Vascular dysfunction in offspring of preeclampsia is related to preeclampsia per se rather than genetically determined

Objectives: Epidemiological studies suggest that adverse events in utero may predispose to premature cardiovascular disease in adulthood, but the mechanisms are not known. Recently, we found that young apparently healthy offspring of mothers with preeclampsia (PE) display systemic endothelial dysfunction. This problem could be related to PE per se or to a genetic abnormality that predisposes the mother to PE and the offspring to vascular dysfunction. To distinguish between these two possibilities, we assessed vascular function in offspring of PE, their siblings who were born after a normal pregnancy, and in control subjects.Methods: We measured endothelium-dependent vasodilation (flow-mediated vasodilation, FMD), in 10 pairs of healthy normotensive siblings, one born after PE (age 15±6 y; mean±SD), the other after normal pregnancy (17±6y) and in 17 (16±7y) controls. All subjects were born at term.Results: The vascular function in siblings of PE who were born after normal pregnancy was normal and comparable to the one in controls (8.6±1.5% vs. 8.1±1.3%, P=0.32), whereas offspring of PE displayed a roughly 30% smaller FMD than the two other groups (5.9±1.6%, P<0.005 vs. both siblings and controls, Figure). The endothelial dysfunction in the offspring of PE was not related to a difference in the central arterial blood pressure or arterial oxygen saturation, because they were comparable in the 3 groups. Figure 1. FMD in the three groups.Conclusions: These findings provide the first evidence that vascular dysfunction in offspring of PE is caused by PE itself, rather than by a genetic abnormality that predisposes the mother to PE and the offspring to a vascular defect. Prevention of PE and/or its successful treatment is expected to prevent vascular dysfunction and premature cardiovascular morbidity and mortality in the offspring.

Macular and retinal dysfunction of unknown origin in adults with normal fundi: evidence for an autoimmune pathophysiology.

Here we report the discovery of and phenotypic characterization of a retinal disorder of unknown origin in adults using clinical, electrophysiological and psychophysical techniques, and to seek the presence of circulating retinal autoantibodies in the sera of these patients. Sixteen patients were identified with progressive bilateral visual loss over a period of months. Ten of the patients were male, and the average age was 55.3 years (range from 43 to 76 years). Known causes such as carcinoma-associated retinopathy, acute zonal occult outer retinopathy and hereditary cone dystrophy appeared unlikely. Investigations included electrophysiology, fundus autofluorescence imaging and psychophysical tests. The sera of these patients were analyzed with indirect immunocytochemistry and Western immunoblot analysis on murine (BALB/c) retinal tissue for the presence of retinal autoantibodies. Bilateral visual loss and photophobia progressed over a period of months to years (average 28.7 months, range 3-67) and subsequently stabilized. No abnormality was observed by biomicroscopy, angiography or autofluorescence imaging. Electrophysiology indicated predominant cone-system dysfunction, either macular or generalized, and post-phototransduction involvement in 9 patients (56%). Photopic and scotopic visual fields and dark adaptation kinetics showed both cone and rod system involvement in all cases. Heterogeneous immunohistochemical staining patterns were seen with the sera of these patients as compared with controls. A majority of the affected patients (9/15) stained with an antinuclear pattern. The retinal autoantibodies from the sera of most patients reacted with the retinal proteins of molecular weight between 34 and 40 kDa. The aetiology of this distinctive retinal disorder therefore appears to be mediated through an autoimmune mechanism.

