Causal relationship between obesity and vitamin D status: bi-directional Mendelian randomization analysis of multiple cohorts.

BACKGROUND: Obesity is associated with vitamin D deficiency, and both are areas of active public health concern. We explored the causality and direction of the relationship between body mass index (BMI) and 25-hydroxyvitamin D [25(OH)D] using genetic markers as instrumental variables (IVs) in bi-directional Mendelian randomization (MR) analysis. METHODS AND FINDINGS: We used information from 21 adult cohorts (up to 42,024 participants) with 12 BMI-related SNPs (combined in an allelic score) to produce an instrument for BMI and four SNPs associated with 25(OH)D (combined in two allelic scores, separately for genes encoding its synthesis or metabolism) as an instrument for vitamin D. Regression estimates for the IVs (allele scores) were generated within-study and pooled by meta-analysis to generate summary effects. Associations between vitamin D scores and BMI were confirmed in the Genetic Investigation of Anthropometric Traits (GIANT) consortium (n = 123,864). Each 1 kg/m(2) higher BMI was associated with 1.15% lower 25(OH)D (p = 6.52×10⁻²⁷). The BMI allele score was associated both with BMI (p = 6.30×10⁻⁶²) and 25(OH)D (-0.06% [95% CI -0.10 to -0.02], p = 0.004) in the cohorts that underwent meta-analysis. The two vitamin D allele scores were strongly associated with 25(OH)D (p≤8.07×10⁻⁵⁷ for both scores) but not with BMI (synthesis score, p = 0.88; metabolism score, p = 0.08) in the meta-analysis. A 10% higher genetically instrumented BMI was associated with 4.2% lower 25(OH)D concentrations (IV ratio: -4.2 [95% CI -7.1 to -1.3], p = 0.005). No association was seen for genetically instrumented 25(OH)D with BMI, a finding that was confirmed using data from the GIANT consortium (p≥0.57 for both vitamin D scores). CONCLUSIONS: On the basis of a bi-directional genetic approach that limits confounding, our study suggests that a higher BMI leads to lower 25(OH)D, while any effects of lower 25(OH)D increasing BMI are likely to be small. Population level interventions to reduce BMI are expected to decrease the prevalence of vitamin D deficiency.

Prograde mica 40Ar/39Ar growth ages recorded in high pressure rocks (Syros, Cyclades, Greece)

Phengites from the eclogite and blueschist-facies sequences of the Cycladic island of Syros (Greece) have been dated by the in situ UV-laser ablation Ar-40/Ar-39 method. A massive, phengite-rich eclogite and an omphacite-rich metagabbro were investigated. The phengites are eubedral and coarse-grained (several 100 mum), strain-free and exhibit no evidence for late brittle deformation or recrystallization. Apparent ages in these samples range from 43 to 50 Ma for the phengite-rich eclogite and 42 to 52 Ma for the ompbacitic metagabbro. This large spread of ages is visible at all scales-within individual grains as well as in domains of several 100 mum and across the entire sample (ca. 2 cm). Such variations have been traditionally attributed to metamorphic cooling or the incorporation of excess argon. However, the textural equilibrium between the phengites and other high pressure phases and the subtle compositional variations within the phengites, especially the preservation of growth textures, alternatively suggest that the observed range in ages may reflect variations of radiogenic argon acquired during phengite formation and subsequent growth, thus dating a discrete event on the prograde path. This implies that the oldest phengite 40Ar/39Ar ages provide the best estimate of a minimum crystallization age, which is in agreement with recently reported U-Pb and Lu-Hf geochronological data. Our results are consistent with available stable isotope data and further suggest that, under fluid-restricted conditions, both stable and radiogenic isotopic systems can survive without significant isotopic exchange during subduction and exhumation from eclogite-facies P-T conditions. (C) 2004 Elsevier B.V. All rights reserved.

Promoter recognition and activation by the global response regulator CbrB in Pseudomonas aeruginosa.

