Gender-specific modulation of immune system complement gene expression in marine medaka Oryzias melastigma following dietary exposure of BDE-47

BDE-47 is one of the most widely found congeners of PBDEs in marine environments. The potential immunomodulatory effects of BDE-47 on fish complement system were studied using the marine medaka Oryzias melastigma as a model fish. Three-month-old O. melastigma were subjected to short-term (5 days) and long-term (21 days) exposure to two concentrations of BDE-47 (low dose at 290 +/- 172 ng/day; high dose at 580 +/- 344 ng/day) via dietary uptake of BDE-47 encapsulated in Artemia nauplii. Body burdens of BDE-47 and other metabolic products were analyzed in the exposed and control fish. Only a small amount of debrominated product, BDE-28, was detected, while other metabolic products were all under detection limit. Transcriptional expression of six major complement system genes involved in complement activation: C1r/s (classical pathway), MBL-2 (lectin pathway), CFP (alternative pathway), F2 (coagulation pathway), C3 (the central component of complement system), and C9 (cell lysis) were quantified in the liver of marine medaka. Endogenous expression of all six complement system genes was found to be higher in males than in females (p < 0.05). Upon dietary exposure of marine medaka to BDE-47, expression of all six complement genes were downregulated in males at day 5 (or longer), whereas in females, MBl-2, CFP, and F2 mRNAs expression were upregulated, but C3 and C9 remained stable with exposure time and dose. A significant negative relationship was found between BDE-47 body burden and mRNA expression of C1r/s, CFP, and C3 in male fish (r = -0.8576 to -0.9447). The above findings on changes in complement gene expression patterns indicate the complement system may be compromised in male O. melastigma upon dietary exposure to BDE-47. Distinct gender difference in expression of six major complement system genes was evident in marine medaka under resting condition and dietary BDE-47 challenge. The immunomodulatory effects of BDE-47 on transcriptional expression of these complement components in marine medaka were likely induced by the parent compound instead of biotransformed products. Our results clearly demonstrate that future direction for fish immunotoxicology and risk assessment of immunosuppressive chemicals must include parallel evaluation for both genders.

Mechanical antithrombotic intervention by LAA occlusion in atrial fibrillation

Stroke in patients with atrial fibrillation (AF) is often associated with substantial morbidity and mortality. Oral anticoagulation remains the first-line approach to stroke prevention in such individuals; however, for a considerable proportion of patients, traditional treatment using warfarin is limited by a number of factors, such as the inconvenience of frequent therapeutic monitoring and the risk of haemorrhage. The development of new oral anticoagulants with improved efficacy and safety profiles has provided viable options for oral anticoagulation therapy in patients with nonvalvular (nonrheumatic AF). Nonetheless, in patients who have an increased risk of major haemorrhage, a nonpharmacological approach to antithrombotic therapy remains an attractive alternative. The left atrial appendage (LAA) has been found to be the source of >90% of thrombi in patients with nonvalvular AF; thus, prevention of thrombus formation via transcatheter mechanical LAA occlusion is a novel therapeutic target for stroke prevention in this patient population. In this Review, we present the rationale for LAA occlusion in patients with AF, the available occlusion devices and their clinical evidence to date. We also discuss the roles of various imaging techniques in device implantation and the management strategy for associated procedural complications.

Search for long-lived, multi-charged particles in pp collisions at sqrts=7 TeV using the ATLAS detector

A search for highly ionising, penetrating particles with electric charges from |q| = 2e to 6e is performed using the ATLAS detector at the CERN Large Hadron Collider. Proton-proton collision data taken at sqrt(s)=7 TeV during the 2011 running period, corresponding to an integrated luminosity of 4.4 fb^-1, are analysed. No signal candidates are observed, and 95% confidence level cross-section upper limits are interpreted as mass-exclusion lower limits for a simplified Drell--Yan production model. In this model, masses are excluded from 50 GeV up to 430, 480, 490, 470 and 420 GeV for charges 2e, 3e, 4e, 5e and 6e, respectively.

Patterns of Religious Education Policy in Switzerland. The Long Arm of Distanced Christians?

