Rare genomic structural variants in complex disease: lessons from the replication of associations with obesity.

The limited ability of common variants to account for the genetic contribution to complex disease has prompted searches for rare variants of large effect, to partly explain the 'missing heritability'. Analyses of genome-wide genotyping data have identified genomic structural variants (GSVs) as a source of such rare causal variants. Recent studies have reported multiple GSV loci associated with risk of obesity. We attempted to replicate these associations by similar analysis of two familial-obesity case-control cohorts and a population cohort, and detected GSVs at 11 out of 18 loci, at frequencies similar to those previously reported. Based on their reported frequencies and effect sizes (OR≥25), we had sufficient statistical power to detect the large majority (80%) of genuine associations at these loci. However, only one obesity association was replicated. Deletion of a 220 kb region on chromosome 16p11.2 has a carrier population frequency of 2×10(-4) (95% confidence interval [9.6×10(-5)-3.1×10(-4)]); accounts overall for 0.5% [0.19%-0.82%] of severe childhood obesity cases (P = 3.8×10(-10); odds ratio = 25.0 [9.9-60.6]); and results in a mean body mass index (BMI) increase of 5.8 kg.m(-2) [1.8-10.3] in adults from the general population. We also attempted replication using BMI as a quantitative trait in our population cohort; associations with BMI at or near nominal significance were detected at two further loci near KIF2B and within FOXP2, but these did not survive correction for multiple testing. These findings emphasise several issues of importance when conducting rare GSV association, including the need for careful cohort selection and replication strategy, accurate GSV identification, and appropriate correction for multiple testing and/or control of false discovery rate. Moreover, they highlight the potential difficulty in replicating rare CNV associations across different populations. Nevertheless, we show that such studies are potentially valuable for the identification of variants making an appreciable contribution to complex disease.

Rare chromosome abnormalities, prevalence and prenatal diagnosis rates from population-based congenital anomaly registers in Europe.

The aim of this study is to quantify the prevalence and types of rare chromosome abnormalities (RCAs) in Europe for 2000-2006 inclusive, and to describe prenatal diagnosis rates and pregnancy outcome. Data held by the European Surveillance of Congenital Anomalies database were analysed on all the cases from 16 population-based registries in 11 European countries diagnosed prenatally or before 1 year of age, and delivered between 2000 and 2006. Cases were all unbalanced chromosome abnormalities and included live births, fetal deaths from 20 weeks gestation and terminations of pregnancy for fetal anomaly. There were 10,323 cases with a chromosome abnormality, giving a total birth prevalence rate of 43.8/10,000 births. Of these, 7335 cases had trisomy 21,18 or 13, giving individual prevalence rates of 23.0, 5.9 and 2.3/10,000 births, respectively (53, 13 and 5% of all reported chromosome errors, respectively). In all, 473 cases (5%) had a sex chromosome trisomy, and 778 (8%) had 45,X, giving prevalence rates of 2.0 and 3.3/10,000 births, respectively. There were 1,737 RCA cases (17%), giving a prevalence of 7.4/10,000 births. These included triploidy, other trisomies, marker chromosomes, unbalanced translocations, deletions and duplications. There was a wide variation between the registers in both the overall prenatal diagnosis rate of RCA, an average of 65% (range 5-92%) and the prevalence of RCA (range 2.4-12.9/10,000 births). In all, 49% were liveborn. The data provide the prevalence of families currently requiring specialised genetic counselling services in the perinatal period for these conditions and, for some, long-term care.

Primary pineal tumors: outcome and prognostic factors-a study from the Rare Cancer Network (RCN).

