Comparison of the diagnostic accuracy of three current guidelines for the evaluation of asymptomatic pancreatic cystic neoplasms.

Asymptomatic pancreatic cysts are a common clinical problem but only a minority of these cases progress to cancer. Our aim was to compare the accuracy to detect malignancy of the 2015 American Gastroenterological Association (AGA), the 2012 International Consensus/Fukuoka (Fukuoka guidelines [FG]), and the 2010 American College of Radiology (ACR) guidelines.We conducted a retrospective study at 3 referral centers for all patients who underwent resection for an asymptomatic pancreatic cyst between January 2008 and December 2013. We compared the accuracy of 3 guidelines in predicting high-grade dysplasia (HGD) or cancer in resected cysts. We performed logistic regression analyses to examine the association between cyst features and risk of HGD or cancer.A total of 269 patients met inclusion criteria. A total of 228 (84.8%) had a benign diagnosis or low-grade dysplasia on surgical pathology, and 41 patients (15.2%) had either HGD (n = 14) or invasive cancer (n = 27). Of the 41 patients with HGD or cancer on resection, only 3 patients would have met the AGA guideline\u27s indications for resection based on the preoperative cyst characteristics, whereas 30/41 patients would have met the FG criteria for resection and 22/41 patients met the ACR criteria. The sensitivity, specificity, positive predictive value, negative predictive value of HGD, and/or cancer of the AGA guidelines were 7.3%, 88.2%, 10%, and 84.1%, compared to 73.2%, 45.6%, 19.5%, and 90.4% for the FG and 53.7%, 61%, 19.8%, and 88% for the ACR guidelines. In multivariable analysis, cyst size \u3e3 cm, compared to ≤3 cm, (odds ratio [OR] = 2.08, 95% confidence interval [CI] = 1.11, 4.2) and each year increase in age (OR = 1.07, 95% CI = 1.03, 1.11) were positively associated with risk of HGD or cancer on resection.In patients with asymptomatic branch duct-intraductal papillary mucinous neoplasms or mucinous cystic neoplasms who underwent resection, the prevalence rate of HGD or cancer was 15.2%. Using the 2015 AGA criteria for resection would have missed 92.6% of patients with HGD or cancer. The more inclusive FG and ACR had a higher sensitivity for HGD or cancer but lower specificity. Given the current deficiencies of these guidelines, it will be important to determine the acceptable rate of false-positives in order to prevent a single true-positive

GEF-H1 Mediated Control of NOD1 Dependent NF-κB Activation by Shigella Effectors

Shigella flexneri has evolved the ability to modify host cell function with intracellular active effectors to overcome the intestinal barrier. The detection of these microbial effectors and the initiation of innate immune responses are critical for rapid mucosal defense activation. The guanine nucleotide exchange factor H1 (GEF-H1) mediates RhoA activation required for cell invasion by the enteroinvasive pathogen Shigella flexneri. Surprisingly, GEF-H1 is requisite for NF-κB activation in response to Shigella infection. GEF-H1 interacts with NOD1 and is required for RIP2 dependent NF-κB activation by H-Ala-D-γGlu-DAP (γTriDAP). GEF-H1 is essential for NF-κB activation by the Shigella effectors IpgB2 and OspB, which were found to signal in a NOD1 and RhoA Kinase (ROCK) dependent manner. Our results demonstrate that GEF-H1 is a critical component of cellular defenses forming an intracellular sensing system with NOD1 for the detection of microbial effectors during cell invasion by pathogens

SepA Enhances Shigella Invasion of Epithelial Cells by Degrading Alpha-1 Antitrypsin and Producing a Neutrophil Chemoattractant

