Deciphering genetic disease in the genomic era: the model of GnRH deficiency.

Isolated gonadotropin-releasing hormone (GnRH) deficiency is a treatable albeit rare form of reproductive failure that has revealed physiological mechanisms controlling human reproduction, but despite substantial progress in discovering pathogenic single-gene defects, most of the genetic basis of GnRH deficiency remains uncharted. Although unbiased genetic investigations of affected families have identified mutations in previously unsuspected genes as causes of this disease in some cases, their application has been severely limited because of the negative effect of GnRH deficiency on fertility; moreover, relatively few of the many candidate genes nominated because of biological plausibility from in vitro or animal model experiments were subsequently validated in patients. With the advent of exciting technological platforms for sequencing, homozygosity mapping, and detection of structural variation at the whole-genome level, human investigations are again assuming the leading role for gene discovery. Using human GnRH deficiency as a paradigm and presenting original data from the screening of numerous candidate genes, we discuss the emerging model of patient-focused clinical genetic research and its complementarities with basic approaches in the near future.

Parasitism, host immune function, and sexual selection.

Parasite-mediated sexual selection may arise as a consequence of 1) females avoiding mates with directly transmitted parasites, 2) females choosing less-parasitized males that provide parental care of superior quality, or 3) females choosing males with few parasites in order to obtain genes for parasite resistance in their offspring. Studies of specific host-parasite systems and comparative analyses have revealed both supportive and conflicting evidence for these hypotheses. A meta-analysis of the available evidence revealed a negative relationship between parasite load and the expression of male secondary sexual characters. Experimental studies yielded more strongly negative relationships than observations did, and the relationships were more strongly negative for ectoparasites than for endoparasites. There was no significant difference in the magnitude of the negative effect for species with and without male parental care, or between behavioral and morphological secondary sexual characters. There was a significant difference between studies based on host immune function and those based on parasite loads, with stronger effects for measures of immune function, suggesting that the many negative results from previous analyses of parasite-mediated sexual selection may be explained because relatively benign parasites were studied. The multivariate analyses demonstrating strong effect sizes of immune function in relation to the expression of secondary sexual characters, and for species with male parental care as compared to those without, suggest that parasite resistance may be a general determinant of parasite-mediated sexual selection.

Transvaginal specimen extraction in colorectal surgery: current state of the art.

Aim  Background The expected benefit of transvaginal specimen extraction is reduced incision-related morbidity. Objectives A systematic review of transvaginal specimen extraction in colorectal surgery was carried out to assess this expectation. Method  Search strategy The following keywords, in various combinations, were searched: NOSE (natural orifices specimen extraction), colorectal, colon surgery, transvaginal, right hemicolectomy, left hemicolectomy, low anterior resection, sigmoidectomy, ileocaecal resection, proctocolectomy, colon cancer, sigmoid diverticulitis and inflammatory bowel diseases. Selection criteria Selection criteria included large bowel resection with transvaginal specimen extraction, laparoscopic approach, human studies and English language. Exclusion criteria were experimental studies and laparotomic approach or local excision. All articles published up to February 2011 were included. Results  Twenty-three articles (including a total of 130 patients) fulfilled the search criteria. The primary diagnosis was colorectal cancer in 51% (67) of patients, endometriosis in 46% (60) of patients and other conditions in the remaining patients. A concurrent gynaecological procedure was performed in 17% (22) of patients. One case of conversion to laparotomy was reported. In two patients, transvaginal extraction failed. In left- and right-sided resections, the rate of severe complications was 3.7% and 2%, respectively. Two significant complications, one of pelvic seroma and one of rectovaginal fistula, were likely to have been related to transvaginal extraction. The degree of follow up was specified in only one study. Harvested nodes and negative margins were adequate and reported in 70% of oncological cases. Conclusion  Vaginal extraction of a colorectal surgery specimen shows potential benefit, particularly when associated with a gynaecological procedure. Data from prospective randomized trials are needed to support the routine use of this technique.

The evolution, maintenance and adaptive function of genetic colour polymorphism in birds.

