Forum's Advisory Group

The fact that 96 percent of primary schools in Ireland are under denominational patronage is unique among developed countries. The reasons for this are deeply rooted in history and in the belief system of the population. With the establishment of the National (Primary) School system in 1831 the State provided financial support to local patrons for primary school provision, on the condition that patrons observed the regulations of the newly established Commissioners of National Education. While the State favoured applications from patrons of mixed denominations, what evolved, in practice, was that the great majority of schools came under the patronage of individual clergymen of different denominations.

Species differences in the response of liver drug-metabolizing enzymes to (S)-4-O-tolylsulfanyl-2-(4-trifluormethyl-phenoxy)-butyric acid (EMD 392949) in vivo and in vitro.

Induction of drug-metabolizing enzymes (DMEs) is highly species-specific and can lead to drug-drug interaction and toxicities. In this series of studies we tested the species specificity of the antidiabetic drug development candidate and mixed peroxisome proliferator-activated receptor (PPAR) alpha/gamma agonist (S)-4-O-tolylsulfanyl-2-(4-trifluormethyl-phenoxy)-butyric acid (EMD 392949, EMD) with regard to the induction of gene expression and activities of DMEs, their regulators, and typical PPAR target genes. EMD clearly induced PPARalpha target genes in rats in vivo and in rat hepatocytes but lacked significant induction of DMEs, except for cytochrome P450 (P450) 4A. CYP2C and CYP3A were consistently induced in livers of EMD-treated monkeys. Interestingly, classic rodent peroxisomal proliferation markers were induced in monkeys after 17 weeks but not after a 4-week treatment, a fact also observed in human hepatocytes after 72 h but not 24 h of EMD treatment. In human hepatocyte cultures, EMD showed similar gene expression profiles and induction of P450 activities as in monkeys, indicating that the monkey is predictive for human P450 induction by EMD. In addition, EMD induced a similar gene expression pattern as the PPARalpha agonist fenofibrate in primary rat and human hepatocyte cultures. In conclusion, these data showed an excellent correlation of in vivo data on DME gene expression and activity levels with results generated in hepatocyte monolayer cultures, enabling a solid estimation of human P450 induction. This study also clearly highlighted major differences between primates and rodents in the regulation of major inducible P450s, with evidence of CYP3A and CYP2C inducibility by PPARalpha agonists in monkeys and humans.

The central role of mosquito cytochrome P450 CYP6Zs in insecticide detoxification revealed by functional expression and structural modelling.

The resistance of mosquitoes to chemical insecticides is threatening vector control programmes worldwide. Cytochrome P450 monooxygenases (CYPs) are known to play a major role in insecticide resistance, allowing resistant insects to metabolize insecticides at a higher rate. Among them, members of the mosquito CYP6Z subfamily, like Aedes aegypti CYP6Z8 and its Anopheles gambiae orthologue CYP6Z2, have been frequently associated with pyrethroid resistance. However, their role in the pyrethroid degradation pathway remains unclear. In the present study, we created a genetically modified yeast strain overexpressing Ae. aegypti cytochrome P450 reductase and CYP6Z8, thereby producing the first mosquito P450-CPR (NADPH-cytochrome P450-reductase) complex in a yeast recombinant system. The results of the present study show that: (i) CYP6Z8 metabolizes PBAlc (3-phenoxybenzoic alcohol) and PBAld (3-phenoxybenzaldehyde), common pyrethroid metabolites produced by carboxylesterases, producing PBA (3-phenoxybenzoic acid); (ii) CYP6Z8 transcription is induced by PBAlc, PBAld and PBA; (iii) An. gambiae CYP6Z2 metabolizes PBAlc and PBAld in the same way; (iv) PBA is the major metabolite produced in vivo and is excreted without further modification; and (v) in silico modelling of substrate-enzyme interactions supports a similar role of other mosquito CYP6Zs in pyrethroid degradation. By playing a pivotal role in the degradation of pyrethroid insecticides, mosquito CYP6Zs thus represent good targets for mosquito-resistance management strategies.