In spite of its different cantonal jurisdictions and traditions, the development of religious education in Switzerland over the past decade has taken a common direction: the state has assumed a more active role in the field of religious education in public (state-run) schools. In this article, we ask the question: How do key social actors interpret these reforms and how do these interpretations relate to the social structure of religion in Switzerland, in particular with respect to the majority category of the so-called distanced Christians? Drawing on qualitative interviews with members of the schools’ teaching staff, school administrators, and church representatives, the article highlights a dominant interpretative pattern that frames the socially accepted representation of religion in public schools. Thus, rather than addressing the pedagogical dimension of religious education, we discuss the significance of this pattern for the debate on the public presence of religion in Switzerland and Europe.

First direct observation of sputtered lunar oxygen

We present the first direct measurement of neutral oxygen in the lunar exosphere, detected by the Chandrayaan-1 Energetic Neutral Analyzer (CENA). With the lunar surface consisting of about 60% of oxygen in number, the neutral oxygen detected in CENA's energy range (11 eV−3.3 keV) is attributed to have originated from the lunar surface, where it was released through solar wind ion sputtering. Fitting of CENA's mass spectra with calibration spectra from ground and in-flight data resulted in the detection of a robust oxygen signal, with a flux of 0.2 to 0.4 times the flux of backscattered hydrogen, depending on the solar wind helium content and particle velocity. For the two solar wind types observed, we derive subsolar surface oxygen atom densities of N0= (1.1 ± 0.3) · 107m−3 and (1.4 ± 0.4) · 107m−3, respectively, which agree well with earlier model predictions and measured upper limits. From these surface densities, we derive column densities of NC= (1.5 ± 0.5) · 1013 m−2and (1.6 ± 0.5) · 1013 m−2. In addition, we identified for the first time a helium component. This helium is attributed to backscattering of solar wind helium (alpha particles) from the lunar surface as neutral energetic helium atoms, which has also been observed for the first time. This identification is supported by the characteristic energy of the measured helium atoms, which is roughly 4 times the energy of reflected solar wind hydrogen, and the correlation with solar wind helium content.

Sectio caesarea: actual controversy

Caesarean section is one of the most frequently performed operations in human medicine. It has become a routine procedure with a very low morbidity and mortality. Over the centuries, it has emerged an essential achievement in obstetric medicine. In the presence of cephalo-pelvic-disproportion, cervical dystocia, malpresentation, preterm birth, macrosomia, placental insufficiency, placenta praevia or fetal distress it is crucial to improve the perinatal morbiditiy and mortality of mother and child. The procedure has become much more frequent over the past 20 years for multiple reasons. There is variety in incidence between countries but also regional differences. It's occurrence is being influenced by level of education and socio-economic status of the pregnant woman. In the meantime, also the longterm consequences of cesarean section are well known. The potential hazards for future pregnancies and deliveries are well described. Actual controversy addresses cesarean section on demand without any medical indication, which in fact is only seldom performed in Switzerland. The ethical justification of this procedure needs to be discussed in view of the current tendency towards autonomy and self-determination of the pregnant woman.

Cryptococcal Antigenemia in Immunocompromised Human Immunodeficiency Virus Patients in Rural Tanzania: A Preventable Cause of Early Mortality

Background.  Cryptococcal meningitis is a leading cause of death in people living with human immunodeficiency virus (HIV)/acquired immune deficiency syndrome. The World Health Organizations recommends pre-antiretroviral treatment (ART) cryptococcal antigen (CRAG) screening in persons with CD4 below 100 cells/µL. We assessed the prevalence and outcome of cryptococcal antigenemia in rural southern Tanzania. Methods.  We conducted a retrospective study including all ART-naive adults with CD4 <150 cells/µL prospectively enrolled in the Kilombero and Ulanga Antiretroviral Cohort between 2008 and 2012. Cryptococcal antigen was assessed in cryopreserved pre-ART plasma. Cox regression estimated the composite outcome of death or loss to follow-up (LFU) by CRAG status and fluconazole use. Results.  Of 750 ART-naive adults, 28 (3.7%) were CRAG-positive, corresponding to a prevalence of 4.4% (23 of 520) in CD4 <100 and 2.2% (5 of 230) in CD4 100-150 cells/µL. Within 1 year, 75% (21 of 28) of CRAG-positive and 42% (302 of 722) of CRAG-negative patients were dead or LFU (P<.001), with no differences across CD4 strata. Cryptococcal antigen positivity was an independent predictor of death or LFU after adjusting for relevant confounders (hazard ratio [HR], 2.50; 95% confidence interval [CI], 1.29-4.83; P = .006). Cryptococcal meningitis occurred in 39% (11 of 28) of CRAG-positive patients, with similar retention-in-care regardless of meningitis diagnosis (P = .8). Cryptococcal antigen titer >1:160 was associated with meningitis development (odds ratio, 4.83; 95% CI, 1.24-8.41; P = .008). Fluconazole receipt decreased death or LFU in CRAG-positive patients (HR, 0.18; 95% CI, .04-.78; P = .022). Conclusions.  Cryptococcal antigenemia predicted mortality or LFU among ART-naive HIV-infected persons with CD4 <150 cells/µL, and fluconazole increased survival or retention-in-care, suggesting that targeted pre-ART CRAG screening may decrease early mortality or LFU. A CRAG screening threshold of CD4 <100 cells/µL missed 18% of CRAG-positive patients, suggesting guidelines should consider a higher threshold.