The hypothesis that ornaments can honestly signal quality only if their expression is condition-dependent has dominated the study of the evolution and function of colour traits. Much less interest has been devoted to the adaptive function of colour traits for which the expression is not, or is to a low extent, sensitive to body condition and the environment in which individuals live. The aim of the present paper is to review the current theoretical and empirical knowledge of the evolution, maintenance and adaptive function of colour plumage traits for which the expression is mainly under genetic control. The finding that in many bird species the inheritance of colour morphs follows the laws of Mendel indicates that genetic colour polymorphism is frequent. Polymorphism may have evolved or be maintained because each colour morph facilitates the exploitation of alternative ecological niches as suggested by the observation that individuals are not randomly distributed among habitats with respect to coloration. Consistent with the hypothesis that different colour morphs are linked to alternative strategies is the finding that in a majority of species polymorphism is associated with reproductive parameters, and behavioural, life-history and physiological traits. Experimental studies showed that such covariations can have a genetic basis. These observations suggest that colour polymorphism has an adaptive function. Aviary and field experiments demonstrated that colour polymorphism is used as a criterion in mate-choice decisions and dominance interactions confirming the claim that conspecifics assess each other's colour morphs. The factors favouring the evolution and maintenance of genetic variation in coloration are reviewed, but empirical data are virtually lacking to assess their importance. Although current theory predicts that only condition-dependent traits can signal quality, the present review shows that genetically inherited morphs can reveal the same qualities. The study of genetic colour polymorphism will provide important and original insights on the adaptive function of conspicuous traits.

Results from a prospective, randomized, controlled study evaluating the acceptability and effects of routine pre-IVF counselling.

BACKGROUND: The aim of this study was to evaluate a model of routine pre-IVF counselling focusing on the narrative capacities of couples. The acceptability of counselling, the effects on emotional factors and the participants' assessments were considered. METHODS: The study included 141 consecutive childless couples preparing for their first IVF. Randomization was carried out through sealed envelopes attributing participants to counselled and non-counselled groups and was accepted by 100 couples. Another 12 couples refused randomization because they wanted counselling and 29 because they did not. Questionnaires including the State-Trait Anxiety Inventory, the Beck Depression Inventory and assessments of help were mailed to couples before IVF and counselling, and after the IVF outcome. RESULTS: Counselling was accepted by 79% (112/141) of couples. There was no significant effect of counselling on anxiety and depression scores which were within normal ranges at both times. Counselling provided help for 86% (75/87) of initially non-demanding subjects and 96% (25/26) of those initially requesting a session. Help was noted in areas of psychological assistance, technical explanations and discussing relationships. CONCLUSIONS: This model of routine counselling centred on the narrative provides an acceptable form of psychological assistance for pre-IVF couples.

Angiotensin II as an Inducer of Atherosclerosis: Evidence from Mouse Studies

Mechanisms responsible for atherosclerotic plaque development, destabilization, and rupture are still largely unknown. Angiotensin II, the main bioactive peptide of renin angiotensin system, has been shown to be critically involved in the pathogenesis of atherosclerosis and vulnerable plaque. Experimental studies in hypercholesterolemic mouse models with high circulating Angiotensin II levels, provide direct evidence that Angiotensin II induces plaque vulnerability partly by 1/ downregulating vascular expression of anti-atherosclerotic genes and/or upregulating expression of pro-atherosclerotic genes, and 2/ skewing the systemic lymphocyte Th1/Th2 balance towards a proinflammatory Th1 response in early disease phase. Further understanding the pro-atherosclerotic mechanisms of Angiotensin II and associated signaling pathways will help to design better therapeutic strategies for reducing the burden of atherosclerotic cardiovascular disease.

Electronic control device exposure: a review of morbidity and mortality.

The use of electronic control devices has expanded worldwide during the last few years, the most widely used model being the Taser. However, the scientific knowledge about electronic control devices remains limited. We reviewed the medical literature to examine the potential implications of electronic devices in terms of morbidity and mortality, and to identify and evaluate all the existing experimental human studies. A single exposure of an electronic control device on healthy individuals can be assumed to be generally safe, according to 23 prospective human experimental studies and numerous volunteer exposures. In case series, however, electronic control devices could have deleterious effects when used in the field, in particular if persons receive multiple exposures, are intoxicated, show signs of "excited delirium," or present with medical comorbidities. As the use of electronic control devices continues to increase, the controversy about its safety, notably in potentially high-risk individuals, is still a matter of debate. The complications of electronic control device exposure are numerous but often recognizable, usually resulting from barbed dart injuries or from falls. Persons exposed to electronic control devices should therefore be fully examined, and traumatic lesions must be ruled out.

Prospective study of insulin-like growth factor-I, insulin-like growth factor-binding protein 3, genetic variants in the IGF1 and IGFBP3 genes and risk of coronary artery disease.

