Deletion of murine astrocytic vesicular nucleotide transporter increases anxiety and depressive-like behavior and attenuates motivation for reward.

Astrocytes are multi-functional glial cells in the central nervous system that play critical roles in modulation of metabolism, extracellular ion and neurotransmitter levels, and synaptic plasticity. Astrocyte-derived signaling molecules mediate many of these modulatory functions of astrocytes, including vesicular release of ATP. In the present study, we used a unique genetic mouse model to investigate the functional significance of astrocytic exocytosis of ATP. Using primary cultured astrocytes, we show that loss of vesicular nucleotide transporter (Vnut), a primary transporter responsible for loading cytosolic ATP into the secretory vesicles, dramatically reduces ATP loading into secretory lysosomes and ATP release, without any change in the molecular machinery of exocytosis or total intracellular ATP content. Deletion of astrocytic Vnut in adult mice leads to increased anxiety, depressive-like behaviors, and decreased motivation for reward, especially in females, without significant impact on food intake, systemic glucose metabolism, cognition, or sociability. These behavioral alterations are associated with significant decreases in the basal extracellular dopamine levels in the nucleus accumbens. Likewise, ex vivo brain slices from these mice show a strong trend toward a reduction in evoked dopamine release in the nucleus accumbens. Mechanistically, the reduced dopamine signaling we observed is likely due to an increased expression of monoamine oxidases. Together, these data demonstrate a key modulatory role of astrocytic exocytosis of ATP in anxiety, depressive-like behavior, and motivation for reward, by regulating the mesolimbic dopamine circuitry.

Minor effect of patient education for alcohol cessation intervention on outcomes after acute fracture surgery: a randomized trial of 70 patients.

BACKGROUND AND PURPOSE: High alcohol intake is associated with increased risk of postoperative complications. Alcohol cessation intervention is recommended prior to elective surgery. We investigated short- and long-term effects of perioperative intensive alcohol intervention in relation to acute ankle fracture surgery. PATIENTS AND METHODS: 70 patients requiring ankle fracture surgery and consuming ≥ 21 drinks weekly (1 drink = 12 g ethanol) were randomized to a manual-based 6-week intensive standardized alcohol cessation program, the Gold Standard Program (GSP-A), or treatment as usual (TAU), on the day of operation. GSP-A included 5 personal meetings, patient education, and motivational and pharmacological support (alcohol withdrawal prophylaxis, B vitamins, and low-dose disulfiram). Complications requiring treatment were measured after 6 weeks and 1 year. Alcohol intake was validated by biomarkers. Quality of life (QoL) was measured by the SF-36. Hospital costs were obtained from the National Hospital Costs Register. RESULTS: Postoperatively, complete alcohol cessation was higher in the GSP-A than in the TAU group (18/35 vs. 5/35, number needed to treat = 3, p ≤ 0.001), but not lowrisk consumption in the long term (10/35 vs. 7/33, p = 0.5). Number of complications in the short and long term (12/35 vs. 14/33, 16/35 vs. 18/33), the SF-36 score, or hospital costs in the short and long term (€6,294 vs. €8,024, €10,662 vs. €12,198), were similar between the groups. INTERPRETATION: Despite an effect on alcohol cessation and a positive tendency as regards the other outcomes, the postoperative complications, QoL, and costs were similar. Better perioperative strategies for acute surgical patients with high alcohol intake therefore need to be developed.

Perioperative alcohol cessation intervention for postoperative complications.

