The genetics of coronary heart disease: the contribution of twin studies

Despite the decline in coronary heart disease in many European countries, the disease remains an enormous public health problem. Although we know a great deal about environmental risk factors for coronary heart disease, a heritable component was recognized a long time ago. The earliest and best known examples of how our genetic constitution may determine cardiovascular risk relate to lipoprotein(a), familial hypercholesterolaemia and apolipoprotein E. In the past 20 years a fair number of polymorphisms assessed singly have shown strong associations with the disease but most are subject to poor repeatability. Twins constitute a compelling natural experiment to establish the genetic contribution to coronary heart disease and its risk factors. GenomEUtwin, a recently funded Framework 5 Programme of the European Community, affords the opportunity of comparing the heritability of risk factors in different European Twin Registries. As an illustration we present the heritabilities of systolic and diastolic blood pressure, based on data from over 4000 twin pairs from six different European countries and Australia. Heritabilities for systolic blood pressure are between 52 and 66% and for diastolic blood pressure between 44 and 66%. There is no evidence of sex differences in heritability estimates and very little to no evidence for a significant contribution of shared family environment. A non-twin based prospective case/cohort study of coronary heart disease and stroke (MORGAM) will allow hypotheses relating to cardiovascular disease, generated in the twin cohorts, to be tested prospectively in adult populations. Twin studies have also contributed to our understanding of the life course hypothesis, and GenomEUtwin has the potential to add to this.

Evidence for a QTL on chromosome 19 influencing LDL cholesterol levels in the general population

The genetic basis of cardiovascular disease (CVD) with its complex etiology is still largely elusive. Plasma levels of lipids and apolipoproteins are among the major quantitative risk factors for CVD and are well-established intermediate traits that may be more accessible to genetic dissection than clinical CVD end points. Chromosome 19 harbors multiple genes that have been suggested to play a role in lipid metabolism and previous studies indicated the presence of a quantitative trait locus (QTL) for cholesterol levels in genetic isolates. To establish the relevance of genetic variation at chromosome 19 for plasma levels of lipids and apolipoproteins in the general, out-bred Caucasian population, we performed a linkage study in four independent samples, including adolescent Dutch twins and adult Dutch, Swedish and Australian twins totaling 493 dizygotic twin pairs. The average spacing of short-tandem-repeat markers was 6 - 8 cM. In the three adult twin samples, we found consistent evidence for linkage of chromosome 19 with LDL cholesterol levels ( maximum LOD scores of 4.5, 1.7 and 2.1 in the Dutch, Swedish and Australian sample, respectively); no indication for linkage was observed in the adolescent Dutch twin sample. The QTL effects in the three adult samples were not significantly different and a simultaneous analysis of the samples increased the maximum LOD score to 5.7 at 60 cM pter. Bivariate analyses indicated that the putative LDL-C QTL also contributed to the variance in ApoB levels, consistent with the high genetic correlation between these phenotypes. Our study provides strong evidence for the presence of a QTL on chromosome 19 with a major effect on LDL-C plasma levels in outbred Caucasian populations.

Synthesis, stability, antiviral activity, and protease-bound structures of substrate-mimicking constrained macrocyclic inhibitors of HIV-1 protease

Three new peptidomimetics (1-3) have been developed with highly stable and conformationally constrained macrocyclic components that replace tripeptide segments of protease substrates. Each compound inhibits both HIV-1 protease and viral replication (HIV-I, HIV-2) at nanomolar concentrations without cytotoxicity to uninfected cells below 10 mu M. Their activities against HIV-1 protease (K-i 1.7 nM (1), 0.6 nM (2), 0.3 nM (3)) are 1-2 orders of magnitude greater than their antiviral potencies against HIV-1-infected primary peripheral blood mononuclear cells (IC50 45 nM (1), 56 nM (2), 95 nM (3)) or HIV-1-infected MT2 cells (IC50 90 nM (1), 60 nM (2)), suggesting suboptimal cellular uptake. However their antiviral potencies are similar to those of indinavir and amprenavir under identical conditions. There were significant differences in their capacities to inhibit the replication of HIV-1 and HIV-2 in infected MT2 cells, 1 being ineffective against HIV-2 while 2 was equally effective against both virus types. Evidence is presented that 1 and 2 inhibit cleavage of the HIV-1 structural protein precursor Pr55(gag) to p24 in virions derived from chronically infected cells, consistent with inhibition of the viral protease in cells. Crystal structures refined to 1.75 Angstrom (1) and 1.85 Angstrom (2) for two of the macrocyclic inhibitors bound to HIV-1 protease establish structural mimicry of the tripeptides that the cycles were designed to imitate. Structural comparisons between protease-bound macrocyclic inhibitors, VX478 (amprenavir), and L-735,524 (indinavir) show that their common acyclic components share the same space in the active site of the enzyme and make identical interactions with enzyme residues. This substrate-mimicking minimalist approach to drug design could have benefits in the context of viral resistance, since mutations which induce inhibitor resistance may also be those which prevent substrate processing.

