Sex chromosome trisomies in Europe: prevalence, prenatal detection and outcome of pregnancy.

This study aims to assess prevalence and pregnancy outcome for sex chromosome trisomies (SCTs) diagnosed prenatally or in the first year of life. Data held by the European Surveillance of Congenital Anomalies (EUROCAT) database on SCT cases delivered 2000-2005 from 19 population-based registries in 11 European countries covering 2.5 million births were analysed. Cases included were livebirths diagnosed to 1 year of age, fetal deaths from 20 weeks gestation and terminations of pregnancy for fetal anomaly (TOPFA). In all, 465 cases of SCT were diagnosed between 2000 and 2005, a prevalence of 1.88 per 10,000 births (95% CI 1.71-2.06). Prevalence of XXX, XXY and XYY were 0.54 (95% CI 0.46-0.64), 1.04 (95% CI 0.92-1.17) and 0.30 (95% CI 0.24-0.38), respectively. In all, 415 (89%) were prenatally diagnosed and 151 (36%) of these resulted in TOPFA. There was wide country variation in prevalence (0.19-5.36 per 1000), proportion prenatally diagnosed (50-100%) and proportion of prenatally diagnosed resulting in TOPFA (13-67%). Prevalence of prenatally diagnosed cases was higher in countries with high prenatal detection rates of Down syndrome. The EUROCAT prevalence rate for SCTs diagnosed prenatally or up to 1 year of age represents 12% of the prevalence expected from cytogenetic studies of newborn babies, as the majority of cases are never diagnosed or are diagnosed later in life. There is a wide variation between European countries in prevalence, prenatal detection and TOPFA proportions, related to differences in screening policies as well as organizational and cultural factors.

Improving prediction of recanalization in acute large-vessel occlusive stroke.

BACKGROUND: Recanalization in acute ischemic stroke with large-vessel occlusion is a potent indicator of good clinical outcome. OBJECTIVE: To identify easily available clinical and radiologic variables predicting recanalization at various occlusion sites. METHODS: All consecutive, acute stroke patients from the Acute STroke Registry and Analysis of Lausanne (2003-2011) who had a large-vessel occlusion on computed tomographic angiography (CTA) (< 12 h) were included. Recanalization status was assessed at 24 h (range: 12-48 h) with CTA, magnetic resonance angiography, or ultrasonography. Complete and partial recanalization (corresponding to the modified Treatment in Cerebral Ischemia scale 2-3) were grouped together. Patients were categorized according to occlusion site and treatment modality. RESULTS: Among 439 patients, 51% (224) showed complete or partial recanalization. In multivariate analysis, recanalization of any occlusion site was most strongly associated with endovascular treatment, including bridging therapy (odds ratio [OR] 7.1, 95% confidence interval [CI] 2.2-23.2), and less so with intravenous thrombolysis (OR 1.6, 95% CI 1.0-2.6) and recanalization treatments performed beyond guidelines (OR 2.6, 95% CI 1.2-5.7). Clot location (large vs. intermediate) and tandem pathology (the combination of intracranial occlusion and symptomatic extracranial stenosis) were other variables discriminating between recanalizers and non-recanalizers. For patients with intracranial occlusions, the variables significantly associated with recanalization after 24 h were: baseline National Institutes of Health Stroke Scale (NIHSS) (OR 1.04, 95% CI 1.02-1.1), Alberta Stroke Program Early CT Score (ASPECTS) on initial computed tomography (OR 1.2, 95% CI 1.1-1.3), and an altered level of consciousness (OR 0.2, 95% CI 0.1-0.5). CONCLUSIONS: Acute endovascular treatment is the single most important factor promoting recanalization in acute ischemic stroke. The presence of extracranial vessel stenosis or occlusion decreases recanalization rates. In patients with intracranial occlusions, higher NIHSS score and ASPECTS and normal vigilance facilitate recanalization. Clinical use of these predictors could influence recanalization strategies in individual patients.

Isolated office hypertension: a prehypertensive state?