PURPOSE: To better define outcome and prognostic factors in primary pineal tumors. MATERIALS AND METHODS: Thirty-five consecutive patients from seven academic centers of the Rare Cancer Network diagnosed between 1988 and 2006 were included. Median age was 36 years. Surgical resection consisted of biopsy in 12 cases and resection in 21 (2 cases with unknown resection). All patients underwent radiotherapy and 12 patients received also chemotherapy. RESULTS: Histological subtypes were pineoblastoma (PNB) in 21 patients, pineocytoma (PC) in 8 patients and pineocytoma with intermediate differentiation in 6 patients. Six patients with PNB had evidence of spinal seeding. Fifteen patients relapsed (14 PNB and 1 PC) with PNB cases at higher risk (p = 0.031). Median survival time was not reached. Median disease-free survival was 82 months (CI 50 % 28-275). In univariate analysis, age younger than 36 years was an unfavorable prognostic factor (p = 0.003). Patients with metastases at diagnosis had poorer survival (p = 0.048). Late side effects related to radiotherapy were dementia, leukoencephalopathy or memory loss in seven cases, occipital ischemia in one, and grade 3 seizures in two cases. Side effects related to chemotherapy were grade 3-4 leucopenia in five cases, grade 4 thrombocytopenia in three cases, grade 2 anemia in two cases, grade 4 pancytopenia in one case, grade 4 vomiting in one case and renal failure in one case. CONCLUSIONS: Age and dissemination at diagnosis influenced survival in our series. The prevalence of chronic toxicity suggests that new adjuvant strategies are advisable.

The Early Cretaceous San Juan Plutonic Suite, Ecuador: A magma chamber in an oceanic plateau ?

Sections through an oceanic plateau are preserved in tectonic slices in the Western Cordillera of Ecuador (South America). The San Juan section is a sequence of mafic-ultramafic cumulates. To establish that these plutonic rocks formed in an oceanic plateau setting, we have developed criteria that discriminate intrusions of oceanic plateaus from those of other tectonic settings. The mineralogy and crystallization sequence of the cumulates are similar to those of intra-plate magmas. Clinopyroxene predominates throughout, and orthopyroxene is only a minor component. Rocks of intermediate composition are absent, and hornblende is restricted to the uppermost massive gabbros within the sequence. The ultramafic cumulates are very depleted in light rare-earth elements (LREE), whereas the gabbros have flat or slightly enriched LREE patterns. The composition of the basaltic liquid in equilibrium with the peridotite, calculated using olivine compositions and REE contents of clinopyroxene, contains between 16% and 8% MgO and has a flat REE pattern. This melt is geochemically similar to other accreted oceanic plateau basalts, isotropic gabbros, and differentiated sills in western Ecuador. The Ecuadorian intrusive and extrusive rocks have a narrow range of epsilonNd(i) (+8 to +5) and have a rather large range of Pb isotopic ratios. Pb isotope systematics of the San Juan plutonic rocks and mineral separates lie along a mixing line between the depleted mantle (DMM) and the enriched-plume end members. This suggests that the Ecuadorian plutonic rocks generated from the mixing of two mantle sources, a depleted mid-oceanic ridge basalt (MORB) source and an enriched one. The latter is characterized by high (Pb-207/Pb-204)(i) ratios and could reflect a contamination by recycled either lower continental crust or oceanic pelagic sediments and (or) altered oceanic crust (enriched mantle type I, EMI). These data suggest that the San Juan sequence represents the plutonic components of an Early Cretaceous oceanic plateau, which accreted in the Late Cretaceous to the Ecuadorian margin.

Le sarcome indifférencié du foie: une tumeur rare chez l'enfant [Undifferentiated sarcoma of the liver: a rare tumor of childhood]

Undifferentiated sarcoma of the liver is a rare primary tumor of childhood: only about 150 cases have been reported in the literature. CASE-REPORT: A 10 year-old girl was admitted because of diarrhea and weight loss. Sonography, then CT-scan and MRI showed a large tumor of the liver. COMMENTS: In the differential diagnosis of primary liver tumors in children, one should think about undifferentiated sarcoma of the liver, especially if imaging shows haemorrhagic foci and if sonography and CT/MRI display a discordant appearance. Survival has improved in the last decade due to agressive surgery and intensive chemotherapy.

