Role of BRCA2 in control of the RAD51 recombination and DNA repair protein.

Individuals carrying BRCA2 mutations are predisposed to breast and ovarian cancers. Here, we show that BRCA2 plays a dual role in regulating the actions of RAD51, a protein essential for homologous recombination and DNA repair. First, interactions between RAD51 and the BRC3 or BRC4 regions of BRCA2 block nucleoprotein filament formation by RAD51. Alterations to the BRC3 region that mimic cancer-associated BRCA2 mutations fail to exhibit this effect. Second, transport of RAD51 to the nucleus is defective in cells carrying a cancer-associated BRCA2 truncation. Thus, BRCA2 regulates both the intracellular localization and DNA binding ability of RAD51. Loss of these controls following BRCA2 inactivation may be a key event leading to genomic instability and tumorigenesis.

Gender, family and employment in comparative perspective: the realities and representations of rqual rpportunities in Britain and France

In this paper, we will explore how contrasting national discourses relating to women, and gender equality have been incorporated into and reflected in national policies. In the first section, we will outline the recent history of EU equal opportunities policy, in which positive action has been replaced by a policy of 'mainstreaming'. Second, we will describe the evolution of policies towards women and equal opportunities in Britain and France. It will be argued that whereas some degree of positive action for women has been accepted in Britain, this policy is somewhat alien to French thinking about equality - although pro-natalist French policies have resulted in favourable conditions for employed mothers in France. In the third section, we will present some attitudinal evidence, drawn from national surveys, which would appear to reflect the national policy differences we have identified in respect of the 'equality agenda'. In the fourth section, we will draw upon biographical interviews carried out with men and women in British and French banks in order to illustrate the impact of these cross-national differences within organizations and on individual lives. We demonstrate that positive action gender equality policies have made an important impact in British banks, while overt gender exclusionary practices still persist in the French banks studied. In the conclusion, we reflect on the European policy implications of our findings.

Thyroid function and prevalent and incident metabolic syndrome in older adults: the Health, Ageing and Body Composition Study.

OBJECTIVE: Both subclinical hypothyroidism and the metabolic syndrome have been associated with increased risk of coronary heart disease events. It is unknown whether the prevalence and incidence of metabolic syndrome is higher as TSH levels increase, or in individuals with subclinical hypothyroidism. We sought to determine the association between thyroid function and the prevalence and incidence of the metabolic syndrome in a cohort of older adults. DESIGN: Data were analysed from the Health, Ageing and Body Composition Study, a prospective cohort of 3075 community-dwelling US adults. PARTICIPANTS: Two thousand one hundred and nineteen participants with measured TSH and data on metabolic syndrome components were included in the analysis. MEASUREMENTS: TSH was measured by immunoassay. Metabolic syndrome was defined per revised ATP III criteria. RESULTS: At baseline, 684 participants met criteria for metabolic syndrome. At 6-year follow-up, incident metabolic syndrome developed in 239 individuals. In fully adjusted models, each unit increase in TSH was associated with a 3% increase in the odds of prevalent metabolic syndrome (OR, 1.03; 95% CI, 1.01-1.06; P = 0.02), and the association was stronger for TSH within the normal range (OR, 1.16; 95% CI, 1.03-1.30; P = 0.02). Subclinical hypothyroidism with a TSH > 10 mIU/l was significantly associated with increased odds of prevalent metabolic syndrome (OR, 2.3; 95% CI, 1.0-5.0; P = 0.04); the odds of incident MetS was similar (OR 2.2), but the confidence interval was wide (0.6-7.5). CONCLUSIONS: Higher TSH levels and subclinical hypothyroidism with a TSH > 10 mIU/l are associated with increased odds of prevalent but not incident metabolic syndrome.

Simulation of amoxicillin pharmacokinetics in humans for the prevention of streptococcal endocarditis in rats.

The pharmacokinetic determinants of successful antibiotic prophylaxis of endocarditis are not precisely known. Differences in half-lives of antibiotics between animals and humans preclude extrapolation of animal results to human situations. To overcome this limitation, we have mimicked in rats the amoxicillin kinetics in humans following a 3-g oral dose (as often used for prophylaxis of endocarditis) by delivering the drug through a computerized pump. Rats with catheter-induced vegetations were challenged with either of two strains of antibiotic-tolerant viridans group streptococci. Antibiotics were given either through the pump (to simulate the whole kinetic profile during prophylaxis in humans) or as an intravenous bolus which imitated only the peak level of amoxicillin (18 mg/liter) in human serum. Prophylaxis by intravenous bolus was inoculum dependent and afforded a limited protection only in rats challenged with the minimum inoculum size infecting > or = 90% of untreated controls. In contrast, simulation of kinetics in humans significantly protected animals challenged with 10 to 100 times the inoculum of either of the test organisms infecting > or = 90% of untreated controls. Thus, simulation of the profiles of amoxicillin prophylaxis in human serum was more efficacious than mere imitation of the transient peak level in rats. This confirms previous studies suggesting that the duration for which the serum amoxicillin level remained detectable (not only the magnitude of the peak) was an important parameter in successful prophylaxis of endocarditis. The results also suggest that single-dose prophylaxis with 3 g of amoxicillin in humans might be more effective than predicted by conventional animal models in which only peak levels of antibiotic in human serum were stimulated.