Subclinical thyroid dysfunction and fracture risk: a meta-analysis.

IMPORTANCE Associations between subclinical thyroid dysfunction and fractures are unclear and clinical trials are lacking. OBJECTIVE To assess the association of subclinical thyroid dysfunction with hip, nonspine, spine, or any fractures. DATA SOURCES AND STUDY SELECTION The databases of MEDLINE and EMBASE (inception to March 26, 2015) were searched without language restrictions for prospective cohort studies with thyroid function data and subsequent fractures. DATA EXTRACTION Individual participant data were obtained from 13 prospective cohorts in the United States, Europe, Australia, and Japan. Levels of thyroid function were defined as euthyroidism (thyroid-stimulating hormone [TSH], 0.45-4.49 mIU/L), subclinical hyperthyroidism (TSH <0.45 mIU/L), and subclinical hypothyroidism (TSH ≥4.50-19.99 mIU/L) with normal thyroxine concentrations. MAIN OUTCOME AND MEASURES The primary outcome was hip fracture. Any fractures, nonspine fractures, and clinical spine fractures were secondary outcomes. RESULTS Among 70,298 participants, 4092 (5.8%) had subclinical hypothyroidism and 2219 (3.2%) had subclinical hyperthyroidism. During 762,401 person-years of follow-up, hip fracture occurred in 2975 participants (4.6%; 12 studies), any fracture in 2528 participants (9.0%; 8 studies), nonspine fracture in 2018 participants (8.4%; 8 studies), and spine fracture in 296 participants (1.3%; 6 studies). In age- and sex-adjusted analyses, the hazard ratio (HR) for subclinical hyperthyroidism vs euthyroidism was 1.36 for hip fracture (95% CI, 1.13-1.64; 146 events in 2082 participants vs 2534 in 56,471); for any fracture, HR was 1.28 (95% CI, 1.06-1.53; 121 events in 888 participants vs 2203 in 25,901); for nonspine fracture, HR was 1.16 (95% CI, 0.95-1.41; 107 events in 946 participants vs 1745 in 21,722); and for spine fracture, HR was 1.51 (95% CI, 0.93-2.45; 17 events in 732 participants vs 255 in 20,328). Lower TSH was associated with higher fracture rates: for TSH of less than 0.10 mIU/L, HR was 1.61 for hip fracture (95% CI, 1.21-2.15; 47 events in 510 participants); for any fracture, HR was 1.98 (95% CI, 1.41-2.78; 44 events in 212 participants); for nonspine fracture, HR was 1.61 (95% CI, 0.96-2.71; 32 events in 185 participants); and for spine fracture, HR was 3.57 (95% CI, 1.88-6.78; 8 events in 162 participants). Risks were similar after adjustment for other fracture risk factors. Endogenous subclinical hyperthyroidism (excluding thyroid medication users) was associated with HRs of 1.52 (95% CI, 1.19-1.93) for hip fracture, 1.42 (95% CI, 1.16-1.74) for any fracture, and 1.74 (95% CI, 1.01-2.99) for spine fracture. No association was found between subclinical hypothyroidism and fracture risk. CONCLUSIONS AND RELEVANCE Subclinical hyperthyroidism was associated with an increased risk of hip and other fractures, particularly among those with TSH levels of less than 0.10 mIU/L and those with endogenous subclinical hyperthyroidism. Further study is needed to determine whether treating subclinical hyperthyroidism can prevent fractures.

