Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by inflammation and fibrosis of the bile ducts. Both environmental and genetic factors contribute to its ...pathogenesis. To further clarify its genetic background, we investigated susceptibility loci recently identified for ulcerative colitis (UC) in a large cohort of 1,186 PSC patients and 1,748 controls. Single nucleotide polymorphisms (SNPs) tagging 13 UC susceptibility loci were initially genotyped in 854 PSC patients and 1,491 controls from Benelux (331 cases, 735 controls), Germany (265 cases, 368 controls), and Scandinavia (258 cases, 388 controls). Subsequently, a joint analysis was performed with an independent second Scandinavian cohort (332 cases, 257 controls). SNPs at chromosomes 2p16 (P‐value 4.12 × 10−4), 4q27 (P‐value 4.10 × 10−5), and 9q34 (P‐value 8.41 × 10−4) were associated with PSC in the joint analysis after correcting for multiple testing. In PSC patients without inflammatory bowel disease (IBD), SNPs at 4q27 and 9q34 were nominally associated (P < 0.05). We applied additional in silico analyses to identify likely candidate genes at PSC susceptibility loci. To identify nonrandom, evidence‐based links we used GRAIL (Gene Relationships Across Implicated Loci) analysis showing interconnectivity between genes in six out of in total nine PSC‐associated regions. Expression quantitative trait analysis from 1,469 Dutch and UK individuals demonstrated that five out of nine SNPs had an effect on cis‐gene expression. These analyses prioritized IL2, CARD9, and REL as novel candidates. Conclusion: We have identified three UC susceptibility loci to be associated with PSC, harboring the putative candidate genes REL, IL2, and CARD9. These results add to the scarce knowledge on the genetic background of PSC and imply an important role for both innate and adaptive immunological factors. (HEPATOLOGY 2011;)
This work measured dσ/dΩ for neutral kaon photoproduction reactions from threshold up to a c.m. energy of 1855MeV, focussing specifically on the γp→K0Σ+, γn→K0Λ, and γn→K0Σ0 reactions. Our results ...for γn→K0Σ0 are the first-ever measurements for that reaction. These data will provide insight into the properties of N* resonances and, in particular, will lead to an improved knowledge about those states that couple only weakly to the πN channel. Integrated cross sections were extracted by fitting the differential cross sections for each reaction as a series of Legendre polynomials and our results are compared with prior experimental results and theoretical predictions.
.
This work measured
d
σ
/
d
Ω
for neutral kaon photoproduction reactions from threshold up to a c.m. energy of 1855MeV, focussing specifically on the
γ
p
→
K
0
Σ
+
,
γ
n
→
K
0
Λ
, and
γ
n
→
K
0
Σ
0
...reactions. Our results for
γ
n
→
K
0
Σ
0
are the first-ever measurements for that reaction. These data will provide insight into the properties of
N
*
resonances and, in particular, will lead to an improved knowledge about those states that couple only weakly to the
π
N
channel. Integrated cross sections were extracted by fitting the differential cross sections for each reaction as a series of Legendre polynomials and our results are compared with prior experimental results and theoretical predictions.