La programmmation foetale de la dysfonction vasculaire pulmonaire chez la souris : rôle des mécanismes épigénétiques = Fetal programming of pulmonary vascular dysfunction in mice : role of epigenetic mechanisms

Rapport de synthèseDes événements pathologiques survenant pendant la période foetale prédisposent la descendance aux maladies cardiovasculaires systémiques. Il existe peu de connaissances au sujet de la circulation pulmonaire et encore moins quant aux mécanismes sous-jacents. La sous-alimentation maternelle pendant la grossesse peut représenter un modèle d'investigation de ces mécanismes, parce que chez l'animal et l'homme elle est associée à une dysfonction vasculaire systémique chez la progéniture. Chez le rat, la diète restrictive pendant la grossesse induit une augmentation du stress oxydatif dans le placenta. Les dérivés de l'oxygène sont connus pour induire des altérations épigénétiques et peuvent traverser la barrière placentaire. Nous avons dès lors spéculé que chez la souris la diète restrictive pendant la grossesse induit une dysfonction vasculaire pulmonaire chez sa progéniture qui serait liée à un mécanisme épigénétique.Pour tester cette hypothèse, nous avons examiné la fonction vasculaire pulmonaire et la méthylation de l'ADN pulmonaire à la fin de 2 semaines d'exposition à l'hypoxie chez la progéniture de souris soumises à une diète restrictive pendant la grossesse et des souris contrôles. Nous avons trouvé que la vasodilatation endothélium-dépendante de l'artère pulmonaire in vitro était défectueuse, et que l'hypertension pulmonaire et l'hypertrophie ventriculaire droite induites par l'hypoxie in vivo étaient exagérées chez la progéniture de souris soumises à une diète restrictive pendant la grossesse. Cette dysfonction vasculaire pulmonaire était associée avec une altération de la méthylation de l'ADN pulmonaire. L'administration d'inhibiteurs de la déacétylase des histones, le Butyrate et la Trichostatine-A à la progéniture de souris soumises à une diète restrictive pendant la grossesse a normalisé la méthylation de l'ADN et la fonction vasculaire pulmonaire. Finalement, l'administration du nitroxyde Tempol aux mères durant la diète restrictive pendant la grossesse a prévenu la dysfonction vasculaire et la dysméthylation chez la progéniture.Ces découvertes démontrent que chez la souris la sous-alimentation pendant la gestation induit une dysfonction vasculaire chez la progéniture qui est causée par un mécanisme épigénétique. Il est possible qu'un mécanisme similaire soit impliqué dans la programmation foetale de la dysfonction vasculaire chez les humains.

Subclinical thyroid dysfunction, cardiac function, and the risk of heart failure. The Cardiovascular Health study.

OBJECTIVES: The goal of this study was to determine whether subclinical thyroid dysfunction was associated with incident heart failure (HF) and echocardiogram abnormalities. BACKGROUND: Subclinical hypothyroidism and hyperthyroidism have been associated with cardiac dysfunction. However, long-term data on the risk of HF are limited. METHODS: We studied 3,044 adults>or=65 years of age who initially were free of HF in the Cardiovascular Health Study. We compared adjudicated HF events over a mean 12-year follow-up and changes in cardiac function over the course of 5 years among euthyroid participants, those with subclinical hypothyroidism (subdivided by thyroid-stimulating hormone [TSH] levels: 4.5 to 9.9, >or=10.0 mU/l), and those with subclinical hyperthyroidism. RESULTS: Over the course of 12 years, 736 participants developed HF events. Participants with TSH>or=10.0 mU/l had a greater incidence of HF compared with euthyroid participants (41.7 vs. 22.9 per 1,000 person years, p=0.01; adjusted hazard ratio: 1.88; 95% confidence interval: 1.05 to 3.34). Baseline peak E velocity, which is an echocardiographic measurement of diastolic function associated with incident HF in the CHS cohort, was greater in those patients with TSH>or=10.0 mU/l compared with euthyroid participants (0.80 m/s vs. 0.72 m/s, p=0.002). Over the course of 5 years, left ventricular mass increased among those with TSH>or=10.0 mU/l, but other echocardiographic measurements were unchanged. Those patients with TSH 4.5 to 9.9 mU/l or with subclinical hyperthyroidism had no increase in risk of HF. CONCLUSIONS: Compared with euthyroid older adults, those adults with TSH>or=10.0 mU/l have a moderately increased risk of HF and alterations in cardiac function but not older adults with TSH<10.0 mU/l. Clinical trials should assess whether the risk of HF might be ameliorated by thyroxine replacement in individuals with TSH>or=10.0 mU/l.

