Though major causes of IPD have been discovered via this approach over the past decades, the genetic basis for IPD in many patients remains unknown. The recent application of novel large scale screening methods in proteomics and transcriptomics [31,32], genome-wide association studies (GWAS) [33] and epigenetics [34] plus unprecedented large-scale cooperative efforts, have led to novel insights in platelet biology and of IPD complexity. Next generation sequencing Afatinib clinical trial approaches are expected to unravel IPDs that are already well phenotyped but which still have no identified genetic basis. The identification

of NBEAL2 gene mutations as the causative factor for GPS via RNA or exome sequencing is the first such example. It is now clear that defective α-granule formation Autophagy Compound Library is caused by a

protein family member of LYST and NBEA, proteins that are defective in platelets from patients with abnormal dense granules and broad spectrum IPD [11–14,35]. Advances in our knowledge of both the platelet genome and proteome will lead to further discoveries in MK and platelet biology. The use of novel ‘Omics’ technology via arrays or chips will potentially revolutionize not only current diagnosis of ‘classical’ IPDs through functional platelet testing but will additionally identify individuals with increased risk of bleeding previously hidden by their association with other clinical phenotypes. Discussion of the future of novel DNA-based diagnostic approaches for IPDs is particularly relevant as whole exome sequencing is fast becoming readily available very and economically viable. These novel technologies will bring platelet function testing closer to the

field of medical DNA sequencing [36]. In the future, DNA sequencing will give clinicians important information regarding the IPD genotype of their patients and so improve early diagnosis and prognosis. IPDs are rare disorders manifested by mild to severe mucocutaneous bleeding; for affected patients, e.g. GT or BSS, platelet transfusion is frequently needed for controlling spontaneous bleeding manifestations such as menorrhagia, epistaxis, and gastrointestinal bleeding, and is always needed when trauma occurs or surgery is performed. Childbirth is also a high-risk period [37,38]. For the mild to moderate bleeding entities, e.g. SPD, P2Y12 or TXA2 receptor defects, platelet transfusion is usually unnecessary. Transfusion of platelets should be used selectively and sparingly because of the substantial risk of alloimmunization against HLA antigens and/or platelet αIIbβ3 in GT and GPIb-IX-V in BSS that may lead to refractoriness to therapy [1,39]. To reduce the risk, HLA-matched single donors of platelets are recommended. If such donors are unavailable, leukocyte-depleted blood components should be used. Additional risks of platelet transfusion and blood component therapy are allergic reactions and transmission of infectious agents.

14 We thus hypothesized that abnormal DNA methylation modifications of the X chromosome genes, such as CD40L, may be involved in the pathogenesis of PBC because of the definite role of activated T cells in disease initiation and progression. A specific role of the CD40L gene is suggested by the high Barasertib datasheet IgM titers commonly found in sera from patients with PBC. We herein demonstrate that PBC is associated with significantly lower levels of DNA methylation of the CD40L promoter in CD4+ T cells,

and that these lower levels of DNA methylation inversely correlate with serum IgM levels in PBC patients. These results identify a major role for CD40L in the pathogenesis of PBC and, potentially, in the induction of abnormal humoral immune responses contributing to the disease process. AMA, antimitochondrial antibodies; APC, antigen-presenting cells; BECs, biliary epithelial cells; bp, base pair; CD40L, cluster of differentiation 40 ligand; cDNA, complementary DNA; CI, confidence interval; GADPH, glyceraldehyde 3-phosphate dehydrogenase; CAL-101 in vitro gDNA, genomic DNA; IgM, immunoglobulin

M; mRNA, messenger RNA; PBC, primary biliary cirrhosis; PBMCs, peripheral blood mononuclear cells; PCR, polymerase chain reaction; PDC-E2, pyruvate dehydrogenase E2 subunit; SEM, standard error of the mean; SNPs, single-nucleotide polymorphisms. Fresh heparinized peripheral blood samples were obtained from Italian female patients diagnosed with PBC (n = 20) and unaffected controls (n = 20).8 In addition, female patients with psoriasis vulgaris (n = 9) and type 1 diabetes (n = 9) were recruited as disease controls from the outpatient clinics in the Second Xiangya Hospital, Central South University (Changsha, China). All patients with PBC (Table 1) were women and ifenprodil had readily detectable AMA; the diagnosis was made based on internationally accepted criteria.8 Mean age was 64 years (range, 44-87)