Determination of the effect of lipophilicity on the in vitro permeability and tissue reservoir characteristics of topically applied solutes in human skin layers

In order to establish the relationship between solute lipophilicity and skin penetration (including flux and concentration behavior), we examined the in vitro penetration and membrane concentration of a series of homologous alcohols (C2-C10) applied topically in aqueous solutions to human epidermal, full-thickness, and dermal membranes. The partitioning/distribution of each alcohol between the donor solution, stratum corneum, viable epidermis, dermis, and receptor phase compartments was determined during the penetration process and separately to isolated samples of each tissue type. Maximum flux and permeability coefficients are compared for each membrane and estimates of alcohol diffusivity are made based on flux/concentration data and also the related tissue resistance (the reciprocal of permeability coefficient) for each membrane type. The permeability coefficient increased with increasing lipophilicity to alcohol C8 (octanol) with no further increase for C10 (decanol). Log vehicle:stratum corneum partition coefficients were related to logP , and the concentration of alcohols in each of the tissue layers appeared to increase with lipophilicity. No difference was measured in the diffusivity of smaller more polar alcohols in the three membranes; however, the larger more lipophilic solutes showed slower diffusivity values. The study showed that the dermis may be a much more lipophilic environment than originally believed and that distribution of smaller nonionized solutes into local tissues below a site of topical application may be estimated based on knowledge of their lipophilicity alone.

New fluorescence parameters for monitoring photosynthesis in plants - 1. The effect of illumination on the fluorescence parameters of the JIP-test

Chlorophyll fluorescence measurements have a wide range of applications from basic understanding of photosynthesis functioning to plant environmental stress responses and direct assessments of plant health. The measured signal is the fluorescence intensity (expressed in relative units) and the most meaningful data are derived from the time dependent increase in fluorescence intensity achieved upon application of continuous bright light to a previously dark adapted sample. The fluorescence response changes over time and is termed the Kautsky curve or chlorophyll fluorescence transient. Recently, Strasser and Strasser (1995) formulated a group of fluorescence parameters, called the JIP-test, that quantify the stepwise flow of energy through Photosystem II, using input data from the fluorescence transient. The purpose of this study was to establish relationships between the biochemical reactions occurring in PS II and specific JIP-test parameters. This was approached using isolated systems that facilitated the addition of modifying agents, a PS II electron transport inhibitor, an electron acceptor and an uncoupler, whose effects on PS II activity are well documented in the literature. The alteration to PS II activity caused by each of these compounds could then be monitored through the JIP-test parameters and compared and contrasted with the literature. The known alteration in PS II activity of Chenopodium album atrazine resistant and sensitive biotypes was also used to gauge the effectiveness and sensitivity of the JIP-test. The information gained from the in vitro study was successfully applied to an in situ study. This is the first in a series of four papers. It shows that the trapping parameters of the JIP-test were most affected by illumination and that the reduction in trapping had a run-on effect to inhibit electron transport. When irradiance exposure proceeded to photoinhibition, the electron transport probability parameter was greatly reduced and dissipation significantly increased. These results illustrate the advantage of monitoring a number of fluorescence parameters over the use of just one, which is often the case when the F-V/F-M ratio is used.

The reliability of video based time motion analysis

Time motion analysis is extensively used to assess the demands of team sports. At present there is only limited information on the reliability of measurements using this analysis tool. The aim of this study was to establish the reliability of an individual observer's time motion analysis of rugby union. Ten elite level rugby players were individually tracked in Southern Hemisphere Super 12 matches using a digital video camera. The video footage was subsequently analysed by a single researcher on two occasions one month apart. The test-retest reliability was quantified as the typical error of measurement (TEM) and rated as either good (10% TEM). The total time spent in the individual movements of walking, jogging, striding, sprinting, static exertion and being stationary had moderate to poor reliability (5.8-11.1% TEM). The frequency of individual movements had good to poor reliability (4.3-13.6% TEM), while the mean duration of individual movements had moderate reliability (7.1-9.3% TEM). For the individual observer in the present investigation, time motion analysis was shown to be moderately reliable as an evaluation tool for examining the movement patterns of players in competitive rugby. These reliability values should be considered when assessing the movement patterns of rugby players within competition.

The regulation of complementary health: sacrificing integrity?

In response to the increasing use of complementary and alternative medicine (CAM), governments are exploring ways to ensure patients' safety and respond to complaints. One solution is to establish registration boards and procedures based on the model of existing health practitioner Acts. Registration will require defined minimum standards for competence, which will have to be based on scientific evidence. As scientific evidence accumulates, these modalities are likely to lose their identities as alternative and become assimilated into Western medicine.