The Chemical Space Project

One of the simplest questions that can be asked about molecular diversity is how many organic molecules are possible in total? To answer this question, my research group has computationally enumerated all possible organic molecules up to a certain size to gain an unbiased insight into the entire chemical space. Our latest database, GDB-17, contains 166.4 billion molecules of up to 17 atoms of C, N, O, S, and halogens, by far the largest small molecule database reported to date. Molecules allowed by valency rules but unstable or nonsynthesizable due to strained topologies or reactive functional groups were not considered, which reduced the enumeration by at least 10 orders of magnitude and was essential to arrive at a manageable database size. Despite these restrictions, GDB-17 is highly relevant with respect to known molecules. Beyond enumeration, understanding and exploiting GDBs (generated databases) led us to develop methods for virtual screening and visualization of very large databases in the form of a “periodic system of molecules” comprising six different fingerprint spaces, with web-browsers for nearest neighbor searches, and the MQN- and SMIfp-Mapplet application for exploring color-coded principal component maps of GDB and other large databases. Proof-of-concept applications of GDB for drug discovery were realized by combining virtual screening with chemical synthesis and activity testing for neurotransmitter receptor and transporter ligands. One surprising lesson from using GDB for drug analog searches is the incredible depth of chemical space, that is, the fact that millions of very close analogs of any molecule can be readily identified by nearest-neighbor searches in the MQN-space of the various GDBs. The chemical space project has opened an unprecedented door on chemical diversity. Ongoing and yet unmet challenges concern enumerating molecules beyond 17 atoms and synthesizing GDB molecules with innovative scaffolds and pharmacophores.

Polyethylenimine-based polyplex delivery of self-replicating RNA vaccines

Self-amplifying replicon RNA (RepRNA) are large molecules (12-14kb); their self-replication amplifies mRNA template numbers, affording several rounds of antigen production, effectively increasing vaccine antigen payloads. Their sensitivity to RNase-sensitivity and inefficient uptake by dendritic cells (DCs) - absolute requirements for vaccine design - were tackled by condensing RepRNA into synthetic, nanoparticulate, polyethylenimine (PEI)-polyplex delivery vehicles. Polyplex-delivery formulations for small RNA molecules cannot be transferred to RepRNA due to its greater size and complexity; the N:P charge ratio and impact of RepRNA folding would influence polyplex condensation, post-delivery decompaction and the cytosolic release essential for RepRNA translation. Polyplex-formulations proved successful for delivery of RepRNA encoding influenza virus hemagglutinin and nucleocapsid to DCs. Cytosolic translocation was facilitated, leading to RepRNA translation. This efficacy was confirmed in vivo, inducing both humoral and cellular immune responses. Accordingly, this paper describes the first PEI-polyplexes providing efficient delivery of the complex and large, self-amplifying RepRNA vaccines.

Normal Thyroid Function and the Risk of Atrial Fibrillation: the Rotterdam Study

CONTEXT Hyperthyroidism is an established risk factor for atrial fibrillation (AF), but information concerning the association with variations within the normal range of thyroid function and subgroups at risk is lacking. OBJECTIVE This study aimed to investigate the association between normal thyroid function and AF prospectively and explore potential differential risk patterns. DESIGN, SETTING, AND PARTICIPANTS From the Rotterdam Study we included 9166 participants ≥ 45 y with TSH and/or free T4 (FT4) measurements and AF assessment (1997-2012 median followup, 6.8 y), with 399 prevalent and 403 incident AF cases. MAIN OUTCOME MEASURES Outcome measures were 3-fold: 1) hazard ratios (HRs) for the risk of incident AF by Cox proportional-hazards models, 2) 10-year absolute risks taking competing risk of death into account, and 3) discrimination ability of adding FT4 to the CHARGE-AF simple model, an established prediction model for AF. RESULTS Higher FT4 levels were associated with higher risks of AF (HR 1.63, 95% confidence interval, 1.19-2.22), when comparing those in the highest quartile to those in lowest quartile. Absolute 10-year risks increased with higher FT4 in participants ≤ 65 y from 1-9% and from 6-12% in subjects ≥ 65 y. Discrimination of the prediction model improved when adding FT4 to the simple model (c-statistic, 0.722 vs 0.729; P = .039). TSH levels were not associated with AF. CONCLUSIONS There is an increased risk of AF with higher FT4 levels within the normal range, especially in younger subjects. Adding FT4 to the simple model slightly improved discrimination of risk prediction.