TRAF3IP2 gene is associated with cutaneous extraintestinal manifestations in Inflammatory bowel disease

Background and aims: Genome-wide association (GWA) studies recently identified a novel gene, TRAF3IP2, involved in the susceptibility to psoriasis. Common immune-mediated mechanisms involving the skin or the gut have been suggested. We therefore aimed to assess the role of TRAF3IP2 gene in IBD, with particular regard to the development of cutaneous extraintestinal manifestations (pyoderma gangrenosum, erythema nodosum). The association with psoriasis was also assessed in a secondary analysis. Methods: The analysis included 267 Crohn's disease (CD), 200 ulcerative colitis (UC) patients and 278 healthy controls. Three TRAF3IP2 SNPs were genotyped by allelic discrimination assays. A case/control association study and a genotype/phenotype correlation analysis have been performed. Results: All three SNPs conferred a high risk to develop cutaneous manifestations in IBD. A higher risk of pyoderma gangrenosum and erythema nodosum was observed in CD patients carrying the Rs33980500 variant (OR 3.03; P=0.026)In UC, a significantly increased risk was observed for both the Rs13190932 and the Rs13196377 SNPs (OR 5.05; P=0.02 and OR 4.1; P=0.049). Moreover, association of TRAF3IP2 variants with ileal (OR = 1.92), fibrostricturing (OR = 1.91) and perianal CD (OR = 2.03) was observed. Conclusions: This is the first preliminary report indicating that TRAF3IP2 variants increase the risk of cutaneous extraintestinal manifestations in IBD suggesting that the analysis of the TRAF3IP2 variants may be useful for identifying IBD patients at risk to develop these manifestations. © 2012 European Crohn's and Colitis Organisation

Self-Association of an Activating Natural Killer Cell Receptor, KIR2DS1

As a major component of the innate immune system, natural killer cells are responsible for activating the cytolytic killing of certain pathogen-infected or tumor cells. The self-recognition of natural killer cells is achieved in part by the killer cell immunoglobulin-like receptors (KIRs) protein family. In the current study, using a suite of biophysical methods, we investigate the self-association of an activating KIR, KIR2DS1. This KIR is of particular interest because when in the presence of the HLA-Cw6 protein, KIR2DS1 becomes a major risk factor for psoriasis, an autoimmune chronic skin disease. Using circular dichroism spectroscopy, dynamic light scattering, and atomic force microscopy, we reveal that KIR2DS1 self-associates in a well-defined fashion. Our novel results on an activating KIR allow us to suggest a working model for the KIR2DS1- HLA class I molecular mechanism

U-Pb zircon geochronology and depositional age models for the Upper Triassic Chinle Formation (Petrified Forest National Park, Arizona, USA): implications for Late Triassic paleoecological and paleoenvironmental change

The Upper Triassic Chinle Formation is a critical non-marine archive of low-paleolatitude biotic and environmental change in southwestern North America. The well-studied and highly fossiliferous Chinle strata at Petrified Forest National Park (PFNP), Arizona, preserve a biotic turnover event recorded by vertebrate and palynomorph fossils, which has been alternatively hypothesized to coincide with tectonically driven climate change or with the Manicouagan impact event at ca. 215.5 Ma. Previous outcrop-based geochronologic age constraints are difficult to put in an accurate stratigraphic framework because lateral facies changes and discontinuous outcrops allow for multiple interpretations. A major goal of the Colorado Plateau Coring Project (CPCP) was to retrieve a continuous record in unambiguous superposition designed to remedy this situation. We sampled the 520-m-long core 1A of the CPCP to develop an accurate age model in unquestionable superposition by combining U-Pb zircon ages and magnetostratigraphy. From 13 horizons of volcanic detritus-rich siltstone and sandstone, we screened up to ∼300 zircon crystals per sample using laser ablation−inductively coupled plasma−mass spectrometry and subsequently analyzed up to 19 crystals of the youngest age population using the chemical abrasion−isotope dilution−thermal ionization mass (CA-ID-TIMS) spectrometry method. These data provide new maximum depositional ages for the top of the Moenkopi Formation (ca. 241 Ma), the lower Blue Mesa Member (ca. 222 Ma), and the lower (ca. 218 to 217 Ma) and upper (ca. 213.5 Ma) Sonsela Member. The maximum depositional ages obtained for the upper Chinle Formation fall well within previously proposed age constraints, whereas the maximum depositional ages for the lower Chinle Formation are relatively younger than previously proposed ages from outcrop; however, core to outcrop stratigraphic correlations remain uncertain. By correlating our new ages with the magnetostratigraphy of the core, two feasible age model solutions can be proposed. Model 1 assumes that the youngest, coherent U-Pb age clusters of each sample are representative of the maximum depositional ages and are close to (227 Ma) in age, and hence the biotic turnover event cannot be correlated to the Carnian−Norian boundary but is rather a mid-Norian event. Our age models demonstrate the powers, but also the challenges, of integrating detrital CA-ID-TIMS ages with magnetostratigraphic data to properly interpret complex sedimentary sequences