Treatment of ruptured abdominal aortic aneurysm, a permanent challenge or a waste of resources? Prediction of outcome using a multi-organ-dysfunction score.

OBJECTIVES: in a retrospective study, attempts have been made to identify individual organ-dysfunction risk profiles influencing the outcome after surgery for ruptured abdominal aortic aneurysms. METHODS: out of 235 patients undergoing graft replacement for abdominal aortic aneurysms, 57 (53 men, four women, mean age 72 years [s.d. 8.8]) were treated for ruptured aneurysms in a 3-year period. Forty-eight preoperative, 13 intraoperative and 34 postoperative variables were evaluated statistically. A simple multi-organ dysfunction (MOD) score was adopted. RESULTS: the perioperative mortality was 32%. Three patients died intraoperatively, four within 48 h and 11 died later. A significant influence for pre-existing risk factors was identified only for cardiovascular diseases. Multiple linear-regression analysis indicated that a haemoglobin <90 g/l, systolic blood pressure <80 mmHg and ECG signs of ischaemia at admission were highly significant risk factors. The cause of death for patients, who died more than 48 h postoperatively, was mainly MOD. All patients with a MOD score >/=4 died (n=7). These patients required 27% of the intensive-care unit (ICU) days of all patients and 72% of the ICU days of the non-survivors. CONCLUSION: patients with ruptured aortic aneurysms from treatment should not be excluded. However, a physiological scoring system after 48 h appears justifiable in order to decide on the appropriateness of continual ICU support.

Evolution of uni- and bifactorial sexual compatibility systems in fungi.

Mating systems, that is, whether organisms give rise to progeny by selfing, inbreeding or outcrossing, strongly affect important ecological and evolutionary processes. Large variations in mating systems exist in fungi, allowing the study of their origin and consequences. In fungi, sexual incompatibility is determined by molecular recognition mechanisms, controlled by a single mating-type locus in most unifactorial fungi. In Basidiomycete fungi, however, which include rusts, smuts and mushrooms, a system has evolved in which incompatibility is controlled by two unlinked loci. This bifactorial system probably evolved from a unifactorial system. Multiple independent transitions back to a unifactorial system occurred. It is still unclear what force drove evolution and maintenance of these contrasting inheritance patterns that determine mating compatibility. Here, we give an overview of the evolutionary factors that might have driven the evolution of bifactoriality from a unifactorial system and the transitions back to unifactoriality. Bifactoriality most likely evolved for selfing avoidance. Subsequently, multiallelism at mating-type loci evolved through negative frequency-dependent selection by increasing the chance to find a compatible mate. Unifactoriality then evolved back in some species, possibly because either selfing was favoured or for increasing the chance to find a compatible mate in species with few alleles. Owing to the existence of closely related unifactorial and bifactorial species and the increasing knowledge of the genetic systems of the different mechanisms, Basidiomycetes provide an excellent model for studying the different forces that shape breeding systems.

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.

International differences in alcohol use according to sexual orientation.

Most research on sexual orientation and alcohol use in the United States has found higher rates of alcohol use and abuse among gay men and lesbians. Studies from other countries have found smaller or no differences between sexual minority and heterosexual women and men. The present study used general population survey data from 14 countries to examine high-volume and risky single-occasion drinking by sexual orientation. Data from 248 gay men and lesbians and 3720 heterosexuals were analyzed in a case-control design. In several countries partnered or recently partnered gay men and lesbians had no greater risk of heavy drinking or engaging in heavy drinking than heterosexual controls. Only lesbians in North America showed higher risk for both indicators. Future general population health research should include larger samples of gays and lesbians and use more comprehensive measures of sexual orientation for investigating the prevalence of health risk factors.

Insulin-secreting beta-cell dysfunction induced by human lipoproteins.