OBJECTIVE AND METHOD: Isolated office hypertension, defined as hypertensive blood pressure values in a medical setting but normal self-measured or ambulatory-recorded blood pressures, is frequently encountered in clinical practice. Yet, whether this condition represents a transient state in the development of a sustained ambulatory hypertension is still unknown as no long-term analysis of the evolution of ambulatory blood pressure has been carried out in patients with isolated office hypertension. To evaluate whether such patients should be considered as truly normotensive or hypertensive, we have studied the long-term changes in office and ambulatory blood pressures in 81 patients in whom isolated office hypertension was observed between 1982 and 1988. RESULTS: After a 5-6 year follow-up, 60 of the 81 patients had a mean 12 h daytime ambulatory blood pressure greater than 140/90 mmHg, suggesting an evolution towards ambulatory hypertension. The development of hypertension could not be predicted on the basis of the follow-up office blood pressures as these tended to decrease during the follow-up period. CONCLUSIONS: The results of this study suggest that patients with isolated office hypertension should not be considered as truly normotensive individuals. Hence, these patients require a careful medical follow-up. Office blood pressure readings alone, however, do not appear to provide a good indicator of the long-term outcome of isolated office hypertension.

DAS-28-based EULAR response and HAQ improvement in rheumatoid arthritis patients switching between TNF antagonists

INTRODUCTION No definitive data are available regarding the value of switching to an alternative TNF antagonist in rheumatoid arthritis patients who fail to respond to the first one. The aim of this study was to evaluate treatment response in a clinical setting based on HAQ improvement and EULAR response criteria in RA patients who were switched to a second or a third TNF antagonist due to failure with the first one. METHODS This was an observational, prospective study of a cohort of 417 RA patients treated with TNF antagonists in three university hospitals in Spain between January 1999 and December 2005. A database was created at the participating centres, with well-defined operational instructions. The main outcome variables were analyzed using parametric or non-parametric tests depending on the level of measurement and distribution of each variable. RESULTS Mean (+/- SD) DAS-28 on starting the first, second and third TNF antagonist was 5.9 (+/- 2.0), 5.1 (+/- 1.5) and 6.1 (+/- 1.1). At the end of follow-up, it decreased to 3.3 (+/- 1.6; Delta = -2.6; p > 0.0001), 4.2 (+/- 1.5; Delta = -1.1; p = 0.0001) and 5.4 (+/- 1.7; Delta = -0.7; p = 0.06). For the first TNF antagonist, DAS-28-based EULAR response level was good in 42% and moderate in 33% of patients. The second TNF antagonist yielded a good response in 20% and no response in 53% of patients, while the third one yielded a good response in 28% and no response in 72%. Mean baseline HAQ on starting the first, second and third TNF antagonist was 1.61, 1.52 and 1.87, respectively. At the end of follow-up, it decreased to 1.12 (Delta = -0.49; p < 0.0001), 1.31 (Delta = -0.21, p = 0.004) and 1.75 (Delta = -0.12; p = 0.1), respectively. Sixty four percent of patients had a clinically important improvement in HAQ (defined as > or = -0.22) with the first TNF antagonist and 46% with the second. CONCLUSION A clinically significant effect size was seen in less than half of RA patients cycling to a second TNF antagonist.

Why Public Health Agencies Cannot Depend on Good Laboratory Practices as a Criterion for Selecting Data: The Case of Bisphenol A

In their safety evaluations of bisphenol A (BPA), the U.S. Food and Drug Administration (FDA) and a counterpart in Europe, the European Food Safety Authority (EFSA), have given special prominence to two industry-funded studies that adhered to standards defined by Good Laboratory Practices (GLP). These same agencies have given much less weight in risk assessments to a large number of independently replicated non-GLP studies conducted with government funding by the leading experts in various fields of science from around the world. OBJECTIVES: We reviewed differences between industry-funded GLP studies of BPA conducted by commercial laboratories for regulatory purposes and non-GLP studies conducted in academic and government laboratories to identify hazards and molecular mechanisms mediating adverse effects. We examined the methods and results in the GLP studies that were pivotal in the draft decision of the U.S. FDA declaring BPA safe in relation to findings from studies that were competitive for U.S. National Institutes of Health (NIH) funding, peer-reviewed for publication in leading journals, subject to independent replication, but rejected by the U.S. FDA for regulatory purposes. DISCUSSION: Although the U.S. FDA and EFSA have deemed two industry-funded GLP studies of BPA to be superior to hundreds of studies funded by the U.S. NIH and NIH counterparts in other countries, the GLP studies on which the agencies based their decisions have serious conceptual and methodologic flaws. In addition, the U.S. FDA and EFSA have mistakenly assumed that GLP yields valid and reliable scientific findings (i.e., "good science"). Their rationale for favoring GLP studies over hundreds of publically funded studies ignores the central factor in determining the reliability and validity of scientific findings, namely, independent replication, and use of the most appropriate and sensitive state-of-the-art assays, neither of which is an expectation of industry-funded GLP research. CONCLUSIONS: Public health decisions should be based on studies using appropriate protocols with appropriate controls and the most sensitive assays, not GLP. Relevant NIH-funded research using state-of-the-art techniques should play a prominent role in safety evaluations of chemicals.