Shigella spp. are highly adapted pathogens that cause bacillary dysentery in human and nonhuman primates. An unusual feature of Shigella pathogenesis is that this organism invades the colonic epithelia from the basolateral pole. Therefore, it has evolved the ability to disrupt the intestinal epithelial barrier to reach the basolateral surface. We have shown previously that the secreted serine protease A (SepA), which belongs to the family of serine protease autotransporters of Enterobacteriaceae, is responsible for the initial destabilization of the intestinal epithelial barrier that facilitates Shigella invasion. However, the mechanisms used by SepA to regulate this process remain unknown. To investigate the protein targets cleaved by SepA in the intestinal epithelium, we incubated a sample of homogenized human colon with purified SepA or with a catalytically inactive mutant of this protease. We discovered that SepA targets an array of 18 different proteins, including alpha-1 antitrypsin (AAT), a major circulating serine proteinase inhibitor in humans. In contrast to other serine proteases, SepA cleaved AAT without forming an inhibiting complex, which resulted in the generation of a neutrophil chemoattractant. We demonstrated that the products of the AAT-SepA reaction induce a mild but significant increase in neutrophil transepithelial migration in vitro. Moreover, the presence of AAT during Shigella infection stimulated neutrophil migration and dramatically enhanced the number of bacteria invading the intestinal epithelium in a SepA-dependent manner. We conclude that by cleaving AAT, SepA releases a chemoattractant that promotes neutrophil migration, which in turn disrupts the intestinal epithelial barrier to enable Shigella invasion. IMPORTANCE Shigella is the second leading cause of diarrheal death globally. In this study, we identified the host protein targets of SepA, Shigella\u27s major protein secreted in culture. We demonstrated that by cleaving AAT, a serine protease inhibitor important to protect surrounding tissue at inflammatory sites, SepA releases a neutrophil chemoattractant that enhances Shigella invasion. Moreover, SepA degraded AAT without becoming inhibited by the cleaved product, and SepA catalytic activity was enhanced at higher concentrations of AAT. Activation of SepA by an excess of AAT may be physiologically relevant at the early stages of Shigella infection, when the amount of synthesized SepA is very low compared to the concentration of AAT in the intestinal lumen. This observation may also help to explain the adeptness of Shigella infectivity at low dose, despite the requirement of reaching the basolateral side to invade and colonize the colonic epithelium

The INF Treaty of 1987

Der von Ronald Reagan und Michail Gorbatschow am 8. Dezember 1987 unterzeichnete »Intermediate-Range Nuclear Forces Treaty«, kurz INF-Vertrag, stellte einen Meilenstein der nuklearen Abrüstungsverhandlungen zwischen den Vereinigten Staaten von Amerika und der Sowjetunion dar. Im Jahr 2019 wurde er von Russland und den USA gekündigt. Der englischsprachige Band untersucht die Vorgeschichte des Abkommens, dessen Implementierung und Folgen sowohl in den beiden Supermächten als auch in den mit ihnen verbündeten Staaten. Er ist damit die erste umfassende Darstellung eines der wichtigsten Abrüstungsabkommen der jüngsten Zeit

Loss of function mutations in HARS cause a spectrum of inherited peripheral neuropathies

Using linkage analysis and whole-exome sequencing, Safka Brozkova et al. reveal missense mutations in the histidyl-tRNA synthetase gene in 23 patients from four families with axonal and demyelinating neuropathies of varying severity. The mutations cause loss of function in yeast complementation assays and neurotoxicity in a C. elegans mode

The clustering of galaxies in the SDSS-III Baryon Oscillation Spectroscopic Survey: Baryon Acoustic Oscillations in the Data Release 9 Spectroscopic Galaxy Sample