and 70% of them were taking ursodiol. The PBC patients included in this study were histologically characterized as belonging to stage I (n = 7), stage II (n = 10), or stage III (n = 3). Serum liver function and levels of Igs were assessed utilizing routine laboratory methods. The diagnosis of psoriasis was based on characteristic clinical features and histological confirmation15; type 1 diabetes was diagnosed based on the American Diabetes Association diagnostic criteria.16 Subjects were excluded from the study if they had malignancies or were using immunosuppressive drugs. Patients and controls were matched for sex (all female subjects). After approval from appropriate institutional review boards in Italy, China, and the United States, all subjects provided written informed consent before enrollment in the study. Peripheral blood mononuclear cells (PBMCs) were isolated by centrifugation on a Ficoll-Hypaque gradient for 30 minutes at 500g.

Improvements identified find more included the involvement of the whole pharmacy team to ensure patients understood how they should use them. One implementation pharmacist had given the questionnaires to the wrong patients and therefore the results should be interpreted with caution. It was not possible to remove these from the analysis as they were anonymous. Pharmacists were positive about the use of the cards and felt they could help to encourage

patients that do not collect their own medication to present for MUR. The results suggest that patients who self-present may receive more information from MURs than those who don’t however further work, with clearer implementation guidelines and on a larger scale is required. A. Aggarwala, C. Bellb, V. Collingsa aKings College London, London, UK, bKings College Hospital, London, UK The aim of this project

was to evaluate practitioner’s compliance with NICE guidance for treating patients see more with plaque psoriasis at King’s College Hospital. Only 30.8% of patients initiated on biological therapy satisfied the NICE criteria for severe psoriasis using PASI and DLQI scores. Practitioner’s at King’s College Hospital were not complying to NICE guidelines for all patients treated with biologics for chronic plaque psoriasis. Improvements in documentation may allow for more accurate evaluation of compliance with NICE guidelines. Chronic plaque psoriasis is the most common form of psoriasis.1 Topical 3-oxoacyl-(acyl-carrier-protein) reductase therapy is recommended as first line and second line therapies include phototherapy and standard systemic non-biological agents such as methotrexate.1 Biologic agents are reserved as third line where first and second line have failed and for those with classified severe psoriasis using scoring systems.1 Biologics are expensive (£9500 per patient per year)2 and require extensive monitoring both for response and side effects.1 With wide variations in practice across the UK1 this audit compared standards set by NICE

with practice at King’s College Hospital focusing on whether: Topical therapies were used as first line treatments1 Biologic agents were (a) initiated when both the disease was classified as severe using Psoriasis Area and Severity Index (PASI) and Dermatology Life Quality Index (DLQI) scores and (b) when there was no response, the patient was intolerant or contraindicated to standard systemic therapies1 Biologics were discontinued if there is not an adequate response by the appropriate week.1 A retrospective cohort review was carried out at King’s College Hospital between October and November 2013. A list of patients currently on or about to commence treatment with a biologic for all skin diseases was acquired from the dermatology department. Inclusion criteria were patients aged 18 years or more and currently on or commencing biological therapy for the treatment of plaque psoriasis.

When you combine two DAAs with relatively low barriers to resistance, it

is easy for the virus to produce the double mutants that are resistant to both drugs. RBV slows this down somewhat, but does not add enough antiviral activity to prevent resistance more than 60% of the time with tegobuvir and GS 9256. There is one other factor involved in preventing resistance and that is the activity of the DAA. These extremely potent agents, which rapidly drop the viral load down to undetectable, also prevent resistance. A good example of this is the combination study of BI 201335 and BI 207127.6 This study compared two groups: BI201727 400 mg or 600 mg given thrice daily plus BI 201335 and RBV 1000-1200 mg for 4 weeks. In the 400-mg group, the RVR was 73% (with better response in genotype 1b than 1a, as

Selumetinib purchase one would expect with a protease inhibitor in the regimen). In the 600-mg group, the RVR was 100% and did not phosphatase inhibitor library differ between genotype 1a and 1b. From these data, one can infer that the potency of either the protease inhibitor or the nonnucleoside polymerase inhibitor was different, because the same two classes of drugs, plus RBV, yielded a much higher RVR. To be fair, there was no arm without RBV in this study and, of course, it is hard to compare results between studies. The designs of both studies are elegant, simple, and easy to understand, and they advance the field enormously. Gilead is now aggressively addressing the issue of

