Treatment of genital mycoplasma in colonized pregnant women in late pregnancy is associated with a lower rate of premature labour and neonatal complications.

Mycoplasma hominis and Ureaplasma spp. may colonize the human genital tract and have been associated with adverse pregnancy outcomes such as preterm labour and preterm premature rupture of membranes. However, as these bacteria can reside in the normal vaginal flora, there are controversies regarding their true role during pregnancy and so the need to treat these organisms. We therefore conducted a retrospective analysis to evaluate the treatment of genital mycoplasma in 5377 pregnant patients showing symptoms of potential obstetric complications at 25-37 weeks of gestation. Women presenting with symptoms were routinely screened by culture for the presence of these bacteria and treated with clindamycin when positive. Compared with uninfected untreated patients, women treated for genital mycoplasma demonstrated lower rates of premature labour. Indeed preterm birth rates were, respectively, 40.9% and 37.7% in women colonized with Ureaplasma spp. and M. hominis, compared with 44.1% in uncolonized women (Ureaplasma spp., p 0.024; M. hominis, p 0.001). Moreover, a reduction of neonatal complications rates was observed, with 10.9% of newborns developing respiratory diseases in case of Ureaplasma spp. colonization and 5.9% in the presence of M. hominis, compared with 12.8% in the absence of those bacteria (Ureaplasma spp., p 0.050; M. hominis, p <0.001). Microbiological screening of Ureaplasma spp. and/or M. hominis and pre-emptive antibiotic therapy of symptomatic pregnant women in late pregnancy might represent a beneficial strategy to reduce premature labour and neonatal complications.

A Statistical Analysis of Iowa Premature Concrete Pavement Deterioration, Supplementary Study, HR-1063, 1997

This supplementary project has been undertaken as an effort to continue work previously completed in the Pooled Fund Study of Premature Concrete Pavement Deterioration. As such, it shares the objective of "Identifying the variables that are present in those pavements exhibiting premature deterioration," by collecting additional data and performing statistical analysis of those data. The approach and philosophy of this work are identical to that followed in the above project, and the Pooled Fund Study Final Report provides a detailed description of this process. This project has involved the collection of data for additional sites in the state of Iowa. These sites have then been added to sites collected in the original study, and statistical analysis has been performed on the entire set. It is hoped that this will have two major effects. First, using data from only one state allows for the analysis of a larger set of independent variables with a greater degree of commonality than was possible in the multi-state study, since the data are not limited by state to state differences in data collection and retention. Second, more data on additional sites will increase the degrees of freedom in the model and hopefully add confidence to the results.

Pooled Fund Study of Premature Concrete Pavement Deterioration, HR-1063, Supplementary Study, 1997

Recently, a number of roads have begun to exhibit the onset of deterioration at relatively early ages. Since this deterioration appears to be the result of materials issues, data concerning raw materials, design, and paving conditions have been collected and analyzed for correlation between independent variables and deterioration. This analysis shows that there is a positive and statistically significant correlation between deterioration and the following variables: alkali and sulfate content of the cementitious materials, impermeable base course, paving temperature, and the presence of fly ash. This study also concludes that there is a significant need for improvement in data collection and maintenance by many organizations responsible for the production of concrete.

S100A1 deficiency results in prolonged ventricular repolarization in response to sympathetic activation.

S100A1 is a Ca(2+)-binding protein and predominantly expressed in the heart. We have generated a mouse line of S100A1 deficiency by gene trap mutagenesis to investigate the impact of S100A1 ablation on heart function. Electrocardiogram recordings revealed that after beta-adrenergic stimulation S100A1-deficient mice had prolonged QT, QTc and ST intervals and intraventricular conduction disturbances reminiscent of 2 : 1 bundle branch block. In order to identify genes affected by the loss of S100A1, we profiled the mutant and wild type cardiac transcriptomes by gene array analysis. The expression of several genes functioning to the electrical activity of the heart were found to be significantly altered. Although the default prediction would be that mRNA and protein levels are highly correlated, comprehensive immunoblot analyses of salient up- or down-regulated candidate genes of any cellular network revealed no significant changes on protein level. Taken together, we found that S100A1 deficiency results in cardiac repolarization delay and alternating ventricular conduction defects in response to sympathetic activation accompanied by a significantly different transcriptional regulation.

Antiretroviral therapy during pregnancy and premature birth: analysis of Swiss data.

