Duodenal ulcer is a multifactorial disorder the role of pepsinogen I

Serum pepsinogen I (PGI) levels were measured in 231 duodenal ulcer (DU) patients and 100 sex and age-comparable healthy controls. Significantly higher mean serum PGI levels were found in DU patients than in controls (124,7 ± 3,4 ng/ml v. 92,9 ± 2,3 ng/ml; P < 0,001) (mean ± SE). These levels were higher in male DU patients than in female DU patients (128,5 ± 3,9 ng/IDl v. 107,4 ± 6,4 ng/ml; P < 0,05). Smoking was associated with elevated serum PGI levels in DU patients (145,3 ± 5,1 ng/ml v. 109,0 ± 4,2 ngl/ml; P < 0,001). Healed DUs were associated with lower mean serum PGI levels than active ulcers (110,9 ± 7,6 ng/ml v. 129,4 ± 3,8 ng/ml, P < 0,05). Whether patients were positive or negative for Helicobacter pylori, infection did not affect mean serum PGI levels. All the risk factors for DU may not affect serum PGI levels and DU may therefore be considered a multifactorial disease

Burkhardt-Cottingham sum rule and forward spin polarizabilities in Heavy Baryon Chiral Perturbation Theory

We study spin-dependent sum rules for forward virtual Compton scattering(VVCS) off the nucleon in heavy baryon chiral perturbation theory at order $O(p^4)$. We show how these sum rules can be evaluated from low energy expansions (in the virtual photon energy) of the forward VVCS amplitudes. We study in particular the Burkhardt -Cottingham sum rule in HBChPT and higher terms in the low energy expansion, which can be related to the generalized forward spin polarizabilities of the nucleon. The dependence of these observables on the photon virtuality $Q^2$ can be accessed, at small and intermediate $Q^2$ values, from existing and forthcoming data at Jefferson Lab.Comment: 16 pages,4 fig

Endothelial miR-30c suppresses tumor growth via inhibition of TGF-β–induced Serpine1

In tumors, extravascular fibrin forms provisional scaffolds for endothelial cell (EC) growth and motility during angiogenesis. We report that fibrin-mediated angiogenesis was inhibited and tumor growth delayed following postnatal deletion of Tgfbr2 in the endothelium of Cdh5-CreERT2 Tgfbr2fl/fl mice (Tgfbr2iECKOmice). ECs from Tgfbr2iECKO mice failed to upregulate the fibrinolysis inhibitor plasminogen activator inhibitor 1 (Serpine1, also known as PAI-1), due in part to uncoupled TGF-β–mediated suppression of miR-30c. Bypassing TGF-β signaling with vascular tropic nanoparticles that deliver miR-30c antagomiRs promoted PAI-1–dependent tumor growth and increased fibrin abundance, whereas miR-30c mimics inhibited tumor growth and promoted vascular-directed fibrinolysis in vivo. Using single-cell RNA-Seq and a NanoString miRNA array, we also found that subtypes of ECs in tumors showed spectrums of Serpine1 and miR-30c expression levels, suggesting functional diversity in ECs at the level of individual cells; indeed, fresh EC isolates from lung and mammary tumor models had differential abilities to degrade fibrin and launch new vessel sprouts, a finding that was linked to their inverse expression patterns of miR-30c and Serpine1 (i.e., miR-30chi Serpine1lo ECs were poorly angiogenic and miR-30clo Serpine1hi ECs were highly angiogenic). Thus, by balancing Serpine1 expression in ECs downstream of TGF-β, miR-30c functions as a tumor suppressor in the tumor microenvironment through its ability to promote fibrin degradation and inhibit blood vessel formation

A functional riboSNitch in the 3' untranslated region of FKBP5 alters MicroRNA-320a binding efficiency and mediates vulnerability to chronic post-traumatic pain

Previous studies have shown that common variants of the gene coding for FK506-binding protein 51 (FKBP5), a critical regulator of glucocorticoid sensitivity, affect vulnerability to stress-related disorders. In a previous report, FKBP5 rs1360780 was identified as a functional variant because of its effect on gene methylation. Here we report evidence for a novel functional FKBP5 allele, rs3800373. This study assessed the association between rs3800373 and post-traumatic chronic pain in 1607 women and men from two ethnically diverse human cohorts. The molecular mechanism through which rs3800373 affects adverse outcomes was established via in silico, in vivo, and in vitro analyses. The rs3800373 minor allele predicted worse adverse outcomes after trauma exposure, such that individuals with the minor (risk) allele developed more severe post-traumatic chronic musculoskeletal pain. Among these individuals, peritraumatic circulating FKBP5 expression levels increased as cortisol and glucocorticoid receptor (NR3C1) mRNA levels increased, consistent with increased glucocorticoid resistance. Bioinformatic, in vitro, and mutational analyses indicate that the rs3800373 minor allele reduces the binding of a stress-and pain-associated microRNA, miR-320a, to FKBP5 via altering the FKBP5 mRNA 3'UTR secondary structure (i.e., is a riboSNitch). This results in relatively greater FKBP5 translation, unchecked by miR-320a. Overall, these results identify an important gene–miRNA interaction influencing chronic pain risk in vulnerable individuals and suggest that exogenous methods to achieve targeted reduction in poststress FKBP5 mRNA expression may constitute useful therapeutic strategies

Dynamic Evolution of a Quasi-Spherical General Polytropic Magnetofluid with Self-Gravity