potency by adding a third DAA to tegobuvir and GS 9256 with and without this website RBV.7 The other study in this issue of Hepatology2 advances the field dramatically further. Not only does it move us from RVR without IFN to sustained virological response (SVR), but it does so in null responders! This represents a giant step toward the “Holy Grail” of HCV therapy: once-daily, oral IFN-free treatment. The world of HCV treatment changed forever in April of 2011 when the first IFN-free SVRs were presented using an NS5A inhibitor and a protease inhibitor, the same two drugs used in the Chayama et al. article.8 The 100% SVR with quadruple therapy was overshadowed by the all-oral double DAA combination (without RBV) that resulted in a 36% SVR. This was the long-awaited proof of principle that HCV could be eradicated without IFN. Notably, in the all-oral arm both of the genotype 1b patients achieved an SVR, but only 2/9 of the genotype 1a patients, demonstrating the differences in activity of protease inhibitors in genotypes 1a and 1b. The Chayama et al. study in this issue7 examined the combination of the NS5A BMS-790052 60 mg qd (now called daclatasvir) and the protease inhibitor BMS-650032 600 mg (now called asunaprevir) in null responders, but only in genotype 1b, the most common genotype in Japan. Ten patients received both drugs for 24 weeks. Of the nine patients who completed the study, all achieved an SVR.

, 2011; Marcel, Tegner & Nimmo-Smith, 2004). It is currently unclear and debated to what extent these phenomena are manifestations of independent abnormalities, or the same primary deficit or a combination of deficits. Adding to the complexity is the fact that AHP appears in the context of a number of concomitant sensorimotor and cognitive impairments. During the 1980s and 1990s studies in cognitive neuropsychology attempted to establish whether any of these deficits MI-503 cell line or any given combination of deficits could explain the occurrence of one or more

of the above anosognosic phenomena. While, however, several primary sensorimotor deficits and many higher order deficits such as intellectual impairment, memory loss, confusion, reasoning deficits, dysexecutive symptoms, visuospatial or, personal neglect, have all been reported frequently in patients with AHP, double dissociations between AHP and most of these deficits have been noted in both acute and chronic AHP (e.g., Bisiach, Vallar, Perani, Papagno & Berti, 1986; Marcel et al., 2004). In response, some authors proposed multi-factorial theories of AHP, arguing Dabrafenib supplier for example that deficits in inferential reasoning may prevent sensorimotor deficits before from being ‘discovered’ (Levine,

1990; Levine, Calvanio & Rinn, 1991), or their discovery may not be ‘remembered’ (Cocchini, Beschin & Della Sala, 2002). These explanations of AHP have now been tested in several studies (e.g., see Marcel et al., 2004; Vocat, Staub,

Stroppini & Vuilleumier, 2010 for exceptionally well-conceived studies) and although they have not been equivocally supported, they remain relevant today (e.g., compare Prigatano & Schacter, 1991 with Prigatano, 2010). This understanding of AHP as the secondary consequence of one or more concomitant neuropsychological deficits was however challenged by the progressive establishment of cognitive neuroscience during the 1990s. As topics such as consciousness, awareness, and the self entered the mainstream of cognitive neuroscience, scientists faced the challenge of a scientific understanding of self-consciousness. Advocates of what is generally known as the embodied cognition approach in philosophy of mind and cognitive neuroscience (e.g., Bermúdez, Marcel & Eilan, 1995; Clark, 1996; Damasio, 1994, 2000; Gallagher, 2005; Varela et al., 1991), opted for distinguishing between several kinds and levels of self-consciousness and postulating a bodily ‘core’ or ‘minimal’ self, as the common denominator of all other facets of self-consciousness.

8%. The DQ2 positivity of 85% among our first-degree CD relatives is nearly 4.5–8.5 times higher than the general north Indian population, confirming a

strong genetic association in CD. Other studies15–18 have reported 59% to 73% of all first-degree relatives to be positive for HLA DQ2/DQ8. Our figure of 85% is higher than the 73% reported by Rubio-Tapia et al.18 and this may either be due to higher enrollment and HLA DQ2/8 testing in 97% of all existing first-degree relatives in our study in comparison to 60% of all first-degree relatives by Rubio-Tapia et al. or due to genetic variation in different populations. Recognition of an HLA DQ2/DQ8-negative selleck kinase inhibitor first-degree relative, where the index case is HLA DQ2/DQ8-positive, obviates the need for further serological testing. HLA DQ2/DQ8 was negative in 14% of parents and 14.7% of siblings and this would therefore be applicable only to approximately 14.3% of all first-degree relatives in our study. The two studies of HLA DQ2/DQ8 prevalence in CD from North India showed 93% and 97.1% of cases to be HLA DQ2-positive,

