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Background Postoperative complications are relatively frequent in Crohn's disease (CD) and several risk factors have been identified. The influence of genetic factors, however is unknown. Methods CD patients who underwent CD-related bowel resection were identified from the “Nancy IBD cohort.” Postoperative complications were defined as intraabdominal infectious complications and non–intraabdominal infectious complications occurring within 90 days after operation. The influence of 203 single nucleotide polymorphisms on postoperative complication rates was analyzed. Results Of the 137 patients who had undergone a CD-related bowel resection in our cohort, postoperative complications occurred in 34 cases (24.8%). Postoperative intraabdominal infections occurred in 18 cases (13.1%): 12 had anastomotic leakage and 6 had intraabdominal abscesses. In multivariate analysis, current smoker status (odds ratio [OR], 2.71; 95% CI, 1.18–6.21; P = .02) and homozygosity for the risk allele (T) Nucleotide-binding Oligomerization Domain-containing protein 2 (rs5743289; NOD2; OR, 2.07 [95% CI 1.15–3.72]; P = .01) were independent risk factors of postoperative intraabdominal infectious complications. Current smoker status NOD2 homozygosity for the risk allele (T) were not associated with non–intraabdominal infectious complications. Conclusion Current smoker status was associated with increased risk of postoperative intraabdominal infectious complications. A novel association between the NOD2 allele and an increased risk of postoperative intraabdominal infectious complications was observed in this study. [ABSTRACT FROM AUTHOR]

Background The self-prescribing rates of corticosteroids in inflammatory bowel disease (IBD) patients treated with biologicals are unknown. Aim To investigate the frequency and modalities of self-medication with steroids in adult IBD patients. Methods Patients with IBD who attended Nancy University Hospital between November 2012 and May 2013 were included in the study. Patients were interviewed using an 11 item questionnaire. Results 100 patients participated in the survey. In total 15 patients (15%) had already used corticosteroids without medical prescription since their IBD diagnosis and 4 patients of them (27%) used steroids as self-medication while on anti-TNF treatment. The mean total duration of corticosteroid treatment was 24 days (range 1.5–105). In total 4 patients (27%) used corticosteroids more than 10 times without medical prescription (range 1–20). The two main reasons were the need for quick relief of symptoms ( n = 6) and the unwillingness to consult a physician ( n = 3). Conclusion A relatively high proportion of patients with IBD use corticosteroids without medical prescription. Due to their side effects, self-medication may include ‘steroid dependency’ as it may reflect uncontrolled disease. As steroids have significant side effects and patients may have active disease it is important to counsel patients and to monitor their self-prescribing patterns in IBD patients. [ABSTRACT FROM AUTHOR]

Dopamine plays a prominent role in regulating fast synaptic transmission in the striatum. Following dopamine receptor stimulation, various signal transduction pathways are activated, leading to the altered phosphorylation state and functional activity of substrate proteins, including glutamate-gated ion channels. Protein phosphatase 1 (PP1) plays a central role in these events. Recent studies have revealed a system for targeting PP1 to specific substrates in dendritic spines, via association with the cytoskeletal scaffolding proteins, spinophilin and neurabin. Interactions between these proteins and the actin cytoskeleton are dynamically regulated by the cAMP pathway, and thus play a role in dopamine-mediated striatal plasticity. [Copyright &y& Elsevier]

Examines the biochemical properties of Phosphatase 1 Nuclear Targeting Subunit (PNUTS), a protein that targets protein phosphatase (PP) 1 to the nucleus. Truncation and site-directed mutants of PNUTS; Results of in vitro RNA binding experiments; Regulation of PP1 activity by PNUTS.

Background: Modulation of protein phosphorylation by dopamine is thought to play an important role in drug reward. Protein phosphatase-1 (PP-1) is known to mediate some of the changes in neuronal signaling that occur following activation of the dopaminergic system.Methods: Two endogenous inhibitors of PP-1 are dopamine and cyclic 3′, 5′ adenosine monophosphate-regulated phosphoprotein (DARPP-32) and Inhibitor-1 (I-1). Knockout mice lacking one or both of these PP-1 inhibitors were tested for responses to cocaine using in vivo amperometry and conditioned place preference.Results: Presynaptic dopaminergic function appears to be unaffected by these mutations because stimulation-evoked changes in extracellular dopamine levels were unchanged between wild type mice and mice lacking one or both of these PP-1 inhibitors. In contrast, conditioned place preference to cocaine is reduced in mice lacking DARPP-32, I-1, or both phosphoproteins. This does not appear to be due to a learning deficit because mice lacking both DARPP-32 and I-1 show normal passive avoidance learning.Conclusions: These data imply that increased PP-1 function as a result of deficits in DARPP-32 or I-1 is sufficient to decrease the rewarding properties of cocaine. Furthermore, the mechanism for this altered cocaine place preference does not involve alteration of dopamine release or reuptake. [Copyright &y& Elsevier]