Metabolic Syndrome (MetS), Systemic Inflammatory Response Syndrome (SIRS), and Frailty: Is There any Room for Good Outcome in the Elderly Undergoing Emergency Surgery?

Background: Patients with MetS or SIRS experience higher rates of mortality and morbidity, across both cardiac and noncardiac surgery. Frailty assessment has acquired increasing importance in recent years as it predisposes elderly patients to a worse outcome. The aim of our study was to investigate the influence of MetS, SIRS, and with or without frailty on elderly patients undergoing emergency surgical procedures. Methods: We analyzed data of all patients with nonmalignant diseases requiring an emergency surgical procedure from January 2017 to December 2020. The occurrence of MetS was identified using modified definition criteria used by the NCEP-ATP III Expert Panel: obesity, hypertension, diabetes, or if medication for high triglycerides or for low HDL cholesterol was taken. Systemic inflammatory response syndrome (SIRS) was evaluated according to the original consensus study (Sepsis-1). The frailty profile was investigated by the 5-modified Frailty Index (5-mFI) and the Emergency Surgery Frailty Index (EmSFI). Postoperative complications have been reported and categorized according to the Clavien–Dindo (C–D) classification system. Morbidity and mortality have been mainly considered as the 30-day standard period definition. Results: Of the 2,318 patients included in this study, 1,010 (43.6%) fulfilled the criteria for MetS (MetsG group). Both 5-Items score and EmsFI showed greater fragility in patients with MetS. All patients with MetS showed more frequently a CACI index greater than 6. The occurrence of SIRS was higher in MetSG. LOS was longer in patients with MetS (MetSG 11.4 ± 12 days vs. n-MetSG 10.5 ± 10.2 days, p = 0.046). MetSG has a significantly higher rate of morbidity (353 (35.%) vs. 385 (29.4%), p = 0.005). The mortality rate in patients with MetS (98/1010, 10%) was similar to that in patients without it (129/1308, 10%). Considering patients with MetS who developed SIRS and those who had frailty or both, the occurrence of these conditions was associated with a higher rate of morbidity and mortality. Conclusion: Impact of MetS and SIRS on elderly surgical patient outcomes has yet to be fully elucidated. The present study showed a 43.6% incidence of MetS in the elderly population. In conclusion, age per se should be not considered anymore as the main variable to estimate patient outcomes, while MetS and Frailty should have always a pivotal role

Emergency hernia repair in the elderly. multivariate analysis of morbidity and mortality from an Italian registry

Purpose The incidence of inguinal hernia is higher in elderly because of aging-related diseases like prostatism, bronchitis, collagen laxity. A conservative management is common in elderly to reduce surgery-related risks, however watchful waiting can expose to obstruction and strangulation. The aim of the present study was to assess the impact of emergency surgery in a large series of elderly with complicated groin hernia and to identify the independent risk factors for postoperative morbidity and mortality. The predictive performance of prognostic risk scores has been also assessed. Methods This is a prospective observational study carried out between January 2017 and June 2018 in elderly patients who underwent emergency surgery for complicated hernia in 38 Italian hospitals. Pre-operative, surgical and postoperative data were recorded for each patient. ASA score, Charlson's comorbidity index, P-POSSUM and CR-POSSUM were assessed. Results 259 patients were recruited, mean age was 80 years. A direct repair without mesh was performed in 62 (23.9%) patients. Explorative laparotomy was performed in 56 (21.6%) patients and bowel resection was necessary in 44 (17%). Mortality occurred in seven (2.8%) patients. Fifty-five (21.2%) patients developed complications, 12 of whom had a major one. At univariate and multivariate analyses, Charlson's comorbidity index >= 6, altered mental status, and need for laparotomy were associated with major complications and mortality Conclusion Emergency surgery for complicated hernia is burdened by high morbidity and mortality in elderly patients. Preoperative comorbidity played a pivotal role in predicting complications and mortality and therefore Charlson's comorbidity index could be adopted to select patients for elective operation