Relationship between flocculation of activated sludge and composition of extracellular polymeric substances

Activated sludge floes are a flocculated mass of microorganisms, extracellular polymeric substances (EPS) and adsorbed organic and inorganic material. The structure of the floes is very heterogeneous and floes with very different properties and morphologies may occur, depending on the conditions in the activated sludge treatment plant and wastewater composition. Present thinking suggests that cations, such as calcium, create cationic bridges with EPS excreted by the bacteria and thereby hold the various floe constituents together. However, due to the complex and heterogeneous nature of activated sludge, the mechanisms have neither been thoroughly investigated nor successfully quantified. A better understanding and description of the biological flocculation process is necessary in order to establish more efficient operational strategies. The main aim of this study was to get a comprehensive and unique insight into the floe properties of activated sludge and to assess the relative impact of chemical and physical parameters. A variety of sludges from full scale treatment plants with different settling properties were characterised. The interrelationships between floe parameters such as composition of EPS, surface properties and floe structure, and their effect on the flocculation and separation properties were assessed. The results indicate that the EPS, both in terms of quantity and quality, are very important for the floe properties of the activated sludge. However, presence of filaments may alter the physical properties of the floes considerably. The EPS showed positive correlations to sludge volume index (SVI) if only sludges with low or moderate numbers of filaments were included. The surface properties were more affected by the composition of the EPS than by the number of filaments. The EPS showed positive correlation to negative surface charge and a negative correlation to relative hydrophobicity and flocculation ability. The negative correlation between flocculation ability and amount of EPS was surprising. The shear sensitivity, measured as degree of erosion of floes when subjected to shear, was more affected by floe size and number of filaments than amount of EPS.

Democracry and the Individual

The main question informing this paper is whether it is possible to extend democracy beyond its liberal forms. The paper reflects upon this question with regard to its implications for the individual. For the radicalization of democracy implies a need for self-transformation, if the everyday egoism of contemporary citizens is not to thwart reasonable discussion and participation. Theorists such as Richard Rorty argue that the philosophical resources required to guide such self-transformation can be made available only by sacrificing the political freedom and cultural diversity liberalism has been able to precariously establish. Other theorists insist that the thresholds of pluralism and tolerance that existing liberal democracies are struggling to maintain actually require an extension of democracy. The paper evaluates two different theoretical strategies that aim to identify potentials for democratization without falling prey to the dilemma identified by Rorty: a ‘ deliberative’ strategy explicated with reference to Jürgen Habermas and an ‘existential’ approach represented here by William Connolly.

Levantamento te??rico sobre as causas dos insucessos das tentativas de reforma administrativa

O presente artigo tem como objetivo identificar e analisar os principais motivos apontados na literatura pertinente como causadores dos sucessivos e reiterados fracassos das tentativas de reforma da administra????o p??blica brasileira. As referidas tentativas foram empreendidas em 1938, quando da cria????o do Departamento Administrativo do Servi??o P??blico (DASP), durante a ditadura do Estado Novo; em 1963, quando Ernani do Amaral Peixoto foi designado ministro extraordin??rio para a Reforma Administrativa; em 1967, quando da edi????o do Decreto-Lei n?? 200, de 25/2/1967 e, tamb??m, em 1986, 1990 e 1995, nos Governos Sarney, Collor e Cardoso, respectivamente. Todas elas visavam, basicamente, a implantar a meritocracia na administra????o p??blica brasileira. Segundo os autores consultados, essas tentativas foram malsucedidas devido aos seguintes fatores: a quest??o da depend??ncia da trajet??ria, as caracter??sticas das organiza????es que dificultam a ocorr??ncia de altera????es institucionais, os elementos de natureza sociol??gica, o fato de a reforma administrativa ser bem p??blico sujeito a problemas de a????o coletiva e, finalmente, as peculiaridades do sistema pol??tico brasileiro.

Contradi????es do processo de implementa????o de pol??ticas p??blicas: uma an??lise do Programa Bolsa Fam??lia 2003 ??? 2006

O Programa Bolsa Fam??lia, programa de transfer??ncia condicionada de renda, vem se firmando no cen??rio mundial como uma das mais expressivas iniciativas dessa natureza para o enfrentamento da pobreza e a redu????o da desigualdade. Presente em todos os 5.564 munic??pios brasileiros, caracteriza- se por ser um programa federal que n??o prescinde dos estados e, em especial, dos munic??pios para a sua execu????o. No sentido de estabelecer uma gest??o compartilhada entre todas as esferas governamentais, o governo federal tem buscado implantar mecanismos flex??veis de parceria, com defini????o clara de pap??is e compartilhamento de responsabilidades, bem como auxiliar os governos subnacionais, por meio da transfer??ncia de recursos para a gest??o, na cria????o das condi????es institucionais e de infra-estrutura necess??rias ?? operacionaliza????o de um programa dessa magnitude. Este texto analisa as rela????es intergovernamentais existentes no ??mbito do Programa Bolsa Fam??lia, identificando os avan??os e os desafios na busca da coordena????o federativa. A primeira parte, sobre o federalismo brasileiro, ap??ia-se basicamente em estudos do pesquisador Luiz Fernando Abrucio. J?? os dados e informa????es sobre o Programa foram fornecidos pelo Minist??rio do Desenvolvimento Social e Combate ?? Fome.