Phosphorylation of the α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor subunit GluR1 at Ser845 enhances AMPA channel activity. This study demonstrates that Ser845 is rapidly dephosphorylated upon AMPA receptor activation in nucleus accumbens slices. AMPA-induced dephosphorylation at Ser845 was blocked by CNQX, an AMPA receptor antagonist, by nifedipine, an L-type Ca2+ channel antagonist, or by cyclosporin A, a calcineurin inhibitor. N-methyl-d-aspartate (NMDA) treatment also decreased phosphorylation of Ser845, an effect that was blocked by MK-801, an NMDA receptor antagonist, but not by nifedipine. Accumbens neurons are enriched for dopamine- and cyclic AMP (cAMP)-regulated phosphoprotein, Mr 32,000 (DARPP-32), a potent inhibitor of protein phosphatase 1 (PP1) when phosphorylated by PKA (at Thr34). We tested the hypothesis that the AMPA/KA or NMDA-stimulated dephosphorylation of DARPP-32 via calcineurin, leading to increased PP1 activity and dephosphorylation of GluR1. AMPA or NMDA treatment decreased phospho-Thr34-DARPP-32 levels, effects that were blocked by receptor antagonists, or cyclosporin A. However, dephosphorylation of Ser845 mediated by AMPA or NMDA receptors was unaffected in DARPP-32/inhibitor-1 knockout mice. These data suggest that AMPA- or NMDA-induced dephosphorylation of GluR1 at Ser845 occurs by a mechanism that is independent of DARPP-32 and PP1, but involves activation of calcineurin. Thus, Ca2+-dependent dephosphorylation of GluR1 may serve as a negative feedback mechanism for the regulation of AMPA receptor activity in neurons. [Copyright &y& Elsevier]

The third intracellular (3i) loops of the α[sub 2A]- and α[sub 2B]adrenergic receptor (AR) subtypes are critical for retention of these receptors at the basolateral surface of polarized Madin-Darby canine kidney (MDCKII) cells at steady state. The third intracellular loops of the α[sub 2A], α[sub 2B], and α[sub 2C]-AR subtypes interact with spinophilin, a multidomain protein that, like the three α[sub 2]-AR subtypes, is enriched at the basolateral surface of MDCKH cells. The present studies provide evidence that α[sub 2]-AR interaction with spinophilin contributes to cell surface stabilization of the receptor. We exploited the unique targeting profile of the α[sub 2B]-AR subtype in MDCKII cells: random delivery to apical and basolateral surfaces with rapid (t[sub ½] ≤ 60 min) apical versus slower (t[sub ½] = 10-12 h) basolateral turnover. Apical delivery of a spinophilin subdomain containing the α[sub 2]-AR-interacting region (Sp151-483) by fusion with apically targeted p75[sup NTR] extended the half-life of α[sub 2B]-AR at the apical surface to ∼3.6 h and eliminated the rapid phase (0-60 min) of α[sub 2B]-AR turnover on that surface. Furthermore, we examined α[sub 2B]-AR turnover at the surface of mouse embryo fibroblasts derived from wild type (Sp[sup +/+]) or spinophilin knock-out (Sp[sup -/-]) mice. Two independent experimental approaches demonstrated that agonist-evoked internalization of HA- α[sub 2B]-AR was accelerated in mouse embryo fibroblasts derived from Sp[sup -/-] mice. These findings are consistent with the interpretation that endogenous spinophilin contributes to the stabilization of α[sub 2B]-AR and presumably aH three α[sub 2]-AR subtypes at the surface of target cells and may act as a scaffold that could link α[sub 2]-ARs to proteins interacting with spinophilin via other domains. [ABSTRACT FROM AUTHOR]

Studies the phosphorylation of spinophilin binding protein by protein kinase A. Protein interaction with actin filaments; Major sites of phosphorylation; Ability of spinophilin to bind with protein phosphatase 1.