Obesity is a worldwide health problem. We conducted detailed analyses of anthropometric measures in a comprehensive, population-based, current cohort in Germany.BACKGROUNDObesity is a worldwide ...health problem. We conducted detailed analyses of anthropometric measures in a comprehensive, population-based, current cohort in Germany.In the German National Cohort (NAKO), we analyzed cross-sectional data on body mass index (BMI), waist and hip circumference, subcutaneous (SAT) and visceral adipose tissue (VAT) as measured by ultrasound, and body fat percentage. The data were stratified by sex, age, and self-reported physicians' diagnoses of cardiovascular diseases (CVD), metabolic diseases (MetD), cardiometabolic diseases (CMD), and cancer.METHODSIn the German National Cohort (NAKO), we analyzed cross-sectional data on body mass index (BMI), waist and hip circumference, subcutaneous (SAT) and visceral adipose tissue (VAT) as measured by ultrasound, and body fat percentage. The data were stratified by sex, age, and self-reported physicians' diagnoses of cardiovascular diseases (CVD), metabolic diseases (MetD), cardiometabolic diseases (CMD), and cancer.Data were available from 204 751 participants (age, 49.9 ± 12.8 years; 50.5% women). Body size measures generally increased with age. Men had a higher BMI, larger waist circumference, and more VAT than women, while women had a larger hip circumference, more SAT, and a higher body fat percentage than men. For example, the mean BMI of participants over age 60 was 28.3 kg/m2 in men and 27.6 kg/m2 in women. CVD, MetD, and CMD were associated with higher anthropometric values, while cancer was not. For example, the mean BMI was 25.3 kg/m2 in healthy women, 29.4 kg/m2 in women with CMD, and 25.4 kg/m2 in women with cancer.RESULTSData were available from 204 751 participants (age, 49.9 ± 12.8 years; 50.5% women). Body size measures generally increased with age. Men had a higher BMI, larger waist circumference, and more VAT than women, while women had a larger hip circumference, more SAT, and a higher body fat percentage than men. For example, the mean BMI of participants over age 60 was 28.3 kg/m2 in men and 27.6 kg/m2 in women. CVD, MetD, and CMD were associated with higher anthropometric values, while cancer was not. For example, the mean BMI was 25.3 kg/m2 in healthy women, 29.4 kg/m2 in women with CMD, and 25.4 kg/m2 in women with cancer.Obesity is widespread in Germany, with notable differences between the sexes in anthro - pometric values. Obesity was more common in older participants and those with chronic diseases other than cancer. Elevated values were especially common in multimorbid individuals.CONCLUSIONObesity is widespread in Germany, with notable differences between the sexes in anthro - pometric values. Obesity was more common in older participants and those with chronic diseases other than cancer. Elevated values were especially common in multimorbid individuals.
The ongoing HIV epidemic and the increasing number of patients with drug-resistant tuberculosis (TB) are seriously hampering global TB-control activities, including those in the World Health ...Organization (WHO) Region Europe. Overall, the prevalence of HIV co-infection in TB patients increased from 3.4% in 2008 to 8% in 2014 in the region 1. The prevalence of multidrug-resistant (MDR)-TB (drug resistance against at least isoniazid and rifampicin) reported for Europe – 15% in newly diagnosed TB patients and 48% in previously treated TB patients – is the highest in the world 1.
Zusammenfassung
Hintergrund
Das Raynaud-Phänomen und die damit häufig einhergehenden digitalen Ulzerationen stellen für Patienten mit systemischer Sklerose (Sklerodermie SSc) ein frühes und sehr ...belastendes Symptom mit bedeutenden Einschränkungen der Arbeitsfähigkeit und Lebensqualität dar. Der Einsatz vasoaktiver Medikamente (insbesondere intravenöser Prostazyklinderivate) soll helfen, das Risiko hypoxischer Gewebeschäden bis hin zum Verlust der Finger zu reduzieren.
Methoden
Um Aufschluss über die aktuelle Versorgung von Patienten mit Prostazyklinderivaten im klinischen Alltag in Deutschland zu erhalten, führten wir eine Umfrage unter den im Deutschen Netzwerk für systemische Sklerodermie (DNSS) zusammengeschlossenen Kliniken durch. Zusätzlich erfolgte eine separate Patientenbefragung über die Sklerodermie Selbsthilfe e. V., die sich nur auf die Symptome „Raynaud-Phänomen“ und „Digitale Ulzera“ und den Einsatz intravenöser Prostazyklinderivate bezog.
Ergebnisse
Von den befragten 433 Patienten gaben 56 % an, dass sie bereits aufgrund ihrer Erkrankung und Symptome mit Prostazyklinderivaten behandelt wurden. Insgesamt 61 % erhielten die Therapie aufgrund starker Raynaud-Symptomatik und 39 % aufgrund digitaler Ulzerationen. Die meisten Befragten erfuhren durch die Therapie nicht nur eine Verbesserung des Raynaud-Phänomens und der digitalen Ulzera, sondern auch eine wesentliche Verbesserung von Einschränkungen im Alltag. Sie gaben zudem an, wesentlich weniger fremde Hilfe in Anspruch genommen sowie wesentlich weniger Fehlzeiten bei der Arbeit gehabt zu haben.