Leveraging structure determination with fragment screening for infectious disease drug targets: MECP synthase from Burkholderia pseudomallei

As part of the Seattle Structural Genomics Center for Infectious Disease, we seek to enhance structural genomics with ligand-bound structure data which can serve as a blueprint for structure-based drug design. We have adapted fragment-based screening methods to our structural genomics pipeline to generate multiple ligand-bound structures of high priority drug targets from pathogenic organisms. In this study, we report fragment screening methods and structure determination results for 2C-methyl-D-erythritol-2,4-cyclo-diphosphate (MECP) synthase from Burkholderia pseudomallei, the gram-negative bacterium which causes melioidosis. Screening by nuclear magnetic resonance spectroscopy as well as crystal soaking followed by X-ray diffraction led to the identification of several small molecules which bind this enzyme in a critical metabolic pathway. A series of complex structures obtained with screening hits reveal distinct binding pockets and a range of small molecules which form complexes with the target. Additional soaks with these compounds further demonstrate a subset of fragments to only bind the protein when present in specific combinations. This ensemble of fragment-bound complexes illuminates several characteristics of MECP synthase, including a previously unknown binding surface external to the catalytic active site. These ligand-bound structures now serve to guide medicinal chemists and structural biologists in rational design of novel inhibitors for this enzyme

Colorado Plateau Coring Project, Phase I (CPCP-I): a continuously cored, globally exportable chronology of Triassic continental environmental change from western North America

Phase 1 of the Colorado Plateau Coring Project (CPCP-I) recovered a total of over 850&thinsp;m of stratigraphically overlapping core from three coreholes at two sites in the Early to Middle and Late Triassic age largely fluvial Moenkopi and Chinle formations in Petrified Forest National Park (PFNP), northeastern Arizona, USA. Coring took place during November and December of 2013 and the project is now in its post-drilling science phase. The CPCP cores have abundant detrital zircon-producing layers (with survey LA-ICP-MS dates selectively resampled for CA-ID-TIMS U-Pb ages ranging in age from at least 210 to 241&thinsp;Ma), which together with their magnetic polarity stratigraphy demonstrate that a globally exportable timescale can be produced from these continental sequences and in the process show that a prominent gap in the calibrated Phanerozoic record can be filled. The portion of core CPCP-PFNP13-1A for which the polarity stratigraphy has been completed thus far spans  ∼ 215 to 209&thinsp;Ma of the Late Triassic age, and strongly validates the longer Newark-Hartford Astrochronostratigraphic-calibrated magnetic Polarity Time-Scale (APTS) based on cores recovered in the 1990s during the Newark Basin Coring Project (NBCP).Core recovery was  ∼ 100&thinsp;% in all holes (Table 1). The coreholes were inclined  ∼ 60–75° approximately to the south to ensure azimuthal orientation in the nearly flat-lying bedding, critical to the interpretation of paleomagentic polarity stratigraphy. The two longest of the cores (CPCP-PFNP13-1A and 2B) were CT-scanned in their entirety at the University of Texas High Resolution X-ray CT Facility in Austin, TX, and subsequently along with 2A, all cores were split and processed at the CSDCO/LacCore Facility, in Minneapolis, MN, where they were scanned for physical property logs and imaging. While remaining the property of the Federal Government, the archive half of each core is curated at the NSF-sponsored LacCore Core Repository and the working half is stored at the Rutgers University Core Repository in Piscataway, NJ, where the initial sampling party was held in 2015 with several additional sampling events following. Additional planned study will recover the rest of the polarity stratigraphy of the cores as additional zircon ages, sedimentary structure and paleosol facies analysis, stable isotope geochemistry, and calibrated XRF core scanning are accomplished. Together with strategic outcrop studies in Petrified Forest National Park and environs, these cores will allow the vast amount of surface paleontological and paleoenvironmental information recorded in the continental Triassic of western North America to be confidently placed in a secure context along with important events such as the giant Manicouagan impact at  ∼ 215.5&thinsp;Ma (Ramezani et al., 2005) and long wavelength astronomical cycles pacing global environmental change and trends in atmospheric gas composition during the dawn of the dinosaurs.</p