Diabetes is associated with significant changes in plasma concentrations of lipoproteins. We tested the hypothesis that lipoproteins modulate the function and survival of insulin-secreting cells. We first detected the presence of several receptors that participate in the binding and processing of plasma lipoproteins and confirmed the internalization of fluorescent low density lipoprotein (LDL) and high density lipoprotein (HDL) particles in insulin-secreting beta-cells. Purified human very low density lipoprotein (VLDL) and LDL particles reduced insulin mRNA levels and beta-cell proliferation and induced a dose-dependent increase in the rate of apoptosis. In mice lacking the LDL receptor, islets showed a dramatic decrease in LDL uptake and were partially resistant to apoptosis caused by LDL. VLDL-induced apoptosis of beta-cells involved caspase-3 cleavage and reduction in the levels of the c-Jun N-terminal kinase-interacting protein-1. In contrast, the proapoptotic signaling of lipoproteins was antagonized by HDL particles or by a small peptide inhibitor of c-Jun N-terminal kinase. The protective effects of HDL were mediated, in part, by inhibition of caspase-3 cleavage and activation of Akt/protein kinase B. In conclusion, human lipoproteins are critical regulators of beta-cell survival and may therefore contribute to the beta-cell dysfunction observed during the development of type 2 diabetes.

Insularity and the evolution of melanism, sexual dichromatism and body size in the worldwide-distributed barn owl.

Abstract Island biogeography has provided fundamental hypotheses in population genetics, ecology and evolutionary biology. Insular populations usually face different feeding conditions, predation pressure, intraspecific and interspecific competition than continental populations. This so-called island syndrome can promote the evolution of specific phenotypes like a small (or large) body size and a light (or dark) colouration as well as influence the evolution of sexual dimorphism. To examine whether insularity leads to phenotypic differentiation in a consistent way in a worldwide-distributed nonmigratory species, we compared body size, body shape and colouration between insular and continental barn owl (Tyto alba) populations by controlling indirectly for phylogeny. This species is suitable because it varies in pheomelanin-based colouration from reddish-brown to white, and it displays eumelanic black spots for which the number and size vary between individuals, populations and species. Females are on average darker pheomelanic and display more and larger eumelanic spots than males. Our results show that on islands barn owls exhibited smaller and fewer eumelanic spots and lighter pheomelanic colouration, and shorter wings than on continents. Sexual dimorphism in pheomelanin-based colouration was less pronounced on islands than continents (i.e. on islands males tended to be as pheomelanic as females), and on small islands owls were redder pheomelanic and smaller in size than owls living on larger islands. Sexual dimorphism in the size of eumelanic spots was more pronounced (i.e. females displayed much larger spots than males) in barn owls living on islands located further away from a continent. Our study indicates that insular conditions drive the evolution towards a lower degree of eumelanism, smaller body size and affects the evolution of sexual dichromatism in melanin-based colour traits. The effect of insularity was more pronounced on body size and shape than on melanic traits.

Opportunity for sexual selection and effective population size in the lek-breeding European treefrog (Hyla arborea).

Sexual selection in lek-breeding species might drastically lower male effective population size, with potentially important consequences for evolutionary and conservation biology. Using field-monitoring and parental-assignment methods, we analyzed sex-specific variances in breeding success in a population of European treefrogs, to (1) help understanding the dynamics of genetic variance at sex-specific loci, and (2) better quantify the risk posed by genetic drift in this species locally endangered by habitat fragmentation. The variance in male mating success turned out to be markedly lower than values obtained from other amphibian species with polygamous mating systems. The ratio of effective breeding size to census breeding size was only slightly lower in males (0.44) than in females (0.57), in line with the patterns of genetic diversity previously reported from H. arborea sex chromosomes. Combining our results with data on age at maturity and adult survival, we show that the negative effect of the mating system is furthermore compensated by the effect of delayed maturity, so that the estimated instantaneous effective size broadly corresponded to census breeding size. We conclude that the lek-breeding system of treefrogs impacts only weakly the patterns of genetic diversity on sex-linked genes and the ability of natural populations to resist genetic drift.

Complementary effects of adenosine and angiotensin II in hypoxemia-induced renal dysfunction in the rabbit.