Eligibility for and outcome of treatment of latent tuberculosis infection in a cohort of HIV-infected people in Spain

BACKGROUND Previous studies have demonstrated the efficacy of treatment for latent tuberculosis infection (TLTBI) in persons infected with the human immunodeficiency virus, but few studies have investigated the operational aspects of implementing TLTBI in the co-infected population.The study objectives were to describe eligibility for TLTBI as well as treatment prescription, initiation and completion in an HIV-infected Spanish cohort and to investigate factors associated with treatment completion. METHODS Subjects were prospectively identified between 2000 and 2003 at ten HIV hospital-based clinics in Spain. Data were obtained from clinical records. Associations were measured using the odds ratio (OR) and its 95% confidence interval (95% CI). RESULTS A total of 1242 subjects were recruited and 846 (68.1%) were evaluated for TLTBI. Of these, 181 (21.4%) were eligible for TLTBI either because they were tuberculin skin test (TST) positive (121) or because their TST was negative/unknown but they were known contacts of a TB case or had impaired immunity (60). Of the patients eligible for TLTBI, 122 (67.4%) initiated TLTBI: 99 (81.1%) were treated with isoniazid for 6, 9 or 12 months; and 23 (18.9%) with short-course regimens including rifampin plus isoniazid and/or pyrazinamide. In total, 70 patients (57.4%) completed treatment, 39 (32.0%) defaulted, 7 (5.7%) interrupted treatment due to adverse effects, 2 developed TB, 2 died, and 2 moved away. Treatment completion was associated with having acquired HIV infection through heterosexual sex as compared to intravenous drug use (OR:4.6; 95% CI:1.4-14.7) and with having taken rifampin and pyrazinamide for 2 months as compared to isoniazid for 9 months (OR:8.3; 95% CI:2.7-24.9). CONCLUSIONS A minority of HIV-infected patients eligible for TLTBI actually starts and completes a course of treatment. Obstacles to successful implementation of this intervention need to be addressed.

D-dimer levels and 90-day outcome in patients with acute pulmonary embolism with or without cancer.

BACKGROUND: The prognostic value of D-dimer testing in patients with acute pulmonary embolism (PE) has not been thoroughly studied. METHODS: We used the RIETE Registry data to assess the 90-day prognostic value of increased IL Test D-dimer levels at baseline in patients with PE, according to the presence or absence of cancer. RESULTS: As of May 2013, 3,283 patients with acute PE underwent D-dimer testing using IL Test D-dimer. Among 2,588 patients without cancer, those with D-dimer levels in the highest quartile had a higher rate of fatal PE (2.6% vs. 0.9%; p=0.002), fatal bleeding (1.1% vs. 0.3%; p=0.017) and all-cause death (9.1% vs. 4.4%; p<0.001) at 90 days compared with those with levels in the lowest quartiles. Among 695 patients with cancer, those with levels in the highest quartile had a similar rate of fatal PE or fatal bleeding but higher mortality (35% vs. 24%; p<0.01). On multivariate analysis, non-cancer patients with D-dimer levels in the highest quartile had an increased risk for fatal PE (odds ratio [OR]: 3.3; 95% CI: 1.6-6.6), fatal bleeding (OR: 4.3; 95% CI: 1.4-13.7) and all-cause death (OR: 2.1; 95% CI: 1.4-3.1) compared with patients with levels in the lowest quartiles. CONCLUSIONS: Non-cancer patients with acute PE and IL Test D-dimer levels in the highest quartile had an independently higher risk for fatal PE, fatal bleeding and all-cause death at 90 days than those with levels in the lowest quartiles. In patients with cancer, D-dimer levels failed to predict fatal PE or fatal bleeding.