The Age of the 20 Meter Solo River Terrace, Java, Indonesia and the Survival of Homo erectus in Asia

Homo erectus was the first human lineage to disperse widely throughout the Old World, the only hominin in Asia through much of the Pleistocene, and was likely ancestral to H. sapiens. The demise of this taxon remains obscure because of uncertainties regarding the geological age of its youngest populations. In 1996, some of us co-published electron spin resonance (ESR) and uranium series (U-series) results indicating an age as young as 35–50 ka for the late H. erectus sites of Ngandong and Sambungmacan and the faunal site of Jigar (Indonesia). If correct, these ages favor an African origin for recent humans who would overlap with H. erectus in time and space. Here, we report 40Ar/39Ar incremental heating analyses and new ESR/U-series age estimates from the “20 m terrace" at Ngandong and Jigar. Both data sets are internally consistent and provide no evidence for reworking, yet they are inconsistent with one another. The 40Ar/39Ar analyses give an average age of 546±12 ka (sd±5 se) for both sites, the first reliable radiometric indications of a middle Pleistocene component for the terrace. Given the technical accuracy and consistency of the analyses, the argon ages represent either the actual age or the maximum age for the terrace and are significantly older than previous estimates. Most of the ESR/U-series results are older as well, but the oldest that meets all modeling criteria is 143 ka+20/−17. Most samples indicated leaching of uranium and likely represent either the actual or the minimum age of the terrace. Given known sources of error, the U-series results could be consistent with a middle Pleistocene age. However, the ESR and 40Ar/39Ar ages preclude one another. Regardless, the age of the sites and hominins is at least bracketed between these estimates and is older than currently accepted

Perforated peptic ulcer (PPU) treatment: an Italian nationwide propensity score-matched cohort study investigating laparoscopic vs open approach

BackgroundPerforated peptic ulcer (PPU) remain a surgical emergency accounting for 37% of all peptic ulcer-related deaths. Surgery remains the standard of care. The benefits of laparoscopic approach have been well-established even in the elderly. However, because of inconsistent results with specific regard to some technical aspects of such technique surgeons questioned the adoption of laparoscopic approach. This leads to choose the type of approach based on personal experience. The aim of our study was to critically appraise the use of the laparoscopic approach in PPU treatment comparing it with open procedure.MethodsA retrospective study with propensity score matching analysis of patients underwent surgical procedure for PPU was performed. Patients undergoing PPU repair were divided into: Laparoscopic approach (LapA) and Open approach (OpenA) groups and clinical-pathological features of patients in the both groups were compared.ResultsA total of 453 patients underwent PPU simple repair. Among these, a LapA was adopted in 49% (222/453 patients). After propensity score matching, 172 patients were included in each group (the LapA and the OpenA). Analysis demonstrated increased operative times in the OpenA [OpenA: 96.4 +/- 37.2 vs LapA 88.47 +/- 33 min, p = 0.035], with shorter overall length of stay in the LapA group [OpenA 13 +/- 12 vs LapA 10.3 +/- 11.4 days p = 0.038]. There was no statistically significant difference in mortality [OpenA 26 (15.1%) vs LapA 18 (10.5%), p = 0.258]. Focusing on morbidity, the overall rate of 30-day postoperative morbidity was significantly lower in the LapA group [OpenA 67 patients (39.0%) vs LapA 37 patients (21.5%) p = 0.002]. When stratified using the Clavien-Dindo classification, the severity of postoperative complications was statistically different only for C-D 1-2.ConclusionsBased on the present study, we can support that laparoscopic suturing of perforated peptic ulcers, apart from being a safe technique, could provide significant advantages in terms of postoperative complications and hospital stay