Although experimental studies have suggested that insulin-like growth factor I (IGF-I) and its binding protein IGFBP-3 might have a role in the aetiology of coronary artery disease (CAD), the relevance of circulating IGFs and their binding proteins in the development of CAD in human populations is unclear. We conducted a nested case-control study, with a mean follow-up of six years, within the EPIC-Norfolk cohort to assess the association between circulating levels of IGF-I and IGFBP-3 and risk of CAD in up to 1,013 cases and 2,055 controls matched for age, sex and study enrolment date. After adjustment for cardiovascular risk factors, we found no association between circulating levels of IGF-I or IGFBP-3 and risk of CAD (odds ratio: 0.98 (95% Cl 0.90-1.06) per 1 SD increase in circulating IGF-I; odds ratio: 1.02 (95% Cl 0.94-1.12) for IGFBP-3). We examined associations between tagging single nucleotide polymorphisms (tSNPs) at the IGF1 and IGFBP3 loci and circulating IGF-I and IGFBP-3 levels in up to 1,133 cases and 2,223 controls and identified three tSNPs (rs1520220, rs3730204, rs2132571) that showed independent association with either circulating IGF-I or IGFBP-3 levels. In an assessment of 31 SNPs spanning the IGF1 or IGFBP3 loci, none were associated with risk of CAD in a meta-analysis that included EPIC-Norfolk and eight additional studies comprising up to 9,319 cases and 19,964 controls. Our results indicate that IGF-I and IGFBP-3 are unlikely to be importantly involved in the aetiology of CAD in human populations.

FTO genetic variants, dietary intake and body mass index: insights from 177,330 individuals.

FTO is the strongest known genetic susceptibility locus for obesity. Experimental studies in animals suggest the potential roles of FTO in regulating food intake. The interactive relation among FTO variants, dietary intake and body mass index (BMI) is complex and results from previous often small-scale studies in humans are highly inconsistent. We performed large-scale analyses based on data from 177,330 adults (154 439 Whites, 5776 African Americans and 17 115 Asians) from 40 studies to examine: (i) the association between the FTO-rs9939609 variant (or a proxy single-nucleotide polymorphism) and total energy and macronutrient intake and (ii) the interaction between the FTO variant and dietary intake on BMI. The minor allele (A-allele) of the FTO-rs9939609 variant was associated with higher BMI in Whites (effect per allele = 0.34 [0.31, 0.37] kg/m(2), P = 1.9 × 10(-105)), and all participants (0.30 [0.30, 0.35] kg/m(2), P = 3.6 × 10(-107)). The BMI-increasing allele of the FTO variant showed a significant association with higher dietary protein intake (effect per allele = 0.08 [0.06, 0.10] %, P = 2.4 × 10(-16)), and relative weak associations with lower total energy intake (-6.4 [-10.1, -2.6] kcal/day, P = 0.001) and lower dietary carbohydrate intake (-0.07 [-0.11, -0.02] %, P = 0.004). The associations with protein (P = 7.5 × 10(-9)) and total energy (P = 0.002) were attenuated but remained significant after adjustment for BMI. We did not find significant interactions between the FTO variant and dietary intake of total energy, protein, carbohydrate or fat on BMI. Our findings suggest a positive association between the BMI-increasing allele of FTO variant and higher dietary protein intake and offer insight into potential link between FTO, dietary protein intake and adiposity.

Immunociblage des tumeurs: situation et perspectives en 2000

Following 15 years of experimental studies, tumor immunotargeting using monoclonal antibodies directed against tumor associated antigens shows now important monoclonal antibodies directed against tumor associated antigens shows now important clinical developments. This is mainly due to encouraging therapeutic results which have obtained using humanized antibodies such as the anti-CD20 rituximab in follicular B lymphomas and the anti-DrbB2 herceptin in breast carcinomas. Thanks to genetic engineering it is possible to graft variable or hypervariable regions from murine antibodies to human IgG, and even to obtain fully human antibodies by using either transgenic mice containing a large part of the human repertoire of human IgG, or selection of human antibody fragments expressed by phages. Radiolabeling of antibodies played a major role to demonstrate the tumor immunotargeting specificity and remains attractive for the diagnosis by immunoscintigraphy as well as for the treatment by radioimmunotherapy of some cancers. In this review, the current results and the prospects of diagnostic and therapeutic uses of anti-tumor antibodies and their fragments will be described. Concerning diagnosis, 123-iodine or 99m-technetium labeled Fab fragments allowed very demonstrative tumor images but this technique has a limited effect upon the therapeutic attitude. Immuno-PET (positron emission tomography) could enhance the sensitivity of this imaging method. Radio-immunoguided surgery and immunophotodetection are attractive techniques still under evaluation. Concerning therapy, 131-iodine labeled anti-CD20 antibodies gave spectacular results in non-Hodgkin's B lymphomas. In solid tumors which as less radiosensitive, radioimmunotherapy could concern small tumors and need the use of two-steps targeting and/or alpha emitters radioisotopes. Some other strategies will be described such as bispecific antibodies directed against tumors and immune effector cells, some antibody fragments expressed on T cells called T-bodies or some biological studies using intrabodies. Published data and works in progress demonstrate that immunotargeting of tumors will have a growing place in the treatments of cancer patients.

