Serotonin and Dopamine Receptor Expression in Solid Tumours Including Rare Cancers

In preclinical studies serotonin stimulates and dopamine inhibits tumour growth and angiogenesis. Information regarding serotonin and dopamine receptor (5-HTR and DRD) expression in human cancers is limited. Therefore, we screened a large tumour set for receptor mRNA overexpression using functional genomic mRNA (FGmRNA) profiling, and we analysed protein expression and location of 5-HTR1B, 5-HTR2B, DRD1, and DRD2 with immunohistochemistry in different tumour types. With FGmRNA profiling 11,756 samples representing 43 tumour types were compared to 3,520 normal tissue samples to analyse receptor overexpression. 5-HTR2B overexpression was present in many tumour types, most frequently in uveal melanomas (56%). Receptor overexpression in rare cancers included 5-HTR1B in nasopharyngeal carcinoma (17%), DRD1 in ependymoma (30%) and synovial sarcoma (21%), and DRD2 in astrocytoma (13%). Immunohistochemistry demonstrated high 5-HTR2B protein expression on melanoma and gastro-intestinal stromal tumour cells and endothelial cells of colon, ovarian, breast, renal and pancreatic tumours. 5-HTR1B expression was predominantly low. High DRD2 protein expression on tumour cells was observed in 48% of pheochromocytomas, and DRD1 expression ranged from 14% in melanoma to 57% in renal cell carcinoma. In conclusion, 5-HTR1B, 5-HTR2B, DRD1, and DRD2 show mRNA overexpression in a broad spectrum of common and rare cancers. 5-HTR2B protein is frequently highly expressed in human cancers, especially on endothelial cells. These findings support further investigation of especially 5HTR2B as a potential treatment target

Retrospective analysis of antimicrobial resistance and bacterial spectrum of infection in Gabon, Central Africa

Background: Physicians depend on reliable information on the local epidemiology of infection and antibiotic resistance rates to guide empiric treatment in critically ill patients. As these data are scarce for Central Africa, we performed a retrospective analysis of microbiological findings from a secondary care hospital in Gabon. Methods: Microbiological reports from 2009 to 2012 were used to assess the non-susceptibility rates of the three most common isolates from six major types of infections (bloodstream, ear-eye-nose-throat, surgical site, skin and soft tissue, urinary tract and wound infection). Results: A high diversity of pathogens was found, but Staphylococcus aureus was predominant in the majority of infections. Overall, the three most prevalent pathogens in children were S. aureus (33.7%), Streptococcus pyogenes (8.1%) and Escherichia coli (4.5%) and in adults S. aureus (23.5%), E. coli (15.1%) and Klebsiella pneumoniae (7.4%). In total, 5.8% (n = 19) of all S. aureus isolates were methicillin resistant. The proportion of extended-spectrum beta-lactamase (ESBL) producing Enterobacteriaceae was 15.4% (n = 78), 49.4% of all K. pneumoniae were ESBL-producer (n = 42). Conclusion: The high diversity of potential pathogens and high resistance rates in Gram-negative bacteria challenge a rational empiric use of antibiotics. Countrywide continuous sentinel surveillance is therefore urgently needed.<br

Effect of fibre additions to flatbread flour mixes on glucose kinetics:A randomised controlled trial

