Loss of GABAergic signaling by AgRP neurons to the parabrachial nucleus leads to starvation.

Neurons in the arcuate nucleus that produce AgRP, NPY, and GABA (AgRP neurons) promote feeding. Ablation of AgRP neurons in adult mice results in Fos activation in postsynaptic neurons and starvation. Loss of GABA is implicated in starvation because chronic subcutaneous delivery of bretazenil (a GABA(A) receptor partial agonist) suppresses Fos activation and maintains feeding during ablation of AgRP neurons. Moreover, under these conditions, direct delivery of bretazenil into the parabrachial nucleus (PBN), a direct target of AgRP neurons that also relays gustatory and visceral sensory information, is sufficient to maintain feeding. Conversely, inactivation of GABA biosynthesis in the ARC or blockade of GABA(A) receptors in the PBN of mice promote anorexia. We suggest that activation of the PBN by AgRP neuron ablation or gastrointestinal malaise inhibits feeding. Chronic delivery of bretazenil during loss of AgRP neurons provides time to establish compensatory mechanisms that eventually allow mice to eat.

Effect of one anastomosis gastric bypass on liver function tests: A comparison between 150 cm and 200 cm biliopancreatic limbs.

CONTEXT: Some studies have shown that one anastomosis gastric bypass (OAGB) results in the derangement of liver function tests (LFTs). We wanted to study this in our patients. AIMS: The aims are to study the effect of OAGB on LFTs and to compare the effect of a biliopancreatic limb (BPL) of 150 cm (OAGB-150) to a BPL of 200 cm (OAGB-200). SETTINGS AND DESIGN: The study was a retrospective cohort study conducted at a university hospital. MATERIALS AND METHODS: Information was obtained from our prospectively maintained database and hospital's computerised records. STATISTICAL ANALYSIS: A P < 0.05 was regarded statistically significant; however, given the number of variables examined, findings should be regarded as exploratory. RESULTS: A total of 405 patients underwent an OAGB-200 (n = 234) or OAGB-150 (n = 171) in our unit between October 2012 and July 2018. There were significant improvements in gamma-glutamyl transpeptidase (GGT) levels at 1 and 2 years after OAGB-200 and significant worsening in the levels of alkaline phosphatase (ALP) and albumin at 1 and 2 years. There was a significant improvement in GGT levels at 1 and 2 years after OAGB-150 and in alanine transaminase levels at 1 year. There was a significant worsening in ALP and albumin levels at both follow-up points in this group. OAGB-150 group had a significantly lower bilirubin level at 1 year and significantly fewer abnormal ALP values at 2 years in comparison with OAGB-200 patients. CONCLUSIONS: This exploratory study demonstrates the overall safety of OAGB with regard to its effect on LFTs, with no remarkable difference between OAGB-150 and OAGB-200.

Patches of disorganization in the neocortex of children with autism.

BACKGROUND: Autism involves early brain overgrowth and dysfunction, which is most strongly evident in the prefrontal cortex. As assessed on pathological analysis, an excess of neurons in the prefrontal cortex among children with autism signals a disturbance in prenatal development and may be concomitant with abnormal cell type and laminar development. METHODS: To systematically examine neocortical architecture during the early years after the onset of autism, we used RNA in situ hybridization with a panel of layer- and cell-type-specific molecular markers to phenotype cortical microstructure. We assayed markers for neurons and glia, along with genes that have been implicated in the risk of autism, in prefrontal, temporal, and occipital neocortical tissue from postmortem samples obtained from children with autism and unaffected children between the ages of 2 and 15 years. RESULTS: We observed focal patches of abnormal laminar cytoarchitecture and cortical disorganization of neurons, but not glia, in prefrontal and temporal cortical tissue from 10 of 11 children with autism and from 1 of 11 unaffected children. We observed heterogeneity between cases with respect to cell types that were most abnormal in the patches and the layers that were most affected by the pathological features. No cortical layer was uniformly spared, with the clearest signs of abnormal expression in layers 4 and 5. Three-dimensional reconstruction of layer markers confirmed the focal geometry and size of patches. CONCLUSIONS: In this small, explorative study, we found focal disruption of cortical laminar architecture in the cortexes of a majority of young children with autism. Our data support a probable dysregulation of layer formation and layer-specific neuronal differentiation at prenatal developmental stages. (Funded by the Simons Foundation and others.).