Genome sequence of the Drosophila melanogaster male-killing Spiroplasma strain MSRO endosymbiont.

Spiroplasmas are helical and motile members of a cell wall-less eubacterial group called Mollicutes. Although all spiroplasmas are associated with arthropods, they exhibit great diversity with respect to both their modes of transmission and their effects on their hosts; ranging from horizontally transmitted pathogens and commensals to endosymbionts that are transmitted transovarially (i.e., from mother to offspring). Here we provide the first genome sequence, along with proteomic validation, of an endosymbiotic inherited Spiroplasma bacterium, the Spiroplasma poulsonii MSRO strain harbored by Drosophila melanogaster. Comparison of the genome content of S. poulsonii with that of horizontally transmitted spiroplasmas indicates that S. poulsonii has lost many metabolic pathways and transporters, demonstrating a high level of interdependence with its insect host. Consistent with genome analysis, experimental studies showed that S. poulsonii metabolizes glucose but not trehalose. Notably, trehalose is more abundant than glucose in Drosophila hemolymph, and the inability to metabolize trehalose may prevent S. poulsonii from overproliferating. Our study identifies putative virulence genes, notably, those for a chitinase, the H2O2-producing glycerol-3-phosphate oxidase, and enzymes involved in the synthesis of the eukaryote-toxic lipid cardiolipin. S. poulsonii also expresses on the cell membrane one functional adhesion-related protein and two divergent spiralin proteins that have been implicated in insect cell invasion in other spiroplasmas. These lipoproteins may be involved in the colonization of the Drosophila germ line, ensuring S. poulsonii vertical transmission. The S. poulsonii genome is a valuable resource to explore the mechanisms of male killing and symbiont-mediated protection, two cardinal features of many facultative endosymbionts. IMPORTANCE: Most insect species, including important disease vectors and crop pests, harbor vertically transmitted endosymbiotic bacteria. These endosymbionts play key roles in their hosts' fitness, including protecting them against natural enemies and manipulating their reproduction in ways that increase the frequency of symbiont infection. Little is known about the molecular mechanisms that underlie these processes. Here, we provide the first genome draft of a vertically transmitted male-killing Spiroplasma bacterium, the S. poulsonii MSRO strain harbored by D. melanogaster. Analysis of the S. poulsonii genome was complemented by proteomics and ex vivo metabolic experiments. Our results indicate that S. poulsonii has reduced metabolic capabilities and expresses divergent membrane lipoproteins and potential virulence factors that likely participate in Spiroplasma-host interactions. This work fills a gap in our knowledge of insect endosymbionts and provides tools with which to decipher the interaction between Spiroplasma bacteria and their well-characterized host D. melanogaster, which is emerging as a model of endosymbiosis.

Comment on reversal of hypogonadotropic hypogonadism in a Chinese cohort.