We previously found that guar gum (GG) and chickpea flour (CPF) added to flatbread wheat flour lowered postprandial blood glucose (PPG) and insulin responses dose dependently. However, rates of glucose influx cannot be determined from PPG, which integrates rates of influx, tissue disposal and hepatic glucose production. The objective was to quantify rates of glucose influx and related fluxes as contributors to changes in PPG with GG and CPF additions to wheat-based flatbreads. In a randomised cross-over design, twelve healthy males consumed each of three different C-13-enriched meals: control flatbreads (C), or C incorporating 15 % CPF with either 2 % (GG2) or 4 % (GG4) GG. A dual isotope technique was used to determine the time to reach 50 % absorption of exogenous glucose (T-50 %abs, primary objective), rate of appearance of exogenous glucose (RaE), rate of appearance of total glucose (RaT), endogenous glucose production (EGP) and rate of disappearance of total glucose (RdT). Additional exploratory outcomes included PPG, insulin, glucose-dependent insulinotropic peptide and glucagon-like peptide 1, which were additionally measured over 4 h. Compared with C, GG2 and GG4 had no significant effect on T-50 %abs. However, GG4 significantly reduced 4-h AUC values for RaE, RaT, RdT and EGP, by 11, 14, 14 and 64 %, respectively, whereas GG2 showed minor effects. Effect sizes over 2 and 4 h were similar except for significantly greater reduction in EGP for GG4 at 2 h. In conclusion, a soluble fibre mix added to flatbreads only slightly reduced rates of glucose influx, but more substantially affected rates of postprandial disposal and hepatic glucose production

Hepatic saturated fatty acid fraction is associated with de novo lipogenesis and hepatic insulin resistance

Hepatic steatosis is associated with poor cardiometabolic health, with de novo lipogenesis (DNL) contributing to hepatic steatosis and subsequent insulin resistance. Hepatic saturated fatty acids (SFA) may be a marker of DNL and are suggested to be most detrimental in contributing to insulin resistance. Here, we show in a cross-sectional study design (ClinicalTrials.gov ID: NCT03211299) that we are able to distinguish the fractions of hepatic SFA, mono- and polyunsaturated fatty acids in healthy and metabolically compromised volunteers using proton magnetic resonance spectroscopy (H-1-MRS). DNL is positively associated with SFA fraction and is elevated in patients with non-alcoholic fatty liver and type 2 diabetes. Intriguingly, SFA fraction shows a strong, negative correlation with hepatic insulin sensitivity. Our results show that the hepatic lipid composition, as determined by our H-1-MRS methodology, is a measure of DNL and suggest that specifically the SFA fraction may hamper hepatic insulin sensitivity. Hepatic steatosis is associated with poor cardiometabolic health, with de novo lipogenesis (DNL) contributing to hepatic steatosis and subsequent insulin resistance. Here, the authors use H-1-MRS methodology to show hepatic SFA fraction is a measure of DNL and specifically may hamper hepatic insulin sensitivity.Peer reviewe

Genetic Determinants of Circulating Sphingolipid Concentrations in European Populations

Sphingolipids have essential roles as structural components of cell membranes and in cell signalling, and disruption of their metabolism causes several diseases, with diverse neurological, psychiatric, and metabolic consequences. Increasingly, variants within a few of the genes that encode enzymes involved in sphingolipid metabolism are being associated with complex disease phenotypes. Direct experimental evidence supports a role of specific sphingolipid species in several common complex chronic disease processes including atherosclerotic plaque formation, myocardial infarction (MI), cardiomyopathy, pancreatic beta-cell failure, insulin resistance, and type 2 diabetes mellitus. Therefore, sphingolipids represent novel and important intermediate phenotypes for genetic analysis, yet little is known about the major genetic variants that influence their circulating levels in the general population. We performed a genome-wide association study (GWAS) between 318,237 single-nucleotide polymorphisms (SNPs) and levels of circulating sphingomyelin (SM), dihydrosphingomyelin (Dih-SM), ceramide (Cer), and glucosylceramide (GluCer) single lipid species (33 traits); and 43 matched metabolite ratios measured in 4,400 subjects from five diverse European populations. Associated variants (32) in five genomic regions were identified with genome-wide significant corrected p-values ranging down to 9.08 x 10(-66). The strongest associations were observed in or near 7 genes functionally involved in ceramide biosynthesis and trafficking: SPTLC3, LASS4, SGPP1, ATP10D, and FADS1-3. Variants in 3 loci (ATP10D, FADS3, and SPTLC3) associate with MI in a series of three German MI studies. An additional 70 variants across 23 candidate genes involved in sphingolipid-metabolizing pathways also demonstrate association (p = 10(-4) or less). Circulating concentrations of several key components in sphingolipid metabolism are thus under strong genetic control, and variants in these loci can be tested for a role in the development of common cardiovascular, metabolic, neurological, and psychiatric diseases