Functional identification of an aggression locus in the mouse hypothalamus.

Electrical stimulation of certain hypothalamic regions in cats and rodents can elicit attack behaviour, but the exact location of relevant cells within these regions, their requirement for naturally occurring aggression and their relationship to mating circuits have not been clear. Genetic methods for neural circuit manipulation in mice provide a potentially powerful approach to this problem, but brain-stimulation-evoked aggression has never been demonstrated in this species. Here we show that optogenetic, but not electrical, stimulation of neurons in the ventromedial hypothalamus, ventrolateral subdivision (VMHvl) causes male mice to attack both females and inanimate objects, as well as males. Pharmacogenetic silencing of VMHvl reversibly inhibits inter-male aggression. Immediate early gene analysis and single unit recordings from VMHvl during social interactions reveal overlapping but distinct neuronal subpopulations involved in fighting and mating. Neurons activated during attack are inhibited during mating, suggesting a potential neural substrate for competition between these opponent social behaviours.

Management of super-super obese patients: comparison between one anastomosis (mini) gastric bypass and Roux-en-Y gastric bypass.

BACKGROUND: Gastric bypass can be technically challenging in super-super obese patients. Both Roux-en-Y gastric bypass (RYGB) and one anastomosis (mini) gastric bypass (OAGB/MGB) have been described in these patients, but direct comparisons are lacking. The purpose of this study was to compare the early outcomes with these two procedures in patients with body mass index (BMI) of ≥60 kg/m2 in our unit. METHODS: We identified all super-super obese patients who underwent either OAGB/MGB or RYGB from our prospectively maintained database. Information was also obtained from the case notes and from hospital computerized records. We obtained data regarding patient demographics, operative details, complications, and weight loss, in both groups, and compared them using standard statistical methods. RESULTS: This study compares our results with 19 OAGB/MGB and 47 RYGB super-super obese patients performed in our unit between October 2012 and June 2015. OAGB/MGB group patients had a significantly higher weight and body mass index. There was no mortality or major complication in either group. There were two late complications in the OAGB/MGB group compared to six in the RYGB group. One patient in the OAGB/MGB group needed conversion to RYGB for persistent reflux symptoms. OAGB/MGB patients achieved a significantly higher EWL of 70.4% at 2 years compared to 57.1% in the RYGB group. The difference between TWL of 44.4 and 33.4%, respectively, was also significant at 2 years. TWL of 43.0 and 29.3%, respectively, in OAGB/MGB and RYGB groups at 18 months was also significantly different, but the difference in EWL at 18 months did not reach significance. CONCLUSION: One anastomosis (mini) gastric bypass yields superior weight loss at 18 and 24 months in comparison with Roux-en-Y gastric bypass in patients with BMI of ≥60 kg/m2. Findings need confirmation in larger randomized studies.

Prescription opioid abuse: Problems and responses.

Prescription opioid abuse and addiction, along with consequences such as overdose death and increasing transition to heroin use, constitute a devastating public health problem in the United States. Increasingly it is clear that overprescription of these medications over the past two decades has been a major upstream driver of the opioid abuse epidemic. This commentary considers the factors that have led to overprescription of opioids by clinicians, discusses recent evidence casting doubt on the efficacy of opioids for treating chronic pain, and describes the ongoing efforts by federal and community stakeholders to address this epidemic-for example, supporting prescription drug monitoring programs and improved clinician training in pain management to help reduce the supply of opioids, increasing dissemination of evidence-based primary prevention programs to reduce demand for opioids, and expanding access to effective opioid agonist therapies and antagonist medications for both treatment and overdose prevention.

The American Society of Addiction Medicine Clinical Practice Guideline Development Methodology.

ABSTRACT: The American Society of Addiction Medicine (ASAM) has published clinical practice guidelines (CPGs) since 2015. As ASAM's CPG work continues to develop, it maintains an organizational priority to establish rigorous standards for the trustworthy production of these important documents. In keeping with ASAM's mission to define and promote evidence-based best practices in addiction prevention, treatment, and recovery, ASAM has rigorously updated its CPG methodology to be in line with evolving international standards. The CPG Methodology and Oversight Subcommittee was formed to establish and publish a methodology for the development of ASAM CPGs and to develop an ASAM CPG strategic plan. This article provides a focused overview of the ASAM CPG methodology.