BACKGROUND: There is an ongoing debate as to whether combined antiretroviral treatment (cART) during pregnancy is an independent risk factor for prematurity in HIV-1-infected women. OBJECTIVE: The aim of the study was to examine (1) crude effects of different ART regimens on prematurity, (2) the association between duration of cART and duration of pregnancy, and (3) the role of possibly confounding risk factors for prematurity. METHOD: We analysed data from 1180 pregnancies prospectively collected by the Swiss Mother and Child HIV Cohort Study (MoCHiV) and the Swiss HIV Cohort Study (SHCS). RESULTS: Odds ratios for prematurity in women receiving mono/dual therapy and cART were 1.8 [95% confidence interval (CI) 0.85-3.6] and 2.5 (95% CI 1.4-4.3) compared with women not receiving ART during pregnancy (P=0.004). In a subgroup of 365 pregnancies with comprehensive information on maternal clinical, demographic and lifestyle characteristics, there was no indication that maternal viral load, age, ethnicity or history of injecting drug use affected prematurity rates associated with the use of cART. Duration of cART before delivery was also not associated with duration of pregnancy. CONCLUSION: Our study indicates that confounding by maternal risk factors or duration of cART exposure is not a likely explanation for the effects of ART on prematurity in HIV-1-infected women.

Effects of paralysis with pancuronium bromide on joint mobility in premature infants.

To study the effects of muscle paralysis on joint mobility, we compared eight premature infants treated with pancuronium bromide with a control group. A significant reduction was observed in hip and knee flexion, and in ankle dorsal extension, which tended to resolve in time. We conclude that muscle paralysis reduces the mobility of selected joints; spontaneous activity appears to prevent long-term contractures.

Ebstein's anomaly: one and a half ventricular repair.

Patients with Ebstein's anomaly can present after childhood or adolescence with cyanosis, arrhythmias, severe right ventricular dysfunction and frequently with left ventricular dysfunction secondary to the prolonged cyanosis and to the right ventricular interference. At this point conventional repair is accompanied by elevated mortality and morbidity and poor functional results. We report our experience with three patients (8, 16 and 35 years of age) with Ebstein's anomaly, very dilated right atrium, severe tricuspid valve regurgitation (4/4), bi-directional shunt through an atrial septal defect and reduced left ventricular function (mean ejection fraction = 58%, mean shortening fraction = 25%). All underwent one and a half ventricular repair consisting of closure of the atrial septal defect, tricuspid repair with reduction of the atrialised portion of the right ventricle and end-to-side anastomosis of the superior vena cava to the right pulmonary artery. All patients survived, with a mean follow-up of 33 months. In all there was complete regression of the cyanosis and of the signs of heart failure. Postoperative echocardiography showed reduced degree of tricuspid regurgitation (2/4) and improvement of the left ventricular function (mean ejection fraction = 77%, mean shortening fraction = 40%). In patients with Ebstein's anomaly referred late for surgery with severely compromised right ventricular function or even with reduced biventricular function, the presence of a relatively hypoplastic and/or malfunctioning right ventricular chamber inadequate to sustain the entire systemic venous return but capable of managing part of the systemic venous return, permits a one and a half ventricular repair with good functional results.

Cellular delivery of pyrenyl-arene ruthenium complexes by a water-soluble arene ruthenium metalla-cage.

Three pyrenyl-arene ruthenium complexes (M(1)-M(3)) of the general formula [Ru(η(6)-arene-pyrenyl)Cl(2)(pta)] (pta = 1,3,5-triaza-7-phosphaadamantane) have been synthesised and characterised. Prior to the coordination to ruthenium, pyrene was connected to the arene ligand via an alkane chain containing different functional groups: ester (L(1)), ether (L(2)) and amide (L(3)), respectively. Furthermore, the pyrenyl moieties of the M(n) complexes were encapsulated within the hydrophobic cavity of the water soluble metalla-cage, [Ru(6)(η(6)-p-cymene)(6)(tpt)(2)(donq)(3)](6+) (tpt = 2,4,6-tri-(pyridin-4-yl)-1,3,5-triazine; donq = 5,8-dioxydo-1,4-naphthoquinonato), while the arene ruthenium end was pointing out of the cage, thus giving rise to the corresponding host-guest systems [M(n)⊂Ru(6)(η(6)-p-cymene)(6)(tpt)(2)(donq)(3)](6+) ([M(n)⊂cage](6+)). The antitumor activity of the pyrenyl-arene ruthenium complexes (M(n)) and the corresponding host-guest systems [M(n)⊂cage][CF(3)SO(3)](6) were evaluated in vitro in different types of human cancer cell lines (A549, A2780, A2780cisR, Me300 and HeLa). Complex M(2), which contains an ether group within the alkane chain, demonstrated at least a 10 times higher cytotoxicity than the reference compound [Ru(η(6)-p-cymene)Cl(2)(pta)] (RAPTA-C). All host-guest systems [M(n)⊂cage](6+) showed good anticancer activity with IC(50) values ranging from 2 to 8 μM after 72 h exposure. The fluorescence of the pyrenyl moiety allowed the monitoring of the cellular uptake and revealed an increase of uptake by a factor two of the M(2) complex when encapsulated in the metalla-cage [Ru(6)(η(6)-p-cymene)(6)(tpt)(2)(donq)(3)](6+).