In various astrophysical contexts, we analyze self-similar behaviours of magnetohydrodynamic (MHD) evolution of a quasi-spherical polytropic magnetized gas under self-gravity with the specific entropy conserved along streamlines. In particular, this MHD model analysis frees the scaling parameter $n$ in the conventional polytropic self-similar transformation from the constraint of $n+\gamma=2$ with $\gamma$ being the polytropic index and therefore substantially generalizes earlier analysis results on polytropic gas dynamics that has a constant specific entropy everywhere in space at all time. On the basis of the self-similar nonlinear MHD ordinary differential equations, we examine behaviours of the magnetosonic critical curves, the MHD shock conditions, and various asymptotic solutions. We then construct global semi-complete self-similar MHD solutions using a combination of analytical and numerical means and indicate plausible astrophysical applications of these magnetized flow solutions with or without MHD shocks.Comment: 21 pages, 7 figures, accepted for publication in APS

The association of AGTR2 polymorphisms with preeclampsia and uterine artery bilateral notching is modulated by maternal BMI

On behalf of the SCOPE consortiumIntroductionThis study aimed to determine the association of AGTR1 and AGTR2 polymorphisms with preeclampsia and whether these are affected by environmental factors and fetal sex.MethodsOverall 3234 healthy nulliparous women, their partners and babies were recruited prospectively to the SCOPE study in Adelaide and Auckland. Data analyses were confined to 2121 Caucasian parent-infant trios, among whom 123 had preeclamptic pregnancies. 1185 uncomplicated pregnancies served as controls. DNA was extracted from buffy coats and genotyped by utilizing the Sequenom MassARRAY system. Doppler sonography on the uterine arteries was performed at 20 weeks' gestation.ResultsFour polymorphisms in AGTR1 and AGTR2 genes, including AGTR1 A1166C, AGTR2 C4599A, AGTR2 A1675G and AGTR2 T1134C, were selected and significant associations were predominately observed for AGTR2 C4599A. When the cohort was stratified by maternal BMI, in women with BMI ≥ 25 kg/m(2), the AGTR2 C4599A AA genotype in mothers and neonates was associated with an increased risk for preeclampsia compared with the CC genotype [adjusted OR 2.1 (95% CI 1.0-4.2) and adjusted OR 3.0 (95% CI 1.4-6.4), respectively]. In the same subset of women, paternal AGTR2 C4599A A allele was associated with an increased risk for preeclampsia and uterine artery bilateral notching at 20 weeks' gestation compared with the C allele [adjusted OR 1.9 (95% CI 1.1-3.3) and adjusted OR 2.1 (95% CI 1.3-3.4), respectively].ConclusionAGTR2 C4599A in mothers, fathers and babies was associated with preeclampsia and this association was only apparent in pregnancies in which the women had a BMI ≥ 25 kg/m(2), suggesting a gene-environment interaction.A. Zhou, G.A. Dekker, E.R. Lumbers, S.Y. Lee, S.D. Thompson, L.M.E. McCowan, C.T. Robert

Identification and validation of novel biomarkers and therapeutics for pulpitis using connectivity mapping

International audienceAim To create an irreversible pulpitis gene signature from microarray data of healthy and inflamed dental pulps, followed by a bioinformatics approach using connectivity mapping to identify therapeutic compounds that could potentially treat pulpitis. Methodology The Gene Expression Omnibus (GEO) database, an international public repositor

Tnfa Signaling Through Tnfr2 Protects Skin Against Oxidative Stress-Induced Inflammation

TNFα overexpression has been associated with several chronic inflammatory diseases, including psoriasis, lichen planus, rheumatoid arthritis, and inflammatory bowel disease. Paradoxically, numerous studies have reported new-onset psoriasis and lichen planus following TNFα antagonist therapy. Here, we show that genetic inhibition of Tnfa and Tnfr2 in zebrafish results in the mobilization of neutrophils to the skin. Using combinations of fluorescent reporter transgenes, fluorescence microscopy, and flow cytometry, we identified the local production of dual oxidase 1 (Duox1)-derived H2O2 by Tnfa- and Tnfr2-deficient keratinocytes as a trigger for the activation of the master inflammation transcription factor NF-κB, which then promotes the induction of genes encoding pro-inflammatory molecules. In addition, pharmacological inhibition of Duox1 completely abrogated skin inflammation, placing Duox1-derived H2O2 upstream of this positive feedback inflammatory loop. Strikingly, DUOX1 was drastically induced in the skin lesions of psoriasis and lichen planus patients. These results reveal a crucial role for TNFα/TNFR2 axis in the protection of the skin against DUOX1-mediated oxidative stress and could establish new therapeutic targets for skin inflammatory disorders

Early- Onset Stroke and Vasculopathy Associated with Mutations in ADA2

Adenosine deaminase 2 (ADA2) is an enzyme involved in purine metabolism and a growth factor that influences the development of endothelial cells and leukocytes. This study shows that defects in ADA2 cause recurrent fevers, vascular pathologic features, and mild immunodeficiency. Patients with autoinflammatory disease sometimes present with clinical findings that encompass multiple organ systems.(1) Three unrelated children presented to the National Institutes of Health (NIH) Clinical Center with intermittent fevers, recurrent lacunar strokes, elevated levels of acute-phase reactants, livedoid rash, hepatosplenomegaly, and hypogammaglobulinemia. Collectively, these findings do not easily fit with any of the known inherited autoinflammatory diseases. Hereditary or acquired vascular disorders can have protean manifestations yet be caused by mutations in a single gene. Diseases such as the Aicardi-Goutieres syndrome,(2),(3) polypoidal choroidal vasculopathy,(4) sickle cell anemia,(5) livedoid vasculopathy,(6) and the small-vessel vasculitides(7),(8) are examples of systemic ...</p