The reversal of congenital hypogonadotropic hypogonadism (CHH) is a relatively recent phenomenon that has gained increasing attention over the past 10 years. Yet to date, only one prospective study has been conducted estimating that 10% (95% confidence interval [CI]: 2%-18%) of cases undergo reversal. [1] Other retrospective studies have reported rates in the range of 5%-8% [2],[3] and a recent study showed 44/308 (14%, 95% CI: 11%-19%) CHH patients underwent reversal. [4] Moreover, a time-to-event analysis in this large cohort revealed a lifetime reversal incidence of 22%. The article by Mao and colleagues presented in this issue is a meaningful contribution to our understanding of reversal as it examines the largest retrospective cohort to date. [5] Interestingly, they report the rate of reversal as 5% (95% CI: 3%-8%) in this Chinese cohort. It is difficult to reconcile the discrepancies in rates of reversibility and direct comparisons are hampered by the variable definitions employed. Using a novel definition for reversal (i.e, either endogenous testosterone (T) >270 ng dl−1 , serum T gradually increasing above 150 ng dl−1 with increased testicular volume, or normal spontaneous sperm production/normal erectile function/ejaculation), Mao and colleagues posit that testicular size and triptorelin-stimulated LH levels are reliable predictive factors for reversal. However, these cannot be considered as hard and fast rules for predicting reversal as the groups intersect - akin to the overlap observed between CHH patients and those with delayed puberty. Indeed, the fact that approximately half (44%, 95% CI: 25%-66%) of the reversal patients in the study by Mao et al.[5] were diagnosed between 17 and 19 years of age, underscores the challenge in differentiating CHH from extreme normal variants of puberty. This study further lends credence the recently reported observations that reversals may relapse. [4],[6] The notion that reversal may not be lasting highlights the vulnerability of the reproductive axis among CHH patients. While the mechanism(s) for relapse are unclear, it seems plausible that environmental, metabolic or psychiatric stressors could contribute. The factors that Mao and colleagues identify as significantly different in cases of reversal, were not informative for identifying those cases that relapsed back to a hypogonadal state. Notably, reversal has been reported in probands harboring mutations in genes underlying CHH. [1],[3],[4],[6] Unfortunately, comprehensive genetic screening on the Chinese cohort is not available. The reversal phenomenon is fascinating for its glimpse into the plasticity of the neuroendocrine control of reproduction. Future directions will almost certainly include investigation of specific genetic signatures and novel biomarkers for predicting reversal (and relapse). Yet CHH is a rare condition and to fully elucidate the biology of reversible CHH, it will be important to harmonize definitions of what constitutes a reversal, carefully phenotype patients and chart the natural history of their CHH. In this way, this unique human disease model may offer further insights into the control of human reproduction and provide opportunities to translate discoveries into enhanced approaches to improve the care and quality of life for these patients.

Testing Local Adaptation in a Natural Great Tit-Malaria System: An Experimental Approach.

Finding out whether Plasmodium spp. are coevolving with their vertebrate hosts is of both theoretical and applied interest and can influence our understanding of the effects and dynamics of malaria infection. In this study, we tested for local adaptation as a signature of coevolution between malaria blood parasites, Plasmodium spp. and its host, the great tit, Parus major. We conducted a reciprocal transplant experiment of birds in the field, where we exposed birds from two populations to Plasmodium parasites. This experimental set-up also provided a unique opportunity to study the natural history of malaria infection in the wild and to assess the effects of primary malaria infection on juvenile birds. We present three main findings: i) there was no support for local adaptation; ii) there was a male-biased infection rate; iii) infection occurred towards the end of the summer and differed between sites. There were also site-specific effects of malaria infection on the hosts. Taken together, we present one of the few experimental studies of parasite-host local adaptation in a natural malaria system, and our results shed light on the effects of avian malaria infection in the wild.

Transforming scientific information with everyday thinking: A social representations perspective

Cette thèse examine la circulation et l'intégration des informations scientifiques dans la pensée quotidienne d'après la théorie des représentations sociales (TRS). En tant qu'alternative aux approches traditionnelles de la communication de la science, les transformations survenant entre le discours scientifique et le discours de sens commun sont considérées comme adaptatives. Deux études sur la circulation des informations dans les media (études 1 et 2) montrent des variations dans les thèmes de discours exposés aux profanes, et parmi les discours de ceux-ci, en fonction de différentes sources. Ensuite, le processus d'ancrage dans le positionnement préalable envers la science est étudié, pour l'explication qu'il fournit de la réception et de la transmission d'informations scientifiques dans le sens commun. Les effets d'ancrage dans les attitudes et croyances préexistants sont reportés dans différents contextes de circulation des informations scientifiques (études 3 à 7), incluant des études de type corrélationnel, experimental et de terrain. Globalement, cette thèse procure des arguments en faveur de la pertinence de la TRS pour la recherche sur la communication de la science, et suggère des développements théoriques et méthodologiques pour ces deux domaines de recherche. Drawing on the social representations theory (SRT), this thesis examines the circulation and integration of scientific information into everyday thinking. As an alternative to the traditional approaches of science communication, it considers transformations between scientific and common-sense discourses as adaptive. Two studies, focused on the spreading of information into the media (Studies 1 and 2), show variations in the themes of discourses introduced to laypersons and in the themes among laypersons' discourses, according to different sources. Anchoring in prior positioning toward science is then studied for the explanation it provides on the reception and transmission of scientific information into common sense. Anchoring effects in prior attitudes and beliefs are reported in different contexts of circulation of scientific information (Studies 3 to 7) by using results from correlational, field, and experimental studies. Overall, this thesis provides arguments for the relevance of SRT in science communication research and suggests theoretical and methodological developments for both domains of research.