Timing of adequate antibiotic therapy is a greater determinant of outcome than are TNF and IL-10 polymorphisms in patients with sepsis.

INTRODUCTION Genetic variations may influence clinical outcomes in patients with sepsis. The present study was conducted to evaluate the impact on mortality of three polymorphisms after adjusting for confounding variables, and to assess the factors involved in progression of the inflammatory response in septic patients. METHOD The inception cohort study included all Caucasian adults admitted to the hospital with sepsis. Sepsis severity, microbiological information and clinical variables were recorded. Three polymorphisms were identified in all patients by PCR: the tumour necrosis factor (TNF)-alpha 308 promoter polymorphism; the polymorphism in the first intron of the TNF-beta gene; and the IL-10-1082 promoter polymorphism. Patients included in the study were followed up for 90 days after hospital admission. RESULTS A group of 224 patients was enrolled in the present study. We did not find a significant association among any of the three polymorphisms and mortality or worsening inflammatory response. By multivariate logistic regression analysis, only two factors were independently associated with mortality, namely Acute Physiology and Chronic Health Evaluation (APACHE) II score and delayed initiation of adequate antibiotic therapy. In septic shock patients (n = 114), the delay in initiation of adequate antibiotic therapy was the only independent predictor of mortality. Risk factors for impairment in inflammatory response were APACHE II score, positive blood culture and delayed initiation of adequate antibiotic therapy. CONCLUSION This study emphasizes that prompt and adequate antibiotic therapy is the cornerstone of therapy in sepsis. The three polymorphisms evaluated in the present study appear not to influence the outcome of patients admitted to the hospital with sepsis.

Epileptogenic zone, electrode location and clinical outcome in hippocampal electrical stimulation for mesial temporal lobe epilepsy : a correlation study

Objectif : Etudier les résultats cliniques du traitement de patients atteints pai- une épilepsie mésiale du lobe temporal (MTLE) réfractaire, par stimulation cérébrale profonde (DBS) de l'hippocampe, en fonction de l'emplacement de l'électrode. Méthodes : Huit patients atteints de MTLE implantés dans l'hippocampe et stimulés par DBS à haute fréquence ont été inclus dans cette étude. Cinq ont subi des enregistrements invasifs avec des électrodes profondes dans le but d'estimer la localisation du foyer ictal avant de procéder à une DBS chronique. La position des contacts actifs de l'électrode a été mesurée en utilisant une imagerie post-opératoire. Les distances par rapport au foyer ictal ont été calculées, et les structures hippocampiques influencées par la stimulation ont été identifiées au moyen d'un atlas neuro-anatomique. Ces deux paramètres ont été corrélés avec la réduction de la fréquence d'apparition des crises. Résultats : Les distances entre la localisation estimée des contacts actifs de l'électrode et le foyer ictal étaient respectivement 11.0 +/- 4.3 ou 9.1 +/- 2.3 mm pour les patients présentant une réduction de > 50% ou < 50% de la fréquence des crises. Chez les patients (N = 6) montrant une réduction de > 50% de la fréquence des crises, 100% avaient des contacts actifs situés à < 3 mm du subiculum (p < 0,05). Les 2 patients ne répondant pas au traitement étaient stimulés par des contacts situés à > 3mm du subiculum. Conclusion : La diminution de l'activité épileptogène induite par DBS sur l'hippocampe dans les cas de MTLE réfractaires : 1) ne semble pas directement liée à la proximité des contacts actifs de l'électrode au foyer ictal déterminé par les enregistrements invasifs ; 2) pourrait être obtenue par une neuro-modulation du subiculum.