O papel do governo eletr??nico no fortalecimento da governan??a do setor p??blico

As novas Tecnologias da Informa????o e Comunica????o (TIC), entre as quais se destacam a internet, as redes de computadores, a transmiss??o via sat??lite e a telefonia m??vel, criaram condi????es para o surgimento de Sociedades do Conhecimento. Nesse contexto, o Estado, por interm??dio do governo eletr??nico, ?? o principal instrumento de que os cidad??os disp??em atualmente para enfrentar os desafios impostos pela globaliza????o, por meio de intera????es in??ditas da sociedade, empresas e governos. O objetivo deste trabalho foi estabelecer rela????es entre a governan??a do setor p??blico e o governo eletr??nico, partindo-se de um marco referencial te??rico das duas ??reas de estudo. Para tanto, foram delineados seus escopos e limites de atua????o, instituindo-se v??nculos, de acordo com a????es do Governo Eletr??nico brasileiro: certifica????o digital; Portal da Transpar??ncia; vota????o eletr??nica; preg??es eletr??nicos e Portal da Previd??ncia Social. Conclui-se que, apesar dos avan??os recentes observados pela an??lise de v??rias dimens??es da governan??a, baseados em iniciativas de governo eletr??nico aqui inventariadas, ainda h?? muito que fazer em dire????o ?? inclus??o social no Brasil, assim como em outros pa??ses. As TIC podem vir a ser um poderoso agente de inclus??o digital, apoiando a governan??a com a cria????o de espa??os virtuais para participa????o democr??tica e di??logo c??vico e expans??o da participa????o em tomada de decis??o coletiva, promovendo a igualdade e a cidadania.

Fundamentos para uma pol??tica de carreiras no contexto da reforma gerencial

Com o advento da administra????o gerencial no ??mbito do aparelho do Estado, em complementa????o ?? administra????o burocr??tica, verifica-se certa turbul??ncia na gest??o de pessoal na administra????o p??blica, decorrente da s??bita aus??ncia de fundamentos conceituais s??lidos que permitam pensar a administra????o do capital humano do Estado em um contexto de transforma????o. Este artigo procura estabelecer as bases para a recupera????o destes fundamentos, propondo tr??s crit??rios de design de carreiras: a estrutura de incentivos, os mecanismos de governan??a e a gest??o do conhecimento. Em seguida, exemplifica-se a utiliza????o destes crit??rios pela an??lise de seis temas pr??prios ?? discuss??o sobre carreiras no servi??o p??blico: remunera????o, sele????o, recrutamento e desenvolvimento, mobilidade, promo????o, carreiras para ag??ncias executivas e controle social da burocracia.

A presen??a do Estado no setor sa??de no Brasil

O artigo analisa, de forma introdut??ria, as mudan??as na pol??tica na ??rea de sa??de no Brasil. A partir de uma breve retomada de alguns estudos que discutem o papel do Estado na provis??o, financiamento e regula????o do setor sa??de, a autora procura estabelecer pontes ou interfaces entre estes modelos te??ricos e o processo hist??rico mais recente, que deu origem ao Sistema ??nico de Sa??de ??? SUS. Finalmente, a autora discute o que mudou e o que ainda permanece, e se mant??m como tra??o caracter??stico do sistema de sa??de brasileiro.

Hist??ria das reformas administrativas no Brasil: narrativas, teoriza????es e representa????es

O trabalho se prop??e a oferecer uma modesta contribui????o ao estudo da hist??ria das reformas administrativas realizadas no Brasil a partir da primeira metade do s??culo XX. Mais do que apresentar uma cronologia de fatos e um repert??rio de projetos, recupera as narrativas e an??lises dos estudiosos do tema para identificar as diferentes explica????es para os sucessos e insucessos do passado e estabelecer um sistema de categorias que seja ??til ?? compreens??o da din??mica hist??rica. Relatos, narrativas, teoriza????es, interpreta????es e ideologias se confundem. Em qualquer um dos casos, constituem representa????es do mundo administrativo brasileiro, quer dizer, apresentam-se como formas simb??licas de um Estado em transforma????o.