Somatostatin Subtype‑2 Receptor-Targeted Metal-Based Anticancer Complexes

Conjugates of a dicarba analogue of octreotide, a potent somatostatin agonist whose receptors are overexpressed on tumor cells, with [PtCl2(dap)] (dap = 1-(carboxylic acid)-1,2-diaminoethane) (3), [(η6-bip)Os(4-CO2-pico)Cl] (bip = biphenyl, pico = picolinate) (4), [(η6-p-cym)RuCl(dap)]+ (p-cym = p-cymene) (5), and [(η6-p-cym)RuCl(imidazole-CO2H)(PPh3)]+ (6), were synthesized by using a solid-phase approach. Conjugates 35 readily underwent hydrolysis and DNA binding, whereas conjugate 6 was inert to ligand substitution. NMR spectroscopy and molecular dynamics calculations showed that conjugate formation does not perturb the overall peptide structure. Only 6 exhibited antiproliferative activity in human tumor cells (IC50 = 63 ± 2 μM in MCF-7 cells and IC50 = 26 ± 3 μM in DU-145 cells) with active participation of somatostatin receptors in cellular uptake. Similar cytotoxic activity was found in a normal cell line (IC50 = 45 ± 2.6 μM in CHO cells), which can be attributed to a similar level of expression of somatostatin subtype-2 receptor. These studies provide new insights into the effect of receptor-binding peptide conjugation on the activity of metal-based anticancer drugs, and demonstrate the potential of such hybrid compounds to target tumor cells specifically.

High prevalence of major cardiovascular risk factors in first-degree relatives of individuals with familial premature coronary artery disease : the GENECARD project

Rapport de synthèse La prévalence de l'hypertension artérielle, d'une dyslipidémie, d'une obésité et d'un tabagisme est élevée chez les patients qui souffrent d' une maladie coronarienne familiale précoce (MC-FP). L? e but de cette étude fut d'investiguer la prévalence de ces facteurs de risque cardiovasculaires au sein des membres d'une famille dont un patient est affecté d'une MC-FP. Nous avons étudié 108 familles différentes dont au minimum 2 frères/soeurs ont survécu à une maladie coronarienne précoce. Cette dernière fut définie par la survenue d'un événement coronarien avant l'âge de 51 ans pour les hommes et 56 ans pour les femmes. Au total, nous avons identifié 222 patients atteints de MC-FP chez qui 158 frères/soeurs, 197 enfants et 94 époux/épouses ne souffraient pas de maladie coronarienne. Ces parents proches furent comparés à un collectif d'individus "contrôles" issus de la population générale. Les frères/soeurs non affectés avaient une prévalence plus élevée d'hypertension artérielle (49% versus 24%, p<0.001), d'hypercholestérolémie (47% versus 34%, p=0.002), d'obésité abdominale (35% versus 24%, p=0.006) et de tabagisme (39% versus 24%, p=0.001) par rapport aux individus issus de la population générale. Parmi les enfants, une prévalence plus élevée d'hypertension artérielle fut identifiée chez les femmes, et une prévalence plus élevée d'hypercholestérolémie et d'obésité abdominale dans les deux sexes par rapport aux contrôles de la population générale. Aucune différence parmi les facteurs de risque cardiovasculaire n'a été observée entre les époux/ épouses et les contrôles. Les frères/soeurs affectés et non affectés par la MC-FP ont également été comparés entre eux. La prévalence des facteurs de risque était similaire dans les 2 groupes, sauf pour le tabagisme, qui avait une prévalence plus élevée chez les frères/sueurs affectés (76% versus 39%, p=0.008). La prévalence de l'hypertension artérielle, de l'obésité, et de la dyslipidémie est également élevée chez les parents de premier degré de patients atteints de MC-FP, mais pas chez leurs époux/épouses. Ces personnes-là requièrent donc une attention médicale particulière en raison d'une vulnérabilité familiale et/ou génétique augmentée aux anomalies métaboliques athérogènes. Dans ces familles, le tabagisme pourrait être le facteur déclenchant de la MC-FP.