Gravitational radiation from gamma-ray bursts as observational opportunities for LIGO and VIRGO

Gamma-ray bursts are believed to originate in core-collapse of massive stars. This produces an active nucleus containing a rapidly rotating Kerr black hole surrounded by a uniformly magnetized torus represented by two counter-oriented current rings. We quantify black hole spin-interactions with the torus and charged particles along open magnetic flux-tubes subtended by the event horizon. A major output of Egw=4e53 erg is radiated in gravitational waves of frequency fgw=500 Hz by a quadrupole mass-moment in the torus. Consistent with GRB-SNe, we find (i) Ts=90s (tens of s, Kouveliotou et al. 1993), (ii) aspherical SNe of kinetic energy Esn=2e51 erg (2e51 erg in SN1998bw, Hoeflich et al. 1999) and (iii) GRB-energies Egamma=2e50 erg (3e50erg in Frail et al. 2001). GRB-SNe occur perhaps about once a year within D=100Mpc. Correlating LIGO/Virgo detectors enables searches for nearby events and their spectral closure density 6e-9 around 250Hz in the stochastic background radiation in gravitational waves. At current sensitivity, LIGO-Hanford may place an upper bound around 150MSolar in GRB030329. Detection of Egw thus provides a method for identifying Kerr black holes by calorimetry.Comment: to appear in PRD, 49

Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms

Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Although 58 genomic regions have been associated with CAD thus far, most of the heritability is unexplained, indicating that additional susceptibility loci await identification. An efficient discovery strategy may be larger-scale evaluation of promising associations suggested by genome-wide association studies (GWAS). Hence, we genotyped 56,309 participants using a targeted gene array derived from earlier GWAS results and performed meta-analysis of results with 194,427 participants previously genotyped, totaling 88,192 CAD cases and 162,544 controls. We identified 25 new SNP-CAD associations (P &lt; 5 × 10(-8), in fixed-effects meta-analysis) from 15 genomic regions, including SNPs in or near genes involved in cellular adhesion, leukocyte migration and atherosclerosis (PECAM1, rs1867624), coagulation and inflammation (PROCR, rs867186 (p.Ser219Gly)) and vascular smooth muscle cell differentiation (LMOD1, rs2820315). Correlation of these regions with cell-type-specific gene expression and plasma protein levels sheds light on potential disease mechanisms

Analysis of LIGO data for gravitational waves from binary neutron stars

We report on a search for gravitational waves from coalescing compact binary systems in the Milky Way and the Magellanic Clouds. The analysis uses data taken by two of the three LIGO interferometers during the first LIGO science run and illustrates a method of setting upper limits on inspiral event rates using interferometer data. The analysis pipeline is described with particular attention to data selection and coincidence between the two interferometers. We establish an observational upper limit of $\mathcal{R}<$1.7 \times 10^{2}$per year per Milky Way Equivalent Galaxy (MWEG), with 90coalescence rate of binary systems in which each component has a mass in the range 1--3$M_\odot$.Comment: 17 pages, 9 figure

The Role of Interferon in Hepatitis B Therapy

Despite the introduction of new nucleos(t)ide analogues in recent years, peginterferon is still recommended as a potential first-line treatment option by current practice guidelines for the management of chronic hepatitis B. Peginterferon offers the advantage of higher sustained off-treatment response rates compared to nucleos(t)ide analogues because of its immunomodulatory effects. Sustained transition to the inactive hepatitis B surface antigen (HBsAg) carrier state can be achieved in about 30% of hepatitis B e antigen (HBeAg)–positive patients and 20% of HBeAg-negative patients. Recent studies have focused on identification of pretreatment and on-treatment factors that allow the selection of patients who are likely to achieve a sustained response to peginterferon therapy in order to avoid the side-effects and costs associated with unnecessary treatment. Future studies need to address whether specific virologic benchmarks can guide individualized decisions concerning therapy continuation and whether peginterferon combined with new potent nucleos(t)ide analogues improves treatment outcomes

Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD