The computer-generated intervention was associated with a significant decrease in alcohol use and at-risk drinking. Research is needed to further evaluate and adapt information technology to provide preventive clinical services in the ED.

T helper cell-mediated immunity was significantly suppressed before surgery and possibly led to inadequate cytotoxic lymphocyte and whole blood cell response in long-term alcoholic patients after surgery. This altered cell-mediated immunity might have accounted for the increased infection rate in long-term alcoholic patients after surgery.

Different AUDIT scoring thresholds for men and women are required to achieve comparable sensitivity and specificity when using the AUDIT to screen injured patients in the ED. Computerized AUDIT administration is feasible and may help to overcome time limitations that may compromise screening in this busy clinical environment.

C3a exerts multiple biologic functions through activation of its cognate C3a receptor. C3 and C3aR mice have been instrumental in defining important roles of the C3a/C3aR axis in the regulation of acute and chronic inflammatory diseases, including ischemia/reperfusion injury, allergic asthma, autoimmune nephritis, and rheumatoid arthritis. Surprisingly little is known about C3aR expression and function in immune and stromal cells. To close this gap, we generated a floxed tandem-dye Tomato (tdTomato)-C3aR reporter knock-in mouse, which we used to monitor C3aR expression in cells residing in the lung, airways, lamina propria (LP) of the small intestine, brain, visceral adipose tissue, bone marrow (BM), spleen, and the circulation. We found a strong expression of tdTomato-C3aR in the brain, lung, LP, and visceral adipose tissue, whereas it was minor in the spleen, blood, BM, and the airways. Most macrophage and eosinophil populations were tdTomato-C3aR Interestingly, most tissue eosinophils and some macrophage populations expressed C3aR intracellularly. BM-derived dendritic cells (DCs), lung-resident cluster of differentiation (CD) 11b conventional DCs (cDCs) and monocyte-derived DCs, LP CD103, and CD11b cDCs but not pulmonary CD103 cDCs and splenic DCs were tdTomato-C3aR Surprisingly, neither BM, blood, lung neutrophils, nor mast cells expressed C3aR. Similarly, all lymphoid-derived cells were tdTomato-C3aR, except some LP-derived type 3 innate lymphoid cells. Pulmonary and LP-derived epithelial cells expressed at best minor levels of C3aR. In summary, we provide novel insights into the expression pattern of C3aR in mice. The floxed C3aR knock-in mouse will help to reliably track and conditionally delete C3aR expression in experimental models of inflammation.

ObjectivePancreatic autoantibodies (PABs), comprising antibodies against glycoprotein 2 (anti-GP2), are typically associated with complicated phenotypes in Crohn's disease, but have also been observed with variable frequencies in patients with UC. In a previous study, we observed a high frequency of primary sclerosing cholangitis (PSC) in patients with anti-GP2-positive UC. We therefore aimed to characterise the role of anti-GP2 in PSC.DesignIn an evaluation phase, sera from 138 well-characterised Norwegian patients with PSC were compared with healthy controls (n=52), and patients with UC without PSC (n=62) for the presence of PABs by indirect immunofluorescence. Further, 180 German patients with PSC served as a validation cohort together with 56 cases of cholangiocarcinoma without PSC, 20 of secondary sclerosing cholangitis (SSC) and 18 of autoimmune hepatitis.ResultsAnti-GP2 IgA specifically occurred at considerable rates in large bile duct diseases (cholangiocarcinoma=36%, PSC and SSC about 50%). In PSC, anti-GP2 IgA consistently identified patients with poor survival during follow-up (Norwegian/German cohort: p Log Rank=0.016/0.018). Anti-GP2 IgA was associated with the development of cholangiocarcinoma in both PSC cohorts, yielding an overall OR of cholangiocarcinoma in patients with anti-GP2 IgA-positive PSC of 5.0 (p=0.001). Importantly, this association remained independent of disease duration, bilirubin level and age.ConclusionsAnti-GP2 IgA can be hypothesised as a novel marker in large bile duct diseases. In particular, in PSC, anti-GP2 IgA identified a subgroup of patients with severe phenotype and poor survival due to cholangiocarcinoma. Anti-GP2 IgA may therefore be a clinically valuable tool for risk stratification in PSC.

Endogenous circadian clocks regulate 24-h rhythms of physiology and behavior. Circadian rhythm disruption (CRD) is suggested as a risk factor for inflammatory bowel disease. However, the underlying molecular mechanisms remain unknown. Intestinal biopsies from Per1/2 mutant and wild-type (WT) mice were investigated by electron microscopy, immunohistochemistry, and bromodeoxyuridine pulse-chase experiments. TNF-α was injected intraperitoneally, with or without necrostatin-1, into Per1/2 mice or rhythmic and externally desynchronized WT mice to study intestinal epithelial cell death. Experimental chronic colitis was induced by oral administration of dextran sodium sulfate. , caspase activity was assayed in Per1/2-specific small interfering RNA-transfected cells. was overexpressed to study antiapoptosis and the cell cycle. Genetic ablation of circadian clock function or environmental CRD in mice increased susceptibility to severe intestinal inflammation and epithelial dysregulation, accompanied by excessive necroptotic cell death and a reduced number of secretory epithelial cells. Receptor-interacting serine/threonine-protein kinase (RIP)-3-mediated intestinal necroptosis was linked to increased mitotic cell cycle arrest Per1/2-controlled Wee1, resulting in increased antiapoptosis cellular inhibitor of apoptosis-2. Together, our data suggest that circadian rhythm stability is pivotal for the maintenance of mucosal barrier function. CRD increases intestinal necroptosis, thus rendering the gut epithelium more susceptible to inflammatory processes.-Pagel, R., Bär, F., Schröder, T., Sünderhauf, A., Künstner, A., Ibrahim, S. M., Autenrieth, S. E., Kalies, K., König, P., Tsang, A. H., Bettenworth, D., Divanovic, S., Lehnert, H., Fellermann, K., Oster, H., Derer, S., Sina, C. Circadian rhythm disruption impairs tissue homeostasis and exacerbates chronic inflammation in the intestine.

The constitutive and the heat-shock-induced expression of members of heatshock protein families changed during vegetative development and conidiation of Neurospora crassa as determined by two-dimensional gel electrophoresis. Western blot and ELSA analyses revealed the highest amounts of the constitutive heat-shock protein 70 (HSC70) in conidiating aerial hyphae and dormant conidia. During conidial germination the amount of HSC7O decreased and subsequently increased during vegetative growth. Stationary mycelia and young aerial hyphae exhibited the lowest HSC7O level. The stationary-phase-dependent decrease in HSC70 was accompanied by a concomitant increase in i t s nuclear localization, whereas no significant changes in the amount of nuclear HSC7O were found during aerial hyphae development. The CAMP content during aerial hyphae development was inversely correlated with that of HSC7O. To examine possible causal relations between HSC70 expression and CAMP content, the adenylate-cyclase-def icient mutant crisp (cr-I) was analysed, which exhibits low concentrations of endogenous CAMP. This mutant, however, showed a lower constitutive HSC7O level, compared to the bdA strain. Treatment of the bd strain and cr-I mutant with 20 pM 8-bromo-CAMP did not result in significant changes of the constitutive HSC7O level, but in the level of heat-induced HSOHSP70. In a developmental mutant (acon-2) which is defective in a differentiation step toward conidiation, the expression of HSC7O in aerial hyphae was delayed until the first proconidial chains were observed. It is concluded that the differential expression of HSUHSP7O does not depend on different nuclear levels of HSC7O or on changes in CAMP concentrations, but rather on developmental genes controlling conidiation.

The increase in hepatosplanchnic oxygen consumption, together with an increased lignocaine metabolism and decreased release of hepatic TNF-alpha, indicates improved hepatosplanchnic function and antiinflammatory properties after 12 hrs of enoximone treatment. Therefore, if the inflammatory response should be attenuated in high-risk patients, administration of enoximone in fluid-optimized septic shock patients may be favorable compared with dobutamine.