BACKGROUND: Risky consumption of alcohol is a global problem. More than 3.3 million deaths annually are associated with risky use of alcohol, and global alcohol consumption continues to increase. People who have high alcohol consumption often require planned and emergency surgical procedures.Risky drinking is associated with increased postoperative complications such as infections, cardiopulmonary complications, and bleeding episodes. Alcohol causes disorders of the liver, pancreas, and nervous system. Stopping consumption of alcohol can normalize these organ systems to some degree and may reduce the occurrence of complications after surgery.This review was first published in 2012 and was updated in 2018. OBJECTIVES: To assess the effects of perioperative alcohol cessation interventions on rates of postoperative complications and alcohol consumption. SEARCH METHODS: We searched the following databases up until 21 September 2018: Cochrane Central Register of Controlled Trials (CENTRAL), in the Cochrane Library; MEDLINE; Embase; CINAHL via EBSCOhost; and two trials registers. We scanned the reference lists and citations of included trials and any identified relevant systematic reviews for further references to additional trials. When necessary, we contacted trial authors to ask for additional information. SELECTION CRITERIA: We included all randomized controlled trials (RCTs) that evaluated the effects of perioperative alcohol cessation interventions on postoperative complications and alcohol consumption. We included participants with risky consumption of alcohol who were undergoing all types of elective or acute surgical procedures under general or regional anaesthesia or sedation, who were offered a perioperative alcohol cessation intervention or no intervention.We defined 'risky drinking' as alcohol consumption equivalent to more than 3 alcoholic units (AU)/d or 21 AU/week (with 1 AU containing 12 grams of ethanol) with or without symptoms of alcohol abuse or dependency. This corresponds to the amount of alcohol associated with increased postoperative complication rates in most clinical studies. DATA COLLECTION AND ANALYSIS: We used guidance provided in the Cochrane Handbook for Systematic Reviews of Interventions. We presented main outcomes as dichotomous variables in a meta-analysis. When data were available, we conducted subgroup and sensitivity analyses to explore the risk of bias. Primary outcome measures were postoperative complications and in-hospital and 30-day mortality. Secondary outcomes were successful quitting at the end of the programme, postoperative alcohol use, and length of hospital stay. We assessed the quality of evidence using the GRADE approach. MAIN RESULTS: We included in this updated review one new study (70 participants), resulting in a total of three RCTs (140 participants who drank 3 to 40 AU/d). All three studies were of moderate to good quality. All studies evaluated the effects of intensive alcohol cessation interventions, including pharmacological strategies for alcohol withdrawal symptoms, patient education, and relapse prophylaxis. We identified one ongoing study.Overall, 53 of the 122 participants from three studies who underwent surgery developed any type of postoperative complication that required treatment. Of 61 participants in the intervention groups, 20 had complications, compared with 33 of 61 participants in the control groups (risk ratio (RR) 0.62, 95% confidence interval (CI) 0.40 to 0.96). Results show differences between the three clinical studies regarding outcome measurement and intensity of the interventions. However, all alcohol cessation programmes were intensive and included pharmacological therapy. The overall quality of evidence for this outcome is moderate.In-hospital and 30-day postoperative mortality rates were low in the three studies. Researchers reported one death among 61 participants in the intervention groups, and three deaths among 61 participants in the control groups (RR 0.47, 95% CI 0.07 to 2.96). The quality of evidence for this outcome is low.Investigators describe more successful quitters at the end of the intervention programme than among controls. Forty-one out of 70 participants in the intervention groups successfully quit drinking compared with only five out of 70 participants in the control groups (RR 8.22, 95% CI 1.67 to 40.44). The quality of evidence for this outcome is moderate.All three studies reported postoperative alcohol consumption (grams of alcohol/week) at the end of the programme as median and range values; therefore it was not possible to estimate the mean and the standard deviation (SD). We performed no meta-analysis. All three studies reported length of stay, and none of these studies described a significant difference in length of stay. Data were insufficient for review authors to perform a meta-analysis. No studies reported on the prevalence of participants without risky drinking in the longer term. AUTHORS' CONCLUSIONS: This systematic review assessed the efficacy of perioperative alcohol cessation interventions for postoperative complications and alcohol consumption. All three studies showed a significant reduction in the number of participants who quit drinking alcohol during the intervention period. Intensive alcohol cessation interventions offered for four to eight weeks to participants undergoing all types of surgical procedures to achieve complete alcohol cessation before surgery probably reduced the number of postoperative complications. Data were insufficient for review authors to assess their effects on postoperative mortality. No studies reported an effect on length of stay, and no studies addressed the prevalence of risky drinking in the longer term.Included studies were few and reported small sample sizes; therefore one should be careful about drawing firm conclusions based on these study results. All three studies were conducted in Denmark, and most participants were men. The included participants may represent a selective group, as they could have been more motivated and/or more interested in participating in clinical research or otherwise different, and effects may have been overestimated for both intervention and control groups in these studies. Trial results indicate that these studies are difficult to perform, that strong research competencies are necessary for future studies, and that further evaluation of perioperative alcohol cessation interventions in high-quality randomized controlled trials is needed. Once published and assessed, the one 'ongoing' study identified may alter the conclusions of this review.

Patient education for alcohol cessation intervention at the time of acute fracture surgery: study protocol for a randomised clinical multi-centre trial on a gold standard programme (Scand-Ankle).

BACKGROUND: Patients with hazardous alcohol intake are overrepresented in emergency departments and surgical wards. These patients have an increased risk of postoperative complications with prolonged hospital stays and admissions to intensive care unit after surgery. In elective surgery, preoperative alcohol cessation interventions can reduce postoperative complications, but no studies have investigated the effect of alcohol cessation intervention at the time of acute fracture surgery. This protocol describes a randomised clinical trial that aims to evaluate the effect of a new gold standard programme for alcohol cessation intervention in the perioperative period regarding postoperative complications, alcohol intake and cost-effectiveness. METHODS/DESIGN: Patients with hazardous alcohol intake undergoing ankle fracture surgery will be recruited into the trial from multiple orthopaedic wards at university hospitals in Denmark, Sweden and Norway. Included patients will be randomly allocated to either standard care or the gold standard programme aimed at complete alcohol abstinence before, during and 6 weeks after surgery. It includes a structured patient education programme and weekly interventions meetings at the orthopaedic outpatient clinic. Furthermore, patients are provided with thiamine and B-vitamins, alcohol withdrawal prophylaxis and treatment, and disulfiram to support abstinence. Alcohol intake is biochemically validated (blood, urine and breath tests) at the weekly intervention meetings and follow-up visits. Follow-up assessments will be conducted 6 weeks and 3, 6, 9 and 12 months after surgery for all patients. The effect of the gold standard programme will be assessed comparing the outcome measures between the intervention and control group at each follow-up point. DISCUSSION: The study will provide new knowledge about how to prevent alcohol-related postoperative complications at the time of acute fracture surgery. If effective, the results will be a benefit for the clinical course, patients and society alike. TRIAL REGISTRATION: The protocol is registered in ClinicalTrials.gov (Id: NCT00986791 ).