Defining the role of common variation in the genomic and biological architecture of adult human height.

Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ∼2,000, ∼3,700 and ∼9,500 SNPs explained ∼21%, ∼24% and ∼29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/β-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.

Hirschsprung's disease: the "Swiss roll" technique revisited.

PURPOSE: During pull-through for Hirschsprung's disease (HSCR), the assessment of innervation is mainly based on the presence of ganglion cells when conventional Hematoxylin and Eosin (HE) staining is used. In hypoganglionosis, the evaluation is difficult. We adapted a standardized methodology for the examination of resected bowel after HSCR surgery, using the technique described by Moolenbeek on rodent intestine and later by Meier-Ruge in children. We have analysed the entire innervation of surgically resected bowels and compared the results with the follow up of patients. METHODS: Three longitudinal strips of colon were harvested from the mesenteric, anti-mesenteric and intermediate part in the whole length of resected colon of six patients with HSCR. Each strip was divided into two parts. One of the contiguous strips was assessed with HE and Hematoxylin-Phloxin-Safran, and the other one with acetylcholinesterase (AChE) histochemistry. We analyzed the distribution of ganglion cells and nerve arrangement along the strips with both techniques and compared the results obtained in the three different regions of the bowel. RESULTS: There was no significant difference in the pattern of innervation circumferentially. There was a correlation between a progressive increase of AChE activity and nerve hypertrophy and a decrease of ganglion cells from the proximal to the distal part of the resected colon in the submucosa and the myenteric plexus. Nerve hypertrophy and AChE-positive reaction in the mucosa were found at the resection border in patients who presented postoperative complications. CONCLUSIONS: Simultaneous assessment of nerve cells, nerve fibers and AChE activity is important in the evaluation of the innervation of the bowel segment proximal to the aganglionic zone. The method described is feasible and can be adapted to older children and adults with larger bowels. These results point out the importance of assessing nerve fibers in intraoperative biopsies during pull-through procedures to prevent uncomplete surgical bowel resection.

Isolated congenital atrioventricular block diagnosed in utero: natural history and outcome.

BACKGROUND: Isolated congenital atrioventricular block (CAVB) diagnosed in utero is associated with a high morbidity and mortality. Prognosis is especially poor when heart rate drops below 55 beats per minute (bpm) and when fetal hydrops develops. We describe the natural history and outcome of 24 infants with isolated CAVB diagnosed in utero, review the literature, and assess the risk factors that could predict outcome. METHODS: This was a retrospective multicenter study of 24 patients with isolated CAVB diagnosed in utero. RESULTS: CAVB was detected at a mean gestational age (GA) of 24.7 +/- 5.1 weeks. Ten fetuses initially presented with complete heart block. Low heart rate or incomplete heart block was the first documentation of bradyarrhythmia in the other 14 fetuses. In 11 of them, CAVB developed during pregnancy after a median time of 3 (range 1-16) weeks. Fetal hydrops developed in 10 of 24 (42%) fetuses at a mean GA of 27.6 +/- 5.1 weeks. Hydropic fetuses showed lower heart rates during pregnancy (47 +/- 10 bpm) than non-hydropic fetuses (57 +/- 10 bpm). There were three intrauterine deaths; all were hydropic and female. Nine viable females and 12 males were born at a mean GA of 37.1 +/- 6.1 weeks with an average birth weight of 3097 +/- 852 g. Fifteen CAVB patients required pacemaker (PM) intervention, 10 of them immediately after birth. Dilated cardiomyopathy (DCM) developed in three infants of whom two died of congestive heart failure, shortly after the diagnosis was made; one is still alive. Mortality before or after birth was 21%, and was associated with heart rates below 50 bpm and development of fetal hydrops. Poor outcome, defined as death, PM implantation, or development of DCM, occurred in 83% of cases and was associated with heart rates below 60 bpm during pregnancy. CONCLUSIONS: Isolated CAVB diagnosed in utero is associated with high morbidity and mortality. Patients who develop fetal hydrops show lower heart rates during pregnancy than patients who do not. A fetal heart rate below 50 bpm and development of fetal hydrops is associated with increased mortality. Rates below 60 bpm are associated with PM requirement and/or DCM.

Referral patterns and outcomes in noncritically ill patients with hospital-acquired acute kidney injury.

Background and objectives Despite modern treatment, the case fatality rate of hospital-acquired acute kidney injury (HA-AKI) is still high. We retrospectively described the prevalence and the outcome of HA-AKI without nephrology referral (nrHA-AKI) and late referred HA-AKI patients to nephrologists (lrHA-AKI) compared with early referral patients (erHA-AKI) with respect to renal function recovery, renal replacement therapy (RRT) requirement, and in-hospital mortality of HA-AKI. Design, setting, participants, & measurements Noncritically ill patients admitted to the tertiary care academic center of Lausanne, Switzerland, between 2004 and 2008 in the medical and surgical services were included. Acute kidney injury was defined using the Acute Kidney Injury Network (AKIN) classification. Results During 5 years, 4296 patients (4.12% of admissions) experienced 4727 episodes of HA-AKI during their hospital stay. The mean ± SD age of the patients was 61 ± 15 years with a 55% male predominance. There were 958 patients with nrHA-AKI (22.3%) and 2504 patients with lrHA-AKI (58.3%). RRT was required in 31% of the patients with lrHA-AKI compared with 24% of the patients with erHA-AKI. In the multiple risk factor analysis, compared with erHA-AKI, nrHA-AKI and lrHA-AKI were significantly associated with worse renal outcome and higher in-hospital mortality. Conclusions These data suggest that HA-AKI is frequent and the patients with nrHA-AKI or lrHA-AKI are at increased risk for in-hospital morbidity and mortality.