In Pseudomonas aeruginosa, the CbrA/CbrB two-component system is instrumental in the maintenance of the carbon-nitrogen balance and for growth on carbon sources that are energetically less favorable than the preferred dicarboxylate substrates. The CbrA/CbrB system drives the expression of the small RNA CrcZ, which antagonizes the repressing effects of the catabolite repression control protein Crc, an RNA-binding protein. Dicarboxylates appear to cause carbon catabolite repression by inhibiting the activity of the CbrA/CbrB system, resulting in reduced crcZ expression. Here we have identified a conserved palindromic nucleotide sequence that is present in upstream activating sequences (UASs) of promoters under positive control by CbrB and σ(54) RNA polymerase, especially in the UAS of the crcZ promoter. Evidence for recognition of this palindromic sequence by CbrB was obtained in vivo from mutational analysis of the crcZ promoter and in vitro from electrophoretic mobility shift assays using crcZ promoter fragments and purified CbrB protein truncated at the N terminus. Integration host factor (IHF) was required for crcZ expression. CbrB also activated the lipA (lipase) promoter, albeit less effectively, apparently by interacting with a similar but less conserved palindromic sequence in the UAS of lipA. As expected, succinate caused CbrB-dependent catabolite repression of the lipA promoter. Based on these results and previously published data, a consensus CbrB recognition sequence is proposed. This sequence has similarity to the consensus NtrC recognition sequence, which is relevant for nitrogen control.

Panobacumab adjunctive immuno-therapy for Pseudomonas aeruginosa hospital-acquired pneumonia versus a cohort group

Objectives: To assess the efficacy of Panobacumab, a fully human IgM monoclonal antibody against P. aeruginosa serotype O11, by comparing a phase IIa trial with a standard care cohort trial both in hospital acquired pneumonia (HAP) caused by P. aeruginosa O11. Methods: Demographics, outcome and survival of HAP including Ventilator Associated Pneumonia (VAP) in patients either treated with standard antimicrobial therapy in a retrospective cohort trial (CT) or with adjunctive Panobacumab therapy during an open phase IIa trial were compared. Both trials applied the same inclusion exclusion criteria and the same trial period of 30 days. Results: 17 patients with VAP/HAP (14 / 3) caused by P. aeruginosa O11 were enrolled in a phase IIa trial (ITT population) and treated with Panobacumab, 13 of them received the full treatment course of 3 infusions (PP population, 12 VAP, 1 HAP) and 4 patients received only one infusion. In the cohort trial 14 patients (VAP/HAP: 12 / 2) treated with standard antibiotic therapy were included. The mean age and weight were 65.8 y (years) (SD 17.2) and 78.0 kg (SD 22.1) in the PP, 67.8 y (SD 15.4) and 77.1 kg (SD 20.2) in the ITT population and 51.8 y (SD 22.3) and 67.1 kg (SD 13.0) in the CT. At the time of suspicion of pneumonia a mean APACHE II and CPIS of 19.4 (13 - 33) and 8.7 (7 - 11) in the PP, 18.9 (13-33) and 8.5 (7 -11) in the ITT and 14.5 (2 - 24) and 7.5 (3 -12) in the CT population were observed. Tracheostomy was present in 53.8% and 52.9% in the PP and ITT populations and 38.4% in the CT. The pneumonia was polymicrobial in 69.2%, 70.6% and 85.7% in the PP, ITT and CT respectively. Stay at ICU and hospital before diagnosis of pneumonia were similar in the 3 groups. All 13 patients that received 3 doses of Panobacumab achieved resolution of pneumonia with only two relapsing during the study. Hence 85% achieved resolution and 15% recurrence at day 30. In the ITT group 64.7% of the pneumonia resolved 11.8% recurred and 23.5% continued while in the CT 57% resolved, 7% recurred and 34% continued. Resolution of pneumonia occurred markedly earlier in the Panobacumab trial (8.9 days, SD: 3.3) than in the cohort trial (15.3 days, SD: 9.5). The expected mortality derived from APACHE II score was 31% and 32% in the PP and ITT population and 22% in the cohort group. All patients who received 3 doses of Panobacumab survived, 18% died in the ITT group while in the CT 21% mortality matched the predicted mortality. Conclusions: Treatment of VAP/HAP caused by P. aeruginosa O11 with 3 doses of Panobacumab resulted in 100% survival, with highest pneumonia resolution (85%), and in a shorter time when compared with patients under standard therapy. The results indicate that Panobacumab may be effective in such life-threatening indication and warrants larger controlled trials.