Climatic niche shifts are rare among terrestrial plant invaders.

The assumption that climatic niche requirements of invasive species are conserved between their native and invaded ranges is key to predicting the risk of invasion. However, this assumption has been challenged recently by evidence of niche shifts in some species. Here, we report the first large-scale test of niche conservatism for 50 terrestrial plant invaders between Eurasia, North America, and Australia. We show that when analog climates are compared between regions, fewer than 15% of species have more than 10% of their invaded distribution outside their native climatic niche. These findings reveal that substantial niche shifts are rare in terrestrial plant invaders, providing support for an appropriate use of ecological niche models for the prediction of both biological invasions and responses to climate change.

Superinfection with drug-resistant HIV is rare and does not contribute substantially to therapy failure in a large European cohort.

BACKGROUND: Superinfection with drug resistant HIV strains could potentially contribute to compromised therapy in patients initially infected with drug-sensitive virus and receiving antiretroviral therapy. To investigate the importance of this potential route to drug resistance, we developed a bioinformatics pipeline to detect superinfection from routinely collected genotyping data, and assessed whether superinfection contributed to increased drug resistance in a large European cohort of viremic, drug treated patients. METHODS: We used sequence data from routine genotypic tests spanning the protease and partial reverse transcriptase regions in the Virolab and EuResist databases that collated data from five European countries. Superinfection was indicated when sequences of a patient failed to cluster together in phylogenetic trees constructed with selected sets of control sequences. A subset of the indicated cases was validated by re-sequencing pol and env regions from the original samples. RESULTS: 4425 patients had at least two sequences in the database, with a total of 13816 distinct sequence entries (of which 86% belonged to subtype B). We identified 107 patients with phylogenetic evidence for superinfection. In 14 of these cases, we analyzed newly amplified sequences from the original samples for validation purposes: only 2 cases were verified as superinfections in the repeated analyses, the other 12 cases turned out to involve sample or sequence misidentification. Resistance to drugs used at the time of strain replacement did not change in these two patients. A third case could not be validated by re-sequencing, but was supported as superinfection by an intermediate sequence with high degenerate base pair count within the time frame of strain switching. Drug resistance increased in this single patient. CONCLUSIONS: Routine genotyping data are informative for the detection of HIV superinfection; however, most cases of non-monophyletic clustering in patient phylogenies arise from sample or sequence mix-up rather than from superinfection, which emphasizes the importance of validation. Non-transient superinfection was rare in our mainly treatment experienced cohort, and we found a single case of possible transmitted drug resistance by this route. We therefore conclude that in our large cohort, superinfection with drug resistant HIV did not compromise the efficiency of antiretroviral treatment.

Lymphocoele: a rare and little known complication of anterior lumbar surgery.

Lymphocoele is a rare and little known complication with only a handful of reports available. We report two cases of lymphocoele after anterior lumbar surgery that have occurred in two different centres and discuss diagnosis and management options. The first case is that of a 53-year-old male patient undergoing two level anterior lumbar interbody fusion (ALIF) for disabling back pain due to disc degeneration in the context of an old spondylodiscitis. He developed a large fluid mass postoperatively. Fluid levels of creatinin were low and intravenous urography ruled out a urinoma suggesting the diagnosis of a lymphocoele. Following two unsuccessful drainage attempts he underwent a laparoscopic marsupialization. The second case was that of a 32-year-old female patient developing a large fluid mass following a L5 corpectomy for a burst fracture. She was treated successfully with insertion of a vacuum drain during 7 days. Lymphocoele is a rare complication but should be suspected if fluid collects postoperatively following anterior lumbar spine procedures. Chemical analysis of the fluid can help in diagnosis. Modern treatment consists of laparoscopic marsupialization. Lymph vessel anatomy should be borne in mind while exposing the anterior lumbar spine.