Schlussfolgerung
Die Patienten empfanden durchweg einen positiven Effekt der Therapie mit Prostazyklinderivaten auf das Raynaud-Phänomen, ihre digitalen Ulzerationen, Schmerzen und Alltagseinschränkung und fühlten sich durch die stationäre Therapie gut und sicher betreut. Diese positiven Effekte in der Patientenwahrnehmung sind eine eindrückliche Stütze und bestätigen nachdrücklich die auf europäischer und internationaler Ebene erarbeiteten Therapieempfehlungen.
deletions and
mutations frequently cooccur in prostate cancer with lower frequencies reported in castration-resistant prostate cancer (CRPC). We monitored CHD1 expression during disease progression ...and assessed the molecular and clinical characteristics of
-deleted/
-mutated metastatic CRPC (mCRPC).
We identified 89 patients with mCRPC who had hormone-naive and castration-resistant tumor samples available: These were analyzed for CHD1, PTEN, and ERG expression by IHC.
status was determined by targeted next-generation sequencing (NGS). We studied the correlations between these biomarkers and (i) overall survival from diagnosis; (ii) overall survival from CRPC; (iii) duration of abiraterone treatment; and (iv) response to abiraterone. Relationship with outcome was analyzed using Cox regression and log-rank analyses.
CHD1 protein loss was detected in 11 (15%) and 13 (17%) of hormone-sensitive prostate cancer (HSPC) and CRPC biopsies, respectively. Comparison of CHD1 expression was feasible in 56 matched, same patient HSPC and CRPC biopsies. CHD1 protein status in HSPC and CRPC correlated in 55 of 56 cases (98%). We identified 22 patients with somatic
mutations, with six of these mutations not reported previously in prostate cancer.
mutations and/or CHD1 loss was associated with a higher response rate to abiraterone (SPOP: OR, 14.50
= 0.001; CHD1: OR, 7.30,
= 0.08) and a longer time on abiraterone (SPOP: HR, 0.37,
= 0.002, CHD1: HR, 0.50,
= 0.06).
-mutated mCRPCs are strongly enriched for CHD1 loss. These tumors appear highly sensitive to abiraterone treatment.
.
The IceCube Neutrino Observatory instruments about 1 km3 of deep, glacial ice at the geographic South Pole. It uses 5160 photomultipliers to detect Cherenkov light emitted by charged relativistic ...particles. An unexpected light propagation effect observed by the experiment is an anisotropic attenuation, which is aligned with the local flow direction of the ice. We examine birefringent light propagation through the polycrystalline ice microstructure as a possible explanation for this effect. The predictions of a first-principles model developed for this purpose, in particular curved light trajectories resulting from asymmetric diffusion, provide a qualitatively good match to the main features of the data. This in turn allows us to deduce ice crystal properties. Since the wavelength of the detected light is short compared to the crystal size, these crystal properties include not only the crystal orientation fabric, but also the average crystal size and shape, as a function of depth. By adding small empirical corrections to this first-principles model, a quantitatively accurate description of the optical properties of the IceCube glacial ice is obtained. In this paper, we present the experimental signature of ice optical anisotropy observed in IceCube light-emitting diode (LED) calibration data, the theory and parameterization of the birefringence effect, the fitting procedures of these parameterizations to experimental data, and the inferred crystal properties.
Acute lung injury (ALI) still represents a major cause of morbidity and mortality in intensive care units. Beneficial effects have been described after activation of the peroxisome ...proliferator-activated receptor (PPAR)-alpha by fibrates such as WY 14,643 (WY) in inflammatory models. In the present study, the impact of WY was investigated in a model of endotoxin (lipopolysaccharide; LPS)-induced ALI in mice. Intratracheal LPS challenge dose-dependently resulted in leukocyte invasion, protein leakage and release of tumour necrosis factor-alpha as well as macrophage inflammatory protein-2, prostaglandin E(2) and thromboxane B(2) into the alveolar space after 8 and 24 h. Lung ventilator compliance was reduced at both time-points. In isolated perfused mouse lungs, platelet-activating factor (PAF) induced an acute increase in pulmonary artery pressure (P(pa)) and in capillary filtration coefficient (K(fc)). WY significantly improved all features of ALI in vivo and blunted the increase in K(fc) in isolated perfused mice lungs. In mice with genetic deletion of PPAR-alpha, all characteristics of ALI, P(pa), and K(fc) were not significantly different from wild-type mice but WY failed to improve ALI and PAF-induced increase in K(fc). Activation of peroxisome proliferator-activated receptor-alpha by WY 14,643 reduced acute lung injury and vascular leakage. Fibrates may possess beneficial effects in acute pulmonary diseases beyond their lipid-lowering capability.
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