The VAD connection : connecting ventricular assist devices to the aorta in silico

Les systèmes d'assistance ventriculaire sont apparus durant la dernière décade comme une approche thérapeutique efficace du traitement de l'insuffisance cardiaque terminale, en particulier dans le contexte de manque de donneurs d'organes. Néanmoins, et ceci malgré les progrès techniques majeurs, les taux de complications restent élevés et sont en partie liés à la configuration géométrique, en particulier le site d'implantation de la cannule de sortie à l'aorte thoracique. Bien que l'anastomose à l'aorte descendante permette une chirurgie moins invasive, les bénéfices de cette technique sont toujours controversés, comparée à la méthode standard de l'aorte ascendante, en raison du risque thrombo-embolique possiblement augmenté et des modifications hémodynamiques induites au niveau de l'arc aortique. Dans ce travail, nous comparons in silico en terme de débit et pression les deux possibilités anastomotiques. Nous développons un réseau de modèles mathématiques unidimensionnels, et l'appliquons à diverses situations cliniques, pour différents stades d'insuffisance cardiaque et de vitesses de rotation de la machine. Les données initiales sont obtenues grâce à un modèle OD (c'est-à-dire qui dépend uniquement du temps mais pas de l'espace) du système cardiovasculaire comprenant une assistance circulatoire, validé avec des données cliniques. Les simulations réalisées montrent que les deux méthodes sont similaires, en terme de débit et courbes de pression, ceci pour tous les cas cliniques étudiés. Ces résultats numériques soutiennent la possibilité d'utiliser la technique d'anastomose à l'aorte thoracique descendante, permettant une chirurgie moins invasive. Sur un plan plus fondamental, le système cardiovasculaire peut être simulé par le biais de multiples modèles de niveau de complexité différents, au prix d'un coût computationnel toujours plus élevé. Nous évaluons les avantages de modèles géométriques à plusieurs échelles (uni- et tridimensionnelle) avec données provenant de patients, comparés à des modèles simplifiés. Les résultats montrent que ces modèles de dimensions hétérogènes apportent un bénéfice important en terme de ressources de calcul, tout en conservant une précision acceptable. En conclusion, ces résultats encourageant montrent la relevance des études numériques dans le domaine médical, tant sur le plan fondamental et la compréhension des mécanismes physiopathologiques, que sur le plan applicatif et le développement de nouvelles thérapeutiques.

Cardiac raptor deletion impairs adaptive hypertrophy, alters metabolic gene expression and causes heart failure in mice

Background: Mammalian target of rapamycin (mTOR), a central regulator of cell growth, is found in two structurally and functionally distinct multiprotein complexes called mTOR complex (mTORC)1 and mTORC2. The specific roles of each of these branches of mTOR signaling have not been dissected in the adult heart. In the present study, we aimed to bring new insights into the function of cardiac mTORC1-mediated signaling in physiological as well as pathological situations.Methods: We generated mice homozygous for loxP-flanked raptor and positive for the tamoxifen-inducible Cre recombinase (MerCreMer) under control of the α- myosin heavy chain promoter. The raptor gene encodes an essential component of mTORC1. Gene ablation was induced at the age of 10-12 weeks, and two weeks later the raptor cardiac-knockout (raptor-cKO) mice started voluntary cagewheel exercise or were subjected to transverse aortic constriction (TAC) to induce pressure overload.Results: In sedentary raptor-cKO mice, ejection fractions gradually decreased, resulting in significantly reduced values at 38 days (P < 0.001). Raptor-cKO mice started to die during the fifth week after the last tamoxifen injection. At that time, the mortality rate was 36% in sedentary (n = 11) and 64% in exercising (n = 14) mice. TAC-induced pressure overload resulted in severe cardiac dysfunction already at earlier timepoints. Thus, at 7-9 days after surgery, ejection fraction and fractional shortening values were 22.3% vs 43.5% and 10.2% vs 21.5% in raptor-cKO vs wild-type mice, respectively. This was accompanied by significant reductions of ventricular wall and septal thickness as well as an increase in left ventricular internal diameter. Moreover, ventricular weight to tibial length ratios were increased in wild-type, but not in the raptor-cKO TAC mice. Together, this shows that raptor-cKO mice rapidly developed dilated cardiomyopathy without going through a phase of adaptive hypertrophy. Expression of ANP and β-MHC was induced in all raptor-cKO mice irrespective of the cardiac load conditions. Consistent with reduced mTORC1 activity, phosphorylation of ribosomal S6 kinase and 4E-BP1 was blunted, indicating reduced protein synthesis. Moreover, expression of multiple genes involved in the regulation of energy metabolism was altered, and followed by a shift from fatty acid to glucose oxidation.Conclusion: Our study suggests that mTORC1 coordinates protein and energy metabolic pathways in the heart. Moreover, we demonstrate that raptor is essential for the cardiac adaptation to increased workload and importantly, also for normal physiological cardiac function.