Fréquence des incidentalomes lors d'un examen PET/CT effectué pour une pathologie oncologique

Contexte¦Le PET/CT au 18Fluor (FDG) fait aujourd'hui partie intégrante des moyens diagnostiques¦à disposition pour la stadification des cancers suspectés ou connus. Il n'est pas rare de¦découvrir des lésions fortuites.¦Objectifs¦Notre but était de déterminer la fréquence des lésions tumorales ou non, cliniquement¦silencieuses (incidentalomes), chez des patients consécutifs non sélectionnés examinés¦par PET/CT au FDG pour un cancer connu ou supposé au sein du bassin populationnel¦du CHUV.¦Méthode¦Nous avons rétrospectivement lu les 1226 des rapports d'examens faits d'août 2009 à¦juillet 2010 pour toute indication oncologique et relevé les lésions de découverte¦fortuite et leur localisation, avant de rechercher leur investigation et leur prise en¦charge.¦Résultats¦Nous avons retenu 309 lésions fortuites chez 260 patients (25,2% des rapports lus),¦dont 141 chez 127 patients investiguées. Ont été relevés 31 patients présentant 32¦incidentalomes (2,6%), dont 6 étaient malins, 6 pré-malins et 20 bénins, soit un taux de¦1% pour les malins et pré-malins. Les sites les plus fréquents étaient les mêmes que¦dans la littérature, à savoir la thyroïde, le poumon, la sphère colorectale (lésions prémalignes¦uniquement) et les lymphomes. Pour ces trois derniers, les lésions étaient¦moins fréquentes que ce qui est rapporté. Tous ces foyers sont à investiguer¦soigneusement, afin de différencier une nouvelle atteinte d'une métastase.¦Conclusion¦En tant que première étude suisse sur le sujet, nous obtenons 1% d'incidentalomes¦(pré)malins, soit l'équivalent de la limite inférieure de la littérature, dans des sites¦similaires. Une amélioration serait possible en augmentant l'attention portée aux lésions¦jugées peu significatives. A l'instar de nombreuses autres études, nous sommes aussi¦confrontés au problème lié à l'interprétation des foyers de captation et à la nonspécificité¦du FDG.

Three-dimensional radiobiological dosimetry of kidneys for treatment planning in peptide receptor radionuclide therapy.

PURPOSE: Peptide receptor radionuclide therapy (PRRT) delivers high absorbed doses to kidneys and may lead to permanent nephropathy. Reliable dosimetry of kidneys is thus critical for safe and effective PRRT. The aim of this work was to assess the feasibility of planning PRRT based on 3D radiobiological dosimetry (3D-RD) in order to optimize both the amount of activity to administer and the fractionation scheme, while limiting the absorbed dose and the biological effective dose (BED) to the renal cortex. METHODS: Planar and SPECT data were available for a patient examined with (111)In-DTPA-octreotide at 0.5 (planar only), 4, 24, and 48 h post-injection. Absorbed dose and BED distributions were calculated for common therapeutic radionuclides, i.e., (111)In, (90)Y and (177)Lu, using the 3D-RD methodology. Dose-volume histograms were computed and mean absorbed doses to kidneys, renal cortices, and medullae were compared with results obtained using the MIRD schema (S-values) with the multiregion kidney dosimetry model. Two different treatment planning approaches based on (1) the fixed absorbed dose to the cortex and (2) the fixed BED to the cortex were then considered to optimize the activity to administer by varying the number of fractions. RESULTS: Mean absorbed doses calculated with 3D-RD were in good agreement with those obtained with S-value-based SPECT dosimetry for (90)Y and (177)Lu. Nevertheless, for (111)In, differences of 14% and 22% were found for the whole kidneys and the cortex, respectively. Moreover, the authors found that planar-based dosimetry systematically underestimates the absorbed dose in comparison with SPECT-based methods, up to 32%. Regarding the 3D-RD-based treatment planning using a fixed BED constraint to the renal cortex, the optimal number of fractions was found to be 3 or 4, depending on the radionuclide administered and the value of the fixed BED. Cumulative activities obtained using the proposed simulated treatment planning are compatible with real activities administered to patients in PRRT. CONCLUSIONS: The 3D-RD treatment planning approach based on the fixed BED was found to be the method of choice for clinical implementation in PRRT by providing realistic activity to administer and number of cycles. While dividing the activity in several cycles is important to reduce renal toxicity, the clinical outcome of fractionated PRRT should be investigated in the future.

Global phylogenomic analysis of nonencapsulated Streptococcus pneumoniae reveals a deep-branching classic lineage that is distinct from multiple sporadic lineages.