Trypanosoma cruzi benznidazole susceptibility in vitro does not predict the therapeutic outcome of human Chagas disease

Therapeutic failure of benznidazole (BZ) is widely documented in Chagas disease and has been primarily associated with variations in the drug susceptibility of Trypanosoma cruzi strains. In humans, therapeutic success has been assessed by the negativation of anti-T. cruzi antibodies, a process that may take up to 10 years. A protocol for early screening of the drug resistance of infective strains would be valuable for orienting physicians towards alternative therapies, with a combination of existing drugs or new anti-T. cruzi agents. We developed a procedure that couples the isolation of parasites by haemoculture with quantification of BZ susceptibility in the resultant epimastigote forms. BZ activity was standardized with reference strains, which showed IC50 to BZ between 7.6-32 µM. The assay was then applied to isolates from seven chronic patients prior to administration of BZ therapy. The IC50 of the strains varied from 15.6 ± 3-51.4 ± 1 µM. Comparison of BZ susceptibility of the pre-treatment isolates of patients considered cured by several criteria and of non-cured patients indicates that the assay does not predict therapeutic outcome. A two-fold increase in BZ resistance in the post-treatment isolates of two patients was verified. Based on the profile of nine microsatellite loci, sub-population selection in non-cured patients was ruled out.

Extracellular tumor-related mRNA in plasma of lymphoma patients and survival implications.

BACKGROUND We studied anomalous extracellular mRNAs in plasma from patients with diffuse large B-cell lymphoma (DLBCL) and their survival implications. mRNAs studied have been reported in the literature as markers of poor (BCL2, CCND2, MYC) and favorable outcome (LMO2, BCL6, FN1) in tumors. These markers were also analyzed in lymphoma tissues to test possible associations with their presence in plasma. METHODOLOGY/PRINCIPAL FINDINGS mRNA from 42 plasma samples and 12 tumors from patients with DLBCL was analyzed by real-time PCR. Samples post-treatment were studied. The immunohistochemistry of BCL2 and BCL6 was defined. Presence of circulating tumor cells was determined by analyzing the clonality of the immunoglobulin heavy-chain genes by PCR. In DLBCL, MYC mRNA was associated with short overall survival. mRNA targets with unfavorable outcome in tumors were associated with characteristics indicative of poor prognosis, with partial treatment response and with short progression-free survival in patients with complete response. In patients with low IPI score, unfavorable mRNA targets were related to shorter overall survival, partial response, high LDH levels and death. mRNA disappeared in post-treatment samples of patients with complete response, and persisted in those with partial response or death. No associations were found between circulating tumor cells and plasma mRNA. Absence of BCL6 protein in tumors was associated with presence of unfavorable plasma mRNA. CONCLUSIONS/SIGNIFICANCE Through a non-invasive procedure, tumor-derived mRNAs can be obtained in plasma. mRNA detected in plasma did not proceed from circulating tumor cells. In our study, unfavorable targets in plasma were associated with poor prognosis in B-cell lymphomas, mainly MYC mRNA. Moreover, the unfavorable targets in plasma could help us to classify patients with poor outcome within the good prognosis group according to IPI.

Intra- and intersexual selection and their potential consequences on fitness-relevant traits in several fish species