MsrR contributes to cell surface characteristics and virulence in Staphylococcus aureus.

MsrR, a factor contributing to methicillin resistance in Staphylococcus aureus, belongs to the LytR-CpsA-Psr family of cell envelope-associated proteins. Deletion of msrR increased cell size and aggregation, and altered envelope properties, leading to a temporary reduction in cell surface hydrophobicity, diminished colony-spreading ability, and an increased susceptibility to Congo red. The reduced phosphorus content of purified cell walls of the msrR mutant suggested a reduction in wall teichoic acids, which may explain some of the observed phenotypes. Microarray analysis of the msrR deletion mutant revealed only minor changes in the global transcriptome, suggesting that MsrR has structural rather than regulatory functions. Importantly, virulence of the msrR mutant was decreased in a nematode-killing assay as well as in rat experimental endocarditis. MsrR is therefore likely to play a role in cell envelope maintenance, cell separation, and pathogenicity of S. aureus.

L'obligation d'usage en droit des marques

Introduction Les marques occupent une place centrale dans le monde économique moderne. Indispensables pour distinguer les produits ou services d'une entreprise sur le marché et guider le consommateur vers l'article de son choix, elles constituent un instrument de marketing et de publicité essentiel. Les investissements souvent considérables liés à la création et au lancement d'une marque méritent une protection adéquate. C'est pourquoi la loi fédérale sur la protection des marques et des indications de provenance (LPM) accorde au titulaire d'un enregistrement de marque le droit exclusif de faire usage de cette marque et d'en disposer. Cette protection est ce¬pendant assortie d'une condition: passé un délai de grâce de cinq ans, la marque doit être utilisée en relation avec les produits ou les services enre-gistrés. C'est le principe de l'obligation d'usage. Ce principe, qui soulève de nombreux problèmes juridiques, n'a pas encore fait l'objet d'une étude systématique approfondie depuis l'entrée en vigueur de la LPM. La présente monographie vise à combler cette lacune. L'étude de l'obligation d'usage implique de se pencher sur deux problèmes principaux: d'une part, l'usage en tant que condition légale au maintien du droit (art. 11 LPM) et, d'autre part, les conséquences du défaut d'usage (art. 12 LPM). Nous avons donc divisé notre recherche en deux parties. La première partie comporte quatre titres. Le titre premier est consacré à la présentation générale de l'obligation d'usage; le deuxième à la notion d'usage de la marque. Le troisième concerne l'usage sous une forme divergeant de la marque enregistrée et la question des produits ou services pour lesquels la marque doit être utilisée. Enfin, le titre quatrième traite des problèmes relatifs au lieu et à l'auteur de l'usage. La seconde partie est divisée en trois titres. Le titre cinquième a pour objet les mécanismes de la déchéance et de la restitution du droit. Le sixième porte sur les justes motifs pour le non-usage et le septième sur les voies de droit permettant d'invoquer la déchéance. Le principe de l'obligation d'usage existait déjà avant l'entrée en vigueur de la loi sur la protection des marques, raison pour laquelle nous commencerons généralement par exposer les principes développés sous l'ancien droit avant d'analyser chaque question. Afin de tenir compte des développements intervenus sur le plan européen, notamment suite à l'adoption de la directive d'harmonisation de 1988, nous examinerons également les solutions retenues en droit français, en droit allemand et en droit communautaire.

Seasonal fluctuations of bacterial community diversity in agricultural soil and experimental validation by laboratory disturbance experiments.

Natural fluctuations in soil microbial communities are poorly documented because of the inherent difficulty to perform a simultaneous analysis of the relative abundances of multiple populations over a long time period. Yet, it is important to understand the magnitudes of community composition variability as a function of natural influences (e.g., temperature, plant growth, or rainfall) because this forms the reference or baseline against which external disturbances (e.g., anthropogenic emissions) can be judged. Second, definition of baseline fluctuations in complex microbial communities may help to understand at which point the systems become unbalanced and cannot return to their original composition. In this paper, we examined the seasonal fluctuations in the bacterial community of an agricultural soil used for regular plant crop production by using terminal restriction fragment length polymorphism profiling (T-RFLP) of the amplified 16S ribosomal ribonucleic acid (rRNA) gene diversity. Cluster and statistical analysis of T-RFLP data showed that soil bacterial communities fluctuated very little during the seasons (similarity indices between 0.835 and 0.997) with insignificant variations in 16S rRNA gene richness and diversity indices. Despite overall insignificant fluctuations, between 8 and 30% of all terminal restriction fragments changed their relative intensity in a significant manner among consecutive time samples. To determine the magnitude of community variations induced by external factors, soil samples were subjected to either inoculation with a pure bacterial culture, addition of the herbicide mecoprop, or addition of nutrients. All treatments resulted in statistically measurable changes of T-RFLP profiles of the communities. Addition of nutrients or bacteria plus mecoprop resulted in bacteria composition, which did not return to the original profile within 14 days. We propose that at less than 70% similarity in T-RFLP, the bacterial communities risk to drift apart to inherently different states.