respectively, and none to be DQ8-positive.33,34 In our study, 29/30 (96.6%) index cases were HLA DQ2-positive and one (3.4%) was positive only for HLA DQA1*05. In a large European genetic study of CD,35 5.6% (57/1008) of CD cases Y-27632 ic50 had only one of the DQ2 alleles, that is, HLA DQA1*05 or HLA DQB1*02. The authors recommended that clinicians should consider the presence of one half of the DQ2 heterodimer as compatible with the diagnosis of CD and it is very rare for CD to occur without one of these genotypes. In the study by Kaur et al.34 of 35 CD cases, 34 were HLA DQ2-positive and one case (2.8%) was positive only for HLA DQB1*02, which is similar Ponatinib mw to our findings. The absence of DQ8 allele in our CD cases is similar to previous Indian studies33,34 and to

a Spanish study,36 where 92.4% of CD cases were DQ2-positive and none were DQ8-positive. Also, Johnson et al.37 showed that the DQ8 allele was more prevalent in the New York CD cohort as compared to the Parisian CD cohort. We feel that this variance in DQ8 positivity in CD cases may be due to differences in genetics across different populations. In our study, IgA-tTGA-positive relatives were significantly more often symptomatic than the IgA-tTGA-negative subjects. Of the four histologically confirmed new CD cases, three (75%) were symptomatic. This is similar to the 78% (11/14) symptom prevalence in the screen-positive relatives reported by Grover R et al.38 This observation is different from that of the screening studies from the developed world where only 40%–50% of screen-detected cases are symptomatic.

Conclusion: Ulcerative colitis associated with neoplastic polyps patients characteristics of histopathological types, risk factors were more similar to polyps canceration, clinical diagnosis and treatment should be given high priority. Key Word(s): 1. Ulcerative Colitis; 2. Neoplastic Polyps; Presenting Author: JIA SONG Additional Authors: XIAOLAN ZHANG Corresponding Author: XIAOLAN ZHANG Affiliations: The Second Hospital of Hebei Medical

University Objective: Intestinal fibrosis is a serious complication of inflammatory bowel disease (IBD), especially Crohn’s disease (CD). Transforming growth factor-β1 (TGF-β1) is one of the most important fibrogenic cytokines secreted by intestinal myofibroblasts which are the key cells Ulixertinib in vitro in intestinal fibrogenesis. TGF-β1/Smad3 signaling pathway plays a critical role in the process of intestinal fibrosis. Tumor necrosis factor ligand-related molecule-1A (TL1A) combines with its receptor death receptor 3, mainly expressed in activated T cells, providing a costimulatory signal for the activation of T lymphocytes and affecting immune regulation in IBD. TL1A may promote the collagen metabolism of intestinal fibroblasts that are activated by TGF-β1 in vitro. Methods: CCD-18Co is intervened with 10 ng/ml TGF-β1

and the supernatant of peripheral DAPT blood mononuclear cells (PBMCs) that are intervened by 10 ng/ml TL1A. Cells were grouped as follows: Control group (cultured without TGF-β1 and the supernatant of PBMCs intervened by TL1A), TL1A group (cultured in without TGF-β1), TGF-β1 group (cultured without the Ribonuclease T1 supernatant of PBMCs intervened by TL1A), TL1A+TGF-β1 group (cultured with TGF-β1 and the supernatant of PBMCs intervened by

TL1A). CCD-18Co proliferation is tested by BrdU assay. The cell cycle is analyzed by Flow cytometric analysis. The activation of CCD-18Co is analyzed by immunocytochemical staining of α-SMA. The hydroxyproline content of CCD-18Co culture medium was measured by hydroxyproline kit (digestion). The expressions of Col1α2, Col3α1, MMP-3, TIMP-1, TGF-β1, Smad3 protein and mRNA in CCD-18Co were detected by western blot and real-time Q-PCR, respectively. Results: Arrested in S phase, the CCD-18Co in TL1A+TGF-β1 group significantly increased the DNA synthesis relative to Control group. Incubation of the CCD-18Co with TL1A and TGF-β1 remarkably changed α-SMA levels. The CCD-18Co in TL1A+TGF-β1 group exhibited enhanced hydroxyproline contents and cell proliferation. The expressions of Col1α2, Col3α1, MMP3, TIMP-1, TGF-β1 and Smad3 protein and mRNA were significantly increased in TL1A+TGF-β1 group compared with that in other groups, while MMP3 /TIMP-1 were declined. Conclusion: Cooperated with TGF-β1, TL1A mediates intestinal fibroblasts activation, proliferation and collagens deposition; its mechanism may be related to TGF-β1/Smad3 signaling pathway. Key Word(s): 1. TL1A; 2. intestinal fibrosis; 3.