Comparative population genomics in animals uncovers the determinants of genetic diversity.

Genetic diversity is the amount of variation observed between DNA sequences from distinct individuals of a given species. This pivotal concept of population genetics has implications for species health, domestication, management and conservation. Levels of genetic diversity seem to vary greatly in natural populations and species, but the determinants of this variation, and particularly the relative influences of species biology and ecology versus population history, are still largely mysterious. Here we show that the diversity of a species is predictable, and is determined in the first place by its ecological strategy. We investigated the genome-wide diversity of 76 non-model animal species by sequencing the transcriptome of two to ten individuals in each species. The distribution of genetic diversity between species revealed no detectable influence of geographic range or invasive status but was accurately predicted by key species traits related to parental investment: long-lived or low-fecundity species with brooding ability were genetically less diverse than short-lived or highly fecund ones. Our analysis demonstrates the influence of long-term life-history strategies on species response to short-term environmental perturbations, a result with immediate implications for conservation policies.

Health-related quality of life and functioning in bipolar disorder: the impact of pharmacotherapy.

Bipolar disorder has a major deleterious impact on many aspects of a patient's functioning and health-related quality of life. Although the formal measurement of these deficits has been neglected until recently, many well-designed trials now include an assessment of functioning and health-related quality of life using one or more rating scales. This review describes recent developments in the measurement of functioning and health-related quality of life in bipolar disorder, and discusses the evidence that medications that improve symptoms in bipolar disorder also offer clinically relevant benefits in functioning and health-related quality of life. Direct comparisons of the benefits of medications including atypical antipsychotics are problematic due to differences in trial populations, study durations and rating scales. Data from quetiapine trials indicate that this medication offers prompt and sustained improvement of functioning in patients with mania and enhancement of health-related quality of life in patients with bipolar depression, to accompany the significant improvements in mood episodes.

The philosophical foundations of classical "rDzogs chen" in Tibet : investigating the distinction between dualistic mind (sems) and primordial knowing (ye shes)

While the syncretistic Tibetan tradition known as rDzogs chen ("Great Perfection") has attracted considerable attention over the past few decades, its philosophical foundations remain largely unknown to those unacquainted with its primary sources. This thesis looks at the essentials of rDzogs chen philosophy through the lens of two principal distinctions that the tradition has considered indispensable for understanding its distinctive views and practices: dualistic mind (sems) versus primordial knowing (ye shes) and dharmakâya versus the 'ground of all' (kun gzhi) conditioned experience. Arguing that the distinctions provided classical rDzogs chen scholars with a crucial framework for (a) articulating the necessary conditions of nondual primordial knowing, the conditio sine qua non of rNying ma soteriology, and (b) schematizing the relationship between the exoteric and esoteric vehicles of Indian Buddhism within a unifying conception of the Buddhist path as the progressive disclosure of primordial knowing, the thesis shows how the rDzogs chen philosophy of mind has been integral to the tradition's complex soteriology. The thesis consists of two parts: (1) a detailed philosophical investigation of the distinctions and (2) an anthology of previously untranslated Tibetan materials on the distinctions accompanied by critical editions and introductions. The first part systematically invesigates the nature and scope of the distinctions and traces their evolution and complex relationships with Indian Buddhist Cittamâtra, Madhyamaka, Pramàriavàda, and Vajrayâna views. It concludes with an exploration of some soteriological implications of the mind/primordial knowing distinction that became central to rDzogs chen path hermeneutics in the classical period as authors of rDzogs chen path summaries used this distinction to reconcile progressivist sutric and non-progressivist tantric models of the Buddhist path. The translations and texts included in part two of the thesis consist of (a) a short treatise from Klong chen pa's Miscellaneous Writings entitled Sems dang ye shes kyi dris lan (Reply to Questions Concerning Mind and Primordial Knowing), (b) selected passages on the distinctions from this author's monumental summary of the rDzogs chen snying thig system, the Theg mchog mdzod (Treasury of the Supreme Vehicle), and (c) an excerpt on rDzogs chen distinctions taken from 'Jigs med gling pa's (1729-1798) 18th century Klong chen sNying thig path summary entitled Treasury of Qualities (Yon tan mdzod) along with a word-by- word commentary by Yon tan rgya mtsho (b. 19th c.).

What is the most relevant standard of success in assisted reproduction?: The cumulated singleton/twin delivery rates per oocyte pick-up: the CUSIDERA and CUTWIDERA.

