Introductions Binge drinking is a deadly pattern of alcohol consumption. Evidence suggests that genetic variation in clock genes is strongly associated with alcohol misuse; however, the neuroanatomical basis for such a relationship is unknown. The shell region of the nucleus accumbens (NAcSh) is well known to play a role in binge drinking. Hence, we examined whether clock genes in the NAcSh regulate binge drinking. Methods To address this question, 2 experiments were performed on male C57BL/6J mice. In the first experiment, mice exposed to alcohol or sucrose under the 4‐day drinking‐in‐the‐dark (DID) paradigm were euthanized at 2 different time points on day 4 [7 hours after light (pre–binge drinking) or dark (post–binge drinking) onset]. The brains were processed for RT–PCR to examine the expression of circadian clock genes (Clock, Per1, and Per2) in the NAcSh and suprachiasmatic nucleus (SCN). In the second experiment, mice were exposed to alcohol, sucrose, or water as described above. On day 4, 1 hour prior to the onset of alcohol exposure, mice were bilaterally infused with either a mixture of circadian clock gene antisense oligodeoxynucleotides (AS‐ODNs; antisense group) or nonsense/random ODNs (R‐ODNs; control group) through surgically implanted cannulas above the NAcSh. Alcohol/sucrose/water consumption was measured for 4 hours. Blood alcohol concentration was measured to confirm binge drinking. Microinfusion sites were histologically verified using cresyl violet staining. Results As compared to sucrose, mice euthanized post–binge drinking (not pre–binge drinking) on day 4 displayed a greater expression of circadian genes in the NAcSh but not in the SCN. Knockdown of clock genes in the NAcSh caused a significantly lower volume of alcohol to be consumed on day 4 than in the control treatment. No differences were found in sucrose or water consumption. Conclusions Our results suggest that clock genes in the NAcSh play a crucial role in binge drinking.

Background Endoscopic placement of hilar stents is an accepted palliative therapy for patients with advanced, unresectable cholangiocarcinoma. However, whether unilateral versus bilateral stent placement provides optimal relief continues to be a subject of debate. The aim of this study was to compare the technical and clinical outcomes in patients with inoperable cholangiocarcinoma who received unilateral or bilateral self-expanding metal stents (SEMS). MethodsWe conducted a multicenter, international retrospective study of 187 patients with cholangiocarcinoma who received unilateral or bilateral SEMS. Outcomes included, but were not limited to, technical success, clinical success, adverse events, stent occlusion, and survival time.Results were further stratified based on the Bismuth classification.Results Fifty patients received unilateral stents and 137 patients received bilateral stents. All patients achieved technical success. The clinical success rates were 86% for unilateral stents and 82.5% for bilateral stents (P>0.99). Clinical success was not statistically different for either group when stratified by the Bismuth classification (P=0.62 and P=0.72 respectively). There were significantly more adverse events in the bilateral stents group (11.7% vs. 0%, P=0.007). There was no greater risk of stent occlusion when bilateral stents were used (unadjusted P=0.71, adjusted P=0.81). There was a greater risk of death for patients who received bilateral SEMS (hazard ratio 1.78, 95% confidence interval 1.09-2.89; P=0.02).Conclusions Unilateral and bilateral drainage had similar technical and clinical success rates. However, bilateral stents had a higher risk of death and more adverse events. Therefore, unilateral SEMS placement is sufficient for relief of biliary obstruction secondary to cholangiocarcinoma.

Recreational cannabis use is increasing with its legalization in many states. Animal studies suggest cannabis can reduce transient lower esophageal sphincter relaxations (TLESRS), reflux and vomiting, while human studies report conflicting findings. There are currently no large studies investigating gastrointestinal symptoms in patients with chronic cannabis use. This was a retrospective case-control study including patients who presented to an outpatient Gastroenterology office, with documented cannabis use. Their main presenting complaint, demographics, frequency and duration of cannabis use, endoscopic and high-resolution esophageal manometry (HREM) with impedance findings were recorded. Cannabis users were more likely to complain of abdominal pain (25% vs. 8%, p < 0.0001), heartburn (15% vs. 9%, p < 0.0001), and nausea & vomiting (7% vs. 1%, p < 0.0001). They were also more likely to have findings of esophagitis (8% vs. 3%, p = 0.0002), non-erosive gastritis (30% vs. 15%, p = 0.0001) and erosive gastritis (14% vs. 3%, p < 0.0001) on upper endoscopy. Cannabis users were more likely to have impaired esophageal bolus clearance (43% vs. 17%, p = 0.04) and a hypertensive lower esophageal sphincter (LES) (29% vs. 7%, p = 0.04). This study is the largest to date evaluating GI complaints of patients with chronic recreational cannabis use. Our results suggest that cannabis use may potentiate or fail to alleviate a variety of GI symptoms which goes against current knowledge.

Circadian genes in the medial accumbal shell (mNAcSh) region regulate binge alcohol consumption. Here, we investigated if antisense-induced knockdown of major circadian genes (Per1, Per2, and NPAS2) in the mNAcSh of mice exposed to intermittent access two-bottle choice (IA2BC) paradigm modulates the expression of histone deacetylase-2 (HDAC-2) and CREB-binding protein (CBP), key epigenetic modifiers associated with withdrawal-associated behaviors such as anxiety. Adult male C57BL/6J mice (N = 28), surgically implanted with bilateral guide cannulas above the mNAcSh, were chronically (4 weeks) exposed to alcohol (20% v/v) or saccharin (0.03%) via IA2BC paradigm. In the fourth week, a mixture of antisense (AS-ODNs; N = 14/group) or nonsense (NS-ODNs; N = 14/group) oligodeoxynucleotides against circadian genes were bilaterally infused into the mNAcSh. Subsequently, alcohol/saccharin consumption and preference were measured followed by euthanization of animals and verification of microinjection sites by visual inspection and the expression of HDAC-2 and CBP by using RT-PCR along with the verification of antisense-induced downregulation of circadian genes in the mNAcSh. As compared with NS-ODNs, AS-ODNs infusion significantly attenuated the alcohol-induced increase in HDAC-2 and reduction in CBP expression in the mNAcSh along with a significant reduction in alcohol consumption and preference. No significant effect was observed on either saccharin consumption or preference. Our results suggest that circadian genes in the mNAcSh may have a causal to play in mediating epigenetic changes observed after chronic alcohol consumption.