Overall, the performance of the 4M panel was superior to the performance of the same panel without CHC (the 3M panel). With staining by at least two markers, the accuracy was 97% and 84.3% in nonsmall and small HCCs, respectively, and this was superior to the accuracy of the panel without the addition of CHC (86% and 76.9%, respectively). For small HCCs, the addition Alisertib in vivo of CHC to the panel consistently increased the sensitivity from 46.8% to 63.8%. Interestingly enough, for nonsmall HCCs, even though the material was sampled with 20- to 21-gauge needles, the accuracy of the novel panel (97%) was better than the accuracy that we previously reported

(78.4%) with a 3M panel in an analogous HCC series sampled with 16- to 18-gauge needles.6 This means that the addition of CHC not only counterbalances the putative loss of sensitivity of thinner core materials but also increases the diagnostic accuracy. Although the use of a 4M panel is more elaborate and time-consuming for pathologists, the unitary cost of

an additional immunoreaction to the panel (approximately $15-20) is much less expensive than confirmatory additional imaging4 or repeat biopsy. When we dissected our HCC series into subpopulations CHIR-99021 solubility dmso according not only to size but also to grading (G1 versus G2/G3), the panel accuracy remained excellent and greater than 90% for G2/G3 HCCs, regardless of the size (Table 5). This confirmed for us that the performance of the 4M panel is optimal when tumor differentiation is compromised; in other words, the individual markers of the panel cooperatively stain HCCs that have progressed. Unfortunately, these are cases for which the pathological diagnosis can be rendered on morphological grounds without the use of staining beyond H&E. Interestingly, although the tumor size was not an issue in G2/G3 HCCs, it was a major issue in well-differentiated (G1) HCCs. Indeed, in this HCC group, which was the most difficult to evaluate, the accuracy of the panel was still excellent in nonsmall G1 HCCs (93.9%)

but dropped to 67.4% in small G1 HCCs (Tables 4 and 5). In the latter, the sensitivity for Vorinostat cell line HCC detection was 50% with 100% specificity, and the performance of the 4M panel was much better than that of the 3M panel (Table 4). In addition, we noticed that a consistent fraction of these tumors showed negative staining (6/30, 20%; Table 2) or one marker only (9/30, 30%; data not shown). The most likely (though speculative) explanation is that G1 HCCs greater than 2 cm and G1 HCCs smaller than 2 cm are not the same disease. An international agreement between Eastern and Western pathologists has recently been obtained for a new HCC entity: very well-differentiated, ≤2-cm HCC (which is also called very early HCC).20 This is the earliest described and well-differentiated form of HCC and is likely the morphological link between HGDN (dysplasia) and HCC that has progressed.

4 U mL−1) or rFVIIa (60 nm). Peak

thrombin generation increased from 85 ± 19 nm in aptamer-treated plasma to 276 ± 83 nm and 119 ± 22 nm after addition of aPCC and rFVIIa respectively (P < 0.001). FXa activity increased within 20 min by 87 ± 6% and by 660 ± 97% after addition of aPCC and rFVIIa respectively (P < 0.001). TPA-induced lysis time increased from 458 ± 378 s in aptamer-treated WB to 1597 ± 366 s (P = 0.001) selleck chemicals llc and 1132 ± 214 s (P = 0.075), after addition of aPCC and rFVIIa respectively. In this haemophilia model using the anti-FIXa aptamer, the larger amount of thrombin was generated with aPCC compared with rFVIIa, while FXa generation was more rapidly increased in the presence of rFVIIa. CH5424802 Furthermore, clot formation in anti-FIXa aptamer-treated WB was less susceptible to tPA-induced fibrinolysis after adding aPCC compared with rFVIIa. “
“Gastrointestinal Unit, Massachusetts General Hospital, Boston, MA, USA Haemophiliacs have high hepatitis C virus