The acute renal effects of hypoxemia and the ability of the co-administration of an angiotensin converting enzyme inhibitor (perindoprilat) and an adenosine receptor antagonist (theophylline) to prevent these effects were assessed in anesthetized and mechanically-ventilated rabbits. Renal blood flow (RBF) and glomerular filtration rate (GFR) were determined by the clearances of para-aminohippuric acid and inulin, respectively. Each animal acted as its own control. In 8 untreated rabbits, hypoxemia induced a significant drop in mean blood pressure (-12 +/- 2%), GFR (-16 +/- 3%) and RBF (-12 +/- 3%) with a concomitant increase in renal vascular resistance (RVR) (+ 18 +/- 5%), without changes in filtration fraction (FF) (-4 +/- 2%). These results suggest the occurrence of both pre- and postglomerular vasoconstriction during the hypoxemic stress. In 7 rabbits pretreated with intravenous perindoprilat (20 microg/kg), the hypoxemia-induced changes in RBF and RVR were prevented. FF decreased significantly (-18 +/- 2%), while the drop in GFR was partially blunted. These results could be explained by the inhibition of the angiotensin-mediated efferent vasoconstriction by perindoprilat. In 7 additional rabbits, co-administration of perindoprilat and theophylline (1 mg/kg) completely prevented the hypoxemia-induced changes in RBF (+ 11 +/- 3%) and GFR (+ 2 +/- 3%), while RVR decreased significantly (-14 +/- 3%). Since adenosine and angiotensin II were both shown to participate, at least in part, in the renal changes induced by hypoxemia, the beneficial effects of perindoprilat and theophylline in this model could be mediated by complementary actions of angiotensin II and adenosine on the renal vasculature.

Having a good relationship with their mother: a protective factor against sexual risk behavior among adolescent females?

STUDY OBJECTIVE: To assess whether having a good relationship with their mother was a protective factor against risky sexual behavior for female adolescents and whether it was independent of family structure. DESIGN: Cross-sectional survey of in-school adolescents aged 14-19 years. SETTING: Catalonia, in northeast Spain. PARTICIPANTS: A total of 3677 females divided according on whether they had a good (n=3335) or a bad (n=342) relationship with their mother. MAIN OUTCOME MEASURES: Rates of sexual activity and sexual behavior. RESULTS: Adolescents in the good relationship group were significantly younger, more likely to live in an intact family, to have a good relationship with their father and siblings, and to talk about sexuality and their partner with their mother. They were also less likely to have ever had sexual intercourse. Among those sexually experienced, they were significantly older at first intercourse and less likely to have multiple partners or a history of STI. After adjusting for potential confounders, females in the good relationship group were less likely to be sexually active and to have had multiple partners, independently of family structure. CONCLUSIONS: Having a good relationship with their mother is a protective factor against sexual intercourse and having multiple sexual partners independently of family structure. Communication between generations and having a good relationship with their father and siblings also play an important role.

Neutral and selection-driven decay of sexual traits in asexual stick insects.

Environmental shifts and lifestyle changes may result in formerly adaptive traits becoming non-functional or maladaptive. The subsequent decay of such traits highlights the importance of natural selection for adaptations, yet its causes have rarely been investigated. To study the fate of formerly adaptive traits after lifestyle changes, we evaluated sexual traits in five independently derived asexual lineages, including traits that are specific to males and therefore not exposed to selection. At least four of the asexual lineages retained the capacity to produce males that display normal courtship behaviours and are able to fertilize eggs of females from related sexual species. The maintenance of male traits may stem from pleiotropy, or from these traits only regressing via drift, which may require millions of years to generate phenotypic effects. By contrast, we found parallel decay of sexual traits in females. Asexual females produced altered airborne and contact signals, had modified sperm storage organs, and lost the ability to fertilize their eggs, impeding reversals to sexual reproduction. Female sexual traits were decayed even in recently derived asexuals, suggesting that trait changes following the evolution of asexuality, when they occur, proceed rapidly and are driven by selective processes rather than drift.