We present measurements of galaxy clustering from the Baryon Oscillation Spectroscopic Survey (BOSS), which is part of the Sloan Digital Sky Survey III (SDSS-III). These use the Data Release 9 (DR9) CMASS sample, which contains 264,283 massive galaxies covering 3275 square degrees with an effective redshift z=0.57 and redshift range 0.43 < z < 0.7. Assuming a concordance Lambda-CDM cosmological model, this sample covers an effective volume of 2.2 Gpc^3, and represents the largest sample of the Universe ever surveyed at this density, n = 3 x 10^-4 h^-3 Mpc^3. We measure the angle-averaged galaxy correlation function and power spectrum, including density-field reconstruction of the baryon acoustic oscillation (BAO) feature. The acoustic features are detected at a significance of 5\sigma in both the correlation function and power spectrum. Combining with the SDSS-II Luminous Red Galaxy Sample, the detection significance increases to 6.7\sigma. Fitting for the position of the acoustic features measures the distance to z=0.57 relative to the sound horizon DV /rs = 13.67 +/- 0.22 at z=0.57. Assuming a fiducial sound horizon of 153.19 Mpc, which matches cosmic microwave background constraints, this corresponds to a distance DV(z=0.57) = 2094 +/- 34 Mpc. At 1.7 per cent, this is the most precise distance constraint ever obtained from a galaxy survey. We place this result alongside previous BAO measurements in a cosmological distance ladder and find excellent agreement with the current supernova measurements. We use these distance measurements to constrain various cosmological models, finding continuing support for a flat Universe with a cosmological constant.Comment: 33 page

Succinate Dehydrogenase Supports Metabolic Repurposing of Mitochondria to Drive Inflammatory Macrophages.

Activated macrophages undergo metabolic reprogramming, which drives their pro-inflammatory phenotype, but the mechanistic basis for this remains obscure. Here, we demonstrate that upon lipopolysaccharide (LPS) stimulation, macrophages shift from producing ATP by oxidative phosphorylation to glycolysis while also increasing succinate levels. We show that increased mitochondrial oxidation of succinate via succinate dehydrogenase (SDH) and an elevation of mitochondrial membrane potential combine to drive mitochondrial reactive oxygen species (ROS) production. RNA sequencing reveals that this combination induces a pro-inflammatory gene expression profile, while an inhibitor of succinate oxidation, dimethyl malonate (DMM), promotes an anti-inflammatory outcome. Blocking ROS production with rotenone by uncoupling mitochondria or by expressing the alternative oxidase (AOX) inhibits this inflammatory phenotype, with AOX protecting mice from LPS lethality. The metabolic alterations that occur upon activation of macrophages therefore repurpose mitochondria from ATP synthesis to ROS production in order to promote a pro-inflammatory state

Association of ACTN3 R577X but not ACE I/D gene variants with elite rugby union player status and playing position

We aimed to quantify the ACE I/D and ACTN3 R577X (rs1815739) genetic variants in elite rugby athletes (rugby union and league), compare genotype frequencies to controls and between playing positions. The rugby athlete cohort consisted of 507 Caucasian men, including 431 rugby union athletes that for some analyses were divided into backs and forwards and into specific positional groups: front five, back row, half backs, centers and back three. Controls were 710 Caucasian men and women. Real-time PCR of genomic DNA was used to determine genotypes using TaqMan probes and groups were compared using Chi-square and odds ratio (OR) statistics. Correction of p-values for multiple comparisons was according to Benjamini-Hochberg. There was no difference in ACE I/D genotype between groups. ACTN3 XX genotype tended to be underrepresented in rugby union backs (15.7%) compared to forwards (24.8%; P=0.06). Interestingly, the 69 back three players (wings and full backs) in rugby union included only six XX genotype individuals (8.7%), with the R allele more common in the back three (68.8%) than controls (58.0%; χ2=6.672, P=0.04; OR=1.60) and forwards (47.5%; χ2=11.768, P=0.01; OR=2.00). Association of ACTN3 R577X with playing position in elite rugby union athletes suggests inherited fatigue resistance is more prevalent in forwards while inherited sprint ability is more prevalent in backs, especially wings and full backs. These results also demonstrate the advantage of focusing genetic studies on a large cohort within a single sport, especially when intra-sport positional differences exist, instead of combining several sports with varied demands and athlete characteristics