The surrounding capsule of Streptococcus pneumoniae has been identified as a major virulence factor and is targeted by pneumococcal conjugate vaccines (PCV). However, nonencapsulated S. pneumoniae (non-Ec-Sp) have also been isolated globally, mainly in carriage studies. It is unknown if non-Ec-Sp evolve sporadically, if they have high antibiotic nonsusceptiblity rates and a unique, specific gene content. Here, whole-genome sequencing of 131 non-Ec-Sp isolates sourced from 17 different locations around the world was performed. Results revealed a deep-branching classic lineage that is distinct from multiple sporadic lineages. The sporadic lineages clustered with a previously sequenced, global collection of encapsulated S. pneumoniae (Ec-Sp) isolates while the classic lineage is comprised mainly of the frequently identified multilocus sequences types (STs) ST344 (n = 39) and ST448 (n = 40). All ST344 and nine ST448 isolates had high nonsusceptiblity rates to β-lactams and other antimicrobials. Analysis of the accessory genome reveals that the classic non-Ec-Sp contained an increased number of mobile elements, than Ec-Sp and sporadic non-Ec-Sp. Performing adherence assays to human epithelial cells for selected classic and sporadic non-Ec-Sp revealed that the presence of a integrative conjugative element (ICE) results in increased adherence to human epithelial cells (P = 0.005). In contrast, sporadic non-Ec-Sp lacking the ICE had greater growth in vitro possibly resulting in improved fitness. In conclusion, non-Ec-Sp isolates from the classic lineage have evolved separately. They have spread globally, are well adapted to nasopharyngeal carriage and are able to coexist with Ec-Sp. Due to continued use of PCV, non-Ec-Sp may become more prevalent.

Rapid cohort generation and analysis of disease spectrum of large animal model of cone dystrophy.

Large animal models are an important resource for the understanding of human disease and for evaluating the applicability of new therapies to human patients. For many diseases, such as cone dystrophy, research effort is hampered by the lack of such models. Lentiviral transgenesis is a methodology broadly applicable to animals from many different species. When conjugated to the expression of a dominant mutant protein, this technology offers an attractive approach to generate new large animal models in a heterogeneous background. We adopted this strategy to mimic the phenotype diversity encounter in humans and generate a cohort of pigs for cone dystrophy by expressing a dominant mutant allele of the guanylate cyclase 2D (GUCY2D) gene. Sixty percent of the piglets were transgenic, with mutant GUCY2D mRNA detected in the retina of all animals tested. Functional impairment of vision was observed among the transgenic pigs at 3 months of age, with a follow-up at 1 year indicating a subsequent slower progression of phenotype. Abnormal retina morphology, notably among the cone photoreceptor cell population, was observed exclusively amongst the transgenic animals. Of particular note, these transgenic animals were characterized by a range in the severity of the phenotype, reflecting the human clinical situation. We demonstrate that a transgenic approach using lentiviral vectors offers a powerful tool for large animal model development. Not only is the efficiency of transgenesis higher than conventional transgenic methodology but this technique also produces a heterogeneous cohort of transgenic animals that mimics the genetic variation encountered in human patients.

Aberrant right hepatic artery with a prepancreatic course visualized prior to pancreaticoduodenectomy.

Liver vascularization is known to present with several different variations. Generally, a normal vascular anatomy is reported in up to 50-80 % of cases. For this reason, a precise preoperative mapping of the hepatic vascularization prior to pancreatic surgery is essential to avoid injuries and subsequent complications. We report here a case of a young patient scheduled for Whipple procedure, who presented an arterial pattern type Michels IV, variation reported in 0.6 to 3 % in the literature. Another interesting particularity of this case was the fact that the right hepatic artery had a prepancreatic course. We think that every surgeon performing hepatopancreatic surgery should have heard of this special and rare situation.

A global analysis of Y-chromosomal haplotype diversity for 23 STR loci.

In a worldwide collaborative effort, 19,630 Y-chromosomes were sampled from 129 different populations in 51 countries. These chromosomes were typed for 23 short-tandem repeat (STR) loci (DYS19, DYS389I, DYS389II, DYS390, DYS391, DYS392, DYS393, DYS385ab, DYS437, DYS438, DYS439, DYS448, DYS456, DYS458, DYS635, GATAH4, DYS481, DYS533, DYS549, DYS570, DYS576, and DYS643) and using the PowerPlex Y23 System (PPY23, Promega Corporation, Madison, WI). Locus-specific allelic spectra of these markers were determined and a consistently high level of allelic diversity was observed. A considerable number of null, duplicate and off-ladder alleles were revealed. Standard single-locus and haplotype-based parameters were calculated and compared between subsets of Y-STR markers established for forensic casework. The PPY23 marker set provides substantially stronger discriminatory power than other available kits but at the same time reveals the same general patterns of population structure as other marker sets. A strong correlation was observed between the number of Y-STRs included in a marker set and some of the forensic parameters under study. Interestingly a weak but consistent trend toward smaller genetic distances resulting from larger numbers of markers became apparent.