Accès à l'information médico-sociale dans le canton de Vaud : degré et sources d'information des personnes âgées

Améliorer la coordination des soins est un des points cardinaux de la politique Vieillissement et Santé du canton de Vaud. Ceci se traduit notamment par une volonté d'optimiser l'accès des personnes âgées à l'information médico-sociale. Un des projets qui en découle consiste à mettre en place un guichet intégré, soit un système centralisé, qui permettrait d'être renseigné·e ou orienté·e sur les prestations existantes efficacement et correctement, quelle que soit l'entité à laquelle on s'adresse. C'est dans ce contexte que le Centre d'Observation et d'Analyse du Vieillissement (COAV) a réalisé en 2013 une enquête sur l'accès à l'information médico-sociale auprès des personnes de 65 ans et plus non-institutionnalisées du canton. Ses résultats montrent que : ? Les besoins en prestations médico-sociales sont potentiellement importants car ces dernières sont susceptibles d'intéresser directement, du fait de difficultés fonctionnelles, un peu plus d'un tiers des personnes non institutionnalisées de plus de 65 ans, et indirectement 17 % des personnes du même âge qui sont aussi des aidant·e·s. Les femmes et les personnes bénéficiant de prestations complémentaires à l'assurance vieillesse (PC), étant plus fragiles, sont particulièrement concernées. ? Si cette population a potentiellement d'importants besoins en prestations médico-sociales, les portes d'accès à l'information sur ces prestations restent dans leur ensemble encore mal connues, même si l'on observe de grandes variations selon le type de services en question (selon les prestations, 27% à 57% des personnes interrogées ont déclaré ne pas savoir où s'adresser pour trouver de l'information à leur sujet). ? Les femmes, les personnes recevant des PC, ainsi que les personnes vulnérables et dépendantes sont proportionnellement plus actives dans la recherche d'information. ? Bien que les personnes ayant récemment eu l'occasion de rechercher de l'information sur certaines prestations médico-sociales semblent mieux connaître le système, 7% d'entre elles ont qualifié cette information de plutôt indisponible, 21% d'incomplète, 33% de dispersée et 15% de contradictoire. ? Deux tiers des personnes âgées pensent que l'information médico-sociale devrait être plus accessible sur l'existence de prestations, leur coût et les possibilités d'aide financière pour pouvoir en bénéficier. ? Parmi les personnes n'ayant pas récemment recherché d'information, les habitants de la région Nord sauraient plus souvent où s'adresser pour s'informer que ceux des autres régions. RAISONS DE SANTÉ 221 ? Etre un homme, être défavorisé financièrement (présence de PC) et, au niveau du statut fonctionnel, être vulnérable plutôt que robuste, sont des facteurs de risque d'accès limité à l'information. ? Les mêmes facteurs de risque se retrouvent en conduisant les analyses par type de prestations, excepté pour l'aide relative aux démarches administratives. L'information sur cette aide est mieux connue des personnes recevant des PC parmi celles ayant récemment recherché de l'information. ? Il n'a cependant pas été possible d'identifier un profil-type de la personne à risque face à l'accès à l'information sur la base des données socio-démographiques et fonctionnelles disponibles. ? D'autre part, cette enquête a mis en évidence le fait que le médecin traitant (désigné par 77% des individus) et le CMS (64 %), ainsi que, dans une moindre mesure, la commune (35%), sont les acteurs vers lesquelles les personnes âgées du canton se dirigeraient le plus volontiers pour trouver des informations sur diverses prestations médico-sociales. ? Cependant, au vu des variations constatées en comparant certains sous-groupes, d'autres sources ne sont pas à négliger lors de la mise en place d'un guichet intégré (telles qu'Internet, les EMS, Pro Senectute, les pharmacies, les BRIO, les hôpitaux, la garde médicale, etc.). Cette enquête montre que malgré les efforts entrepris pour faire connaître les prestations médico-sociales, une proportion non négligeable de ces services est peu connue des bénéficiaires potentiels. Ainsi, il serait intéressant de réitérer une telle étude après la mise en place du guichet intégré afin de pouvoir évaluer son impact.