(HCV) exposure risk from blood products that did not undergo heat inactivation or disease-specific screening prior to 1987. Repeated exposure to infected factor concentrates predisposes haemophiliacs to higher likelihood of HCV from multiple sources. HIV coinfection could result in impaired clearance of less fit variants resulting in enrichment of quasispecies carrying resistance mutations. We postulated that haemophiliacs demonstrate increased prevalence of baseline signature mutations in the HCV NS3/4 serine protease coding domain. We examined the prevalence of putative HCV protease inhibitor mutations, mutations, subclassified into dominant mutations if changes conferred resistance, and minor variants not associated with drug resistance, in patients with haemophilia A or B, infected with HCV or HCV/HIV, prior to HCV PI exposure. A

total of PDK4 151 subjects were evaluated, including 22 haemophiliacs and 129 non-haemophilic controls. Of the 58 mutations detected, 55 (95%) were resistance mutations and three (5%) were minor variants. Dominant mutations were detected in 10 (45.5%) haemophiliacs and in 43 (33.3%) controls (OR 1.67, 95% CI 0.67–4.16). There was no statistical difference in proportion of dominant mutations (P = 0.27) or minor variants (P = 0.47) between groups, despite adjustment for HIV status (P = 0.44). No significant differences in dominant or minor resistance mutations between haemophiliacs and non-haemophiliacs were observed. HIV presence or prior HAART exposure did not affect baseline distribution. We conclude that haemophiliacs are not at higher risk for pre-existing HCV PI mutations, and prospective studies of response to PI-based regimens with HCV activity are indicated. “
“Summary.  Atherosclerotic heart disease (ASHD) is a common cause of morbidity and mortality in Western society.

23 In addition, Sirolimus purchase endogenous production of the nonselective CB1/CB2 ligand, 2-arachidonoylglycerol, is increased in the liver in response to chronic alcohol feeding.27 However, though recent studies have reported the steatogenic and fibrogenic properties of CB1 receptors,27, 28 there are no data as to the functional relevance of CB2 receptors during chronic exposure to ethanol. We show here that during alcohol-induced liver injury, activation of Kupffer-cell CB2 receptors inhibits classical M1 polarization and favors a transition to an M2 alternative phenotype by a mechanism involving heme oxygenase-1 (HO-1) induction, thereby protecting from the deleterious inflammatory response to chronic ethanol feeding.

In addition, our data indicate that activation of macrophage CB2 receptors reduces the development of alcohol-induced fatty liver by paracrine effects on hepatocytes. These findings identify CB2 agonism as a potential therapeutic approach for the management of alcohol-induced liver injury. Arg1, arginase 1; ALT, alanine aminotransferase; AST, aspartate aminotransferase; Ca2+, calcium; CB2, cannabinoid CB2 receptors; CCL, chemokine (C-C motif) ligand; CD, control diet; CD163, cluster of differentiation 163; CM, conditioned medium; DMEM, Dulbecco’s modified Eagle’s medium; FBS, fetal bovine serum; HO-1,

heme oxygenase-1; IL, interleukin; ITS, insulin, transferrin, selenium; LPS, lipopolysaccharide; Mg2+, magnesium; Mgl1, macrophage galactose-type C-type lectin GDC-0068 cell line 1; Mrc2, mannose receptor C type 2; mRNA, messenger RNA; NF-κB, nuclear factor-kappa B; NOS2, nitric oxide synthase 2; oxLDL, oxidized low-density lipoprotein; TLR4, Toll-like receptor 4; TNF-α, tumor necrosis factor alpha; WT: wild type; ZnPP, zinc protoporphyrin. Additional methods are available in the Supporting Information. Female, (8-10 weeks old) mice were used.

selleckchem Experiments included wild-type (WT) C57Bl/6J mice (Janvier, Le Genest, France) and mice with a targeted mutation of the Cnr2 gene.29 Homozygous CB2−/− animals were obtained from heterozygous CB2+/− mice that were back-crossed with WT C57Bl/6J animals over 10 generations, and further intercrossed to obtain homozygous animals. Animals were housed in temperature- and humidity-controlled rooms, kept on a 12-hour light-dark cycle, and provided unrestricted amounts of food and water. Animal procedures were conducted in accord with French government policies (Comité d’éthique COMETH authorization no.: 10-0048). WT and CB2−/− mice were fed for 17 days with a liquid diet adapted from Lieber-De Carli, as described by Gustot et al.30 Briefly, the ethanol diet was obtained by adding absolute ethanol to a solution of caseine, oils (e.g., safflower, corn, and olive oils), and powders (e.g., maltodextrin, vitamins, xanthan gum, choline bitartrate, mineral mix, methionine, and cellulose) in distillated water.