Résumé : Les mécanismes de sélection sexuelle, en particulier la compétition entre mâles (sélection inter-sexuelle) et le choix des femelles (sélection intra-sexuelle), peuvent fortement influencer le succès reproducteur d'un individu, c'est-à-dire son nombre de descendants. On observe ainsi que les mâles dominants et les mâles élaborant des caractères sexuels secondaires marqués ont un succès reproducteur élevé. Toutefois, le succès reproducteur ne suffit pas pour garantir une contribution génétique élevée, parce que la fitness dépend également de la performance des descendants (c'est-à-dire de leur survie et de leur propre succès reproducteur). Si cette performance dépend en partie des gènes paternels, les males ont un avantage certain à signaler leur qualité aux femelles afin d'atteindre des taux de reproduction élevé. Ce mécanisme de signalisation est connu sous le nom de 'good genes hypothesis', toutefois très peu d'études ont clairement démontré le lien entre la qualité génétique des individus et la signalisation. De plus, la performance des descendants peut aussi dépendre des effets génétiques de compatibilité entre mâles et femelles ('compatible genes'). C'est-à-dire que certains allèles paternels n'apporteraient un avantage aux descendants qu'en combinaison avec certains allèles maternels. Nous avons déterminé, durant la période de reproduction, le statut de dominance des mâles pour deux espèces de poissons d'eau douce : la truite (Salmo trotta) et le vairon (Phoxinus phoxinus), puis nous avons évalué la relation entre le succès reproducteur et le statut de dominance et/ou la quantité de signalisation des caractères sexuels secondaires. Nous avons également fécondés artificiellement des oeufs de truites et de corégones (Coregonus palaea), en croisant chaque mâle avec chaque femelle (full-factorial breeding design). Ce type de design autorise la quantification précise des effets génétiques et permet de séparer les effets de 'good genes' et de 'compatible genes'. Cela a été fait sous différentes intensités de stress bactérien, ainsi que dans des conditions naturelles, et nous avons pu ainsi tester si certains indicateurs de qualité génétique des mâles ('good genes') étaient liés a) à la dominance et/ou b) à l'expression des caractères sexuels secondaires des mâles comme l'intensité mélanique ou la taille des tubercules sexuels. En outre, nous cherchons à savoir si la survie des descendants est liée à certaines combinaison des gènes du complexe d'histocompatibilité majeur (MHC) et/ou à la parenté génétique des parents, les deux traits étant soupçonnés d'avoir des influences génétique de compatibilité (`compatible genes') à la performance des descendants. Nous avons constaté que la dominance des mâles est directement liée à la taille et au poids des mâles (truites, vairons), mais également aux caractères sexuels secondaires (tubercules). De plus, les mâles vairons dominant ont eu un succès de fécondation plus élevés que les mâles subordonnés. Nous montrons que les truites et corégones mâles diffèrent dans leur qualité génétique, qui a été mesurée avéc la survie embryonnaire, le temps avant l'éclosion et enfin la croissance juvénile. Contrairement aux prédictions, la dominance (ou les traits indicatifs de dominance) n'était liée à la qualité génétique, dans aucun des traitements, et ne fonctionne donc pas comme indicateur de qualité. Par contre, la qualité génétique était liée aux caractères sexuels secondaires, particulièrement par la teinte mélanique chez les truites. Les embryons de truites issus de pères sombres survivaient mieux que ceux issus de pères clairs dans des environnements difficiles, de plus leur croissance était plus élevée lors de leur première année dans des conditions naturelles. La taille des juvéniles lors de leur première année est un trait important lié au succès dans la compétition pour des ressources telles qu'abri ou nourriture. De plus, les femelles truites peuvent augmenter la survie de leurs descendants en choisissant des mâles selon leur type de MHC ou selon leur degré de parenté. En outre, chez les corégones, la morphologie des tubercules sexuels ne semble pas signaler la qualité génétique. Nous avons également remarqué que l'exposition à des pathogènes non-létaux pouvait influencer la performance des alevins à court et long terme, probablement en affaiblissant leur système immunitaire. Cette thèse montre que les mâles diffèrent dans leur qualité génétique et que différents mécanismes de sélection inter- ou intra-sexuelle (par exemple la préférence pour des mâles sombres, pour des génotypes MHC ou pour des couples avec degré de parenté basse) pouvait avoir un effet positif sur la qualité des descendants, bien que cet effet génétique pouvait changer au cours du temps et entre différents environnements. Contrairement à nos attentes, le résultat de la compétition intra-sexuelle (la hiérarchie de dominance entre mâles) n'était pas lié à la qualité génétique individuelle ('good genes'). Dans ce sens, ce travail permet également de contribuer à l'explication du fait que la sélection sexuelle, de par sa forte sélection directionnelle, ne conduit pas à la diminution de la variance génétique, mais plutôt à la maintenance du polymorphisme génétique. Summary : Sexual selection mechanisms, especially male-male competition (inteasexual selection) and female mate choice (inteasexual selection), can strongly influence individual mating success, often resulting in dominant males and males with elaborate secondary sexual characters having higher fertilisation success. However, siring a high number of offspring alone does not guarantee high individual fitness, as fitness does also strongly depend on offspring performance (i.e. survival, fecundity). If this superiority in offspring performance depends on paternally inherited genes, the fathers are expected to signal this potential indirect benefit to females in order to attain high mating rates. This mechanism is also known as the 'good genes' hypothesis of sexual selection but until now most studies failed to conclusively show the relation of an individual genetic quality and its potential signalling traits. Further, offspring performance could also depend on compatible gene effects. These are alleles that increase offspring performance only in combination with other specific alleles. We first determined male dominance status from intrasexual competition during mating season for brown trout (Salmo trutta) and European minnows (Phoxinus phoxinus). For minnows we additionally checked if dominance and/or secondary sexual traits were linked to fertilisation success. Further, we artificially fertilised brown trout and alpine whitefish (Coregonus palaea) eggs, following full factorial breeding designs, enabling to properly measure `good gene' and `compatible gene' effects on offspring performance. This was done under different intensities of natural stressors, as well as under natural conditions. This procedure allowed us to test if the obtained male genetic quality measures (good genes effects) were indicated by a) dominance or lay traits linked to dominance and/or by b) secondary sexual characteristics such as melanin-based male skin darkness or breeding tubercles. Further, we investigated if offspring survival was linked to the MHC (major histocompatibility complex) gene combinations and/or to the parental genetic relatedness, as both traits were shown to have 'compatible gene' effects that may influence offspring performance. We found that male dominance in intrasexual competition was positively linked to body size, body weight (brown trout, minnows) but also to elaborate secondary sexual characteristics (breeding tubercles in minnows). Further, dominant minnow males did have an increased fertilisation success compared to subordinate ones. We show that brown trout and whitefish males do usually differ in their genetic quality, which was measured as embryo survival, hatching timing and finally as juvenile growth. Contrary to prediction male dominance or dominance indicating traits do not function as a quality signal as they were not linked to genetic quality. This result was constant when measuring genetic quality under different levels of natural stressors and under natural conditions (brown trout). On the other hand genetic quality seemed to be indicated by secondary sexual characteristics, specifically by melanin-based skin darkness in brown trout as brown trout embryos sired by darker fathers had increased survival rates when raised under harsh conditions and. they grew larger as juveniles after one year of growth in a natural stream, which is an important trait influencing success of juveniles in competition for hidings, food and other resources. Furthermore, brown trout females may increase the survival of their embryos when choosing males according to their MHC genotypes or to the general genetic relatedness between themselves and their potential mates. In whitefish on the other hand breeding tubercle morphology did not seem to signal genetic quality. Eventually, we saw that anon-lethal exposure to pathogens might influence short term and long term offspring performance probably by weakening an exposed individual's immune system. This thesis shows that males usually differ in their genetic quality and that different inter- or intrasexual selection mechanisms (e.g. mate selection favouring dark males, preference for MHC genotype combinations or for unrelated mates) may have strong positive effects on genetically dependent offspring performance but that such genetìc effects can change over time and environments. In contrast to our a priori expectations, the outcome of intrasexual selection, namely male dominance hierarchies, with dominant males often having high fertilisation success, was not linked to individual genetic quality (`good genes'). In this sense the present thesis may also be a helpful contribution to understand why sexual selection does not lead to rapid loss of genetic variation by strong directional selection but could even lead to the maintenance of genetic variation in natural populations.