National and international registries are essential tools for establishing new standards and comparing success rates, but they do not take into account the total pregnancy/delivery rate per oocyte recovery. In Switzerland and Germany, because of legal constraints, a maximum of three two-pronuclear zygotes are allocated for transfer whereas all the supernumerary pronuclear zygotes are immediately cryopreserved, preventing selection of the transferred embryos. We report on a 10 years' experience (1993-2002) of our centre which performs transfers of unselected embryos and cryopreservation at the two-pronuclear zygote stage. As approximately 30% of all deliveries are from cryo cycles, it is essential to take into account the contribution of the cryo transfers, and we propose therefore to evaluate, as a measure of IVF performance, the cumulated delivery rate per oocyte pick-up. This delivery rate is broken down further into the cumulated singleton delivery rate (CUSIDERA) and the cumulated twin delivery rate (CUTWIDERA). The sum (S) of these two rates is a measure of efficacy while the ratio CUTWIDERA/S as a percentage is a measure of safety of IVF treatments. Using these new indexes, the average 10 year efficacy and safety of our IVF programme were 26 and 19%, respectively. Both CUSIDERA and CUTWIDERA can be calculated easily in any clinical situation and yield useful parameters for patient counselling and internal/external benchmarking purposes.

Emotional behavior in acute stroke : the Lausanne emotion in stroke study

Résumé : Objectif: Etudier les comportements émotionnels chez les patients ayant souffert d'un accident vasculaire cérébral (AVC) Contexte: Les modifications du comportement émotionnel après un AVC sont actuellement bien reconnues mais ont été très peu étudiées dans la phase aigüe de l'AVC. Méthode: Tous les patients présentant un AVC datant de moins de 24 heures ont été inclus prospectivement. Nous avons validé une échelle (the Emotional Behavior Index (EBI)), comprenant 38 qualificatifs, représentant la tristesse, l'agressivité, la désinhibition, l'adaptation, la passivité, l'indifférence et le déni. Les informations cliniques et radiologiques (CT et IRM) ont été obtenues par le biais de notre Registre des AVC. L'analyse statistique a été faite au moyen de tests uni- et multi-variés Résultats: Des 254 patients inclus, 40% présentaient de la tristesse, 49% de la passivité, 17% de l'agressivité, 53% de l'indifférence, 76% de la désinhibition, 18% un manque d'adaptation et 44% une réaction de déni. Plusieurs interactions statistiquement significatives ont été mises en évidence. En effet, la tristesse semble corréler à des antécédents d'alcoolisme (r = p< 0.037), au sexe féminin (r = p<0.028) et à la nature hémorragique de l'AVC (r = p<0.063). L'agressivité corrèle à des antécédents de troubles dépressifs (r = p<0.046) et à la nature hémorragique de l'AVC (r = p<0.06). Le déni corrèle plutôt au sexe masculin (r = p<0.035) et aux lésions hémorragiques (r = p<0.05). Le comportement émotionnel ne corrèle ni au degré et type d'atteinte neurologique, ni à la localisation de l'AVC mais une association entre Les lésions hémorragiques et un comportement agressif a été mis en évidence (p<0.001) de même qu'avec un manque d'adaptation (r = p<0.015), une certaine indifférence (r = p<0.018) et une réaction de déni (r = p<0.045). Conclusion: L'observation systématique des modifications du comportement émotionnel après un AVC suggère que les altérations émotionnelles sont indépendantes de la thymie et de l'atteinte physique et représentent donc probablement des séquelles à part entière de l'AVC. Abstract: Objective: To study emotional behaviors in an acute stroke population. Background: Alterations in emotional behavior after stroke have been recently recognized, but little attention has been paid to these changes in the very acute phase of stroke. Methods: Adult patients presenting with acute stroke were prospectively recruited and studied. We validated the Emotional Behavior Index (EBI), a 38-item scale designed to evaluate behavioral aspects of sadness, aggressiveness, disinhibition, adaptation, passivity, indifference, and denial. Clinical, historical, and imaging (computed tomography/magnetic resonance imaging) data were obtained on each subject through our Stroke Registry. Statistical analysis was performed with both univariate and multivariate tests. Results: Of the 254 patients, 40% showed sadness, 49% passivity, 17% aggressiveness, 53% indifference, 76% disinhibition, 18% lack of adaptation, and 44% denial reactions. Several significant correlations were identified. Sadness was correlated with a personal history of alcohol abuse (r = P < 0.037), female gender (r = P < 0.028), and hemorrhagic nature of the stroke (r = P < 0.063). Aggressiveness was correlated with a personal history of depression (r = P < 0.046) and hemorrhage (r = P < 0.06). Denial was correlated with male gender (r= P < 0.035) and hemorrhagic lesions (r = P < 0.05). Emotional behavior did not correlate with either neurologic impairment or lesion localization, but there was an association between hemorrhage and aggressive behavior (P < 0.001), lack of adaptation (r = P < 0.015), indifference (r = P < 0.018), and denial (r = P < 0.045). Conclusions: Systematic observations of acute emotional behaviors after stroke suggest that emotional alterations are independent of mood and physical status and should be considered as a separate consequence of stroke.