The outcome of acute schistosomiasis infection in adult mice with postnatal exposure to maternal malnutrition

Maternal malnutrition during the lactation period in early development may have long-term programming effects on adult offspring. We evaluated the combined effects of parasitological behaviour and histopathological features and malnutrition during lactation. Lactating mice and their pups were divided into a control group (fed a normal diet of 23% protein), a protein-restricted group (PR) (fed a diet containing 8% protein) and a caloric-restricted group (CR) (fed according to the PR group intake). At the age of 60 days, the offspring were infected with Schistosoma mansoni cercariae and killed at nine weeks post-infection. Food intake, body and liver masses, leptinaemia, corticosteronaemia, collagen morphometry and neogenesis and the cellular composition of liver granulomas were studied. PR offspring showed reduced weight gain and hypophagia, whereas CR offspring became overweight and developed hyperphagia. The pre-patent period was longer (45 days) in both programmed offspring as compared to controls (40 days). The PR-infected group had higher faecal and intestinal egg output and increased liver damage. The CR-infected group showed a lower number of liver granulomas, increased collagen neogenesis and a higher frequency of binucleate hepatocytes, suggesting a better modulation of the inflammatory response and increased liver regeneration. Taken together, our findings suggest that neonatal malnutrition of offspring during lactation affects the outcome of schistosomiasis in mice.