Influence of Pre-operative HbA1c on Bariatric Surgery Outcomes-the Sunderland (UK) Experience.

PURPOSE: UK guidelines recommend an HbA1c < 8.5% prior to elective surgery. Optimisation of pre-operative glycaemic control can be often difficult. Aim to correlate the effect of pre-operative HbA1c on the peri-operative complication rates and whether elective bariatric surgery should be delayed in poorly controlled diabetics. MATERIAL AND METHODS: Retrospective data of consecutive patients who underwent laparoscopic Roux-en-Y gastric bypass, one-anastomosis gastric bypass and laparoscopic sleeve gastrectomy during January 2014 and April 2018. Patients were categorised into group 1, non-diabetics with an HbA1c < 6.5%; group 2, well-controlled diabetics with HbA1c between 6.5 and 8.4%; and group 3, poorly controlled diabetics with HbA1c ≥ 8.5%. Primary outcome was peri-operative complication rates. RESULTS: Group 1 (n = 978), 81.8% female, median (i.q.r.) age 44.0 (34-52) years, median (i.q.r.) BMI 42.0 (38.7-46.7); group 2 (n = 350), 66.3% female, age 51.0 (45-59) years, BMI 41.8 (37.5-46.5); and group 3 (n = 90), 60% female, age 52.0 (45-56) years and BMI 41.4(36.9-44.8). Early complication rates in each group were low, 1.0% vs 1.7% vs 1.1% (p = 0.592). Mean length of stay was 2 days across the groups (p > 0.05). There was no difference in 30-day re-admission rates between groups 2.8%, 2.9% and 3.3% (p = 0.983). At 6 months and 1 year, there was sustained and equal reduction in HbA1c in all groups (p < 0.05). CONCLUSION: Patients undergoing metabolic surgery for poorly controlled diabetes achieve non-inferior peri-operative outcomes. Hence, delaying metabolic surgery in an attempt to optimise diabetic control is not justifiable.

Transient early-life forebrain corticotropin-releasing hormone elevation causes long-lasting anxiogenic and despair-like changes in mice.

During development, early-life stress, such as abuse or trauma, induces long-lasting changes that are linked to adult anxiety and depressive behavior. It has been postulated that altered expression of corticotropin-releasing hormone (CRH) can at least partially account for the various effects of stress on behavior. In accord with this hypothesis, evidence from pharmacological and genetic studies has indicated the capacity of differing levels of CRH activity in different brain areas to produce behavioral changes. Furthermore, stress during early life or adulthood causes an increase in CRH release in a variety of neural sites. To evaluate the temporal and spatial specificity of the effect of early-life CRH exposure on adult behavior, the tetracycline-off system was used to produce mice with forebrain-restricted inducible expression of CRH. After transient elevation of CRH during development only, behavioral testing in adult mice revealed a persistent anxiogenic and despair-like phenotype. These behavioral changes were not associated with alterations in adult circadian or stress-induced corticosterone release but were associated with changes in CRH receptor type 1 expression. Furthermore, the despair-like changes were normalized with antidepressant treatment. Overall, these studies suggest that forebrain-restricted CRH signaling during development can permanently alter stress adaptation leading to increases in maladaptive behavior in adulthood.

Effect of One Anastomosis Gastric Bypass on Haematinics, Vitamin D and Parathyroid Hormone Levels: a Comparison Between 150 and 200 cm Bilio-Pancreatic Limbs.

INTRODUCTION: There is little data on the effect of one anastomosis gastric bypass (OAGB) on haematinics, vitamin D and parathyroid hormone levels. It is further unclear if an OAGB with a bilio-pancreatic limb (BPL) of 150 cm (OAGB-150) would deliver better outcomes than that with a BPL of 200 cm (OAGB-200). MATERIALS AND METHODS: We investigated our records to obtain information on patients who underwent an OAGB-200 or OAGB-150 until 31st July 2018 in our unit. RESULTS: A total of 405 patients underwent either an OAGB-200 (n = 234) or OAGB-150 (n = 171). The mean age was 46 ± 10.98 years and 276 (68.1%) were females. The mean preoperative weight and the body mass index (BMI) were 139 ± 29.96 kg and 49 ± 8.14 kg/m2 respectively. With OAGB-200, there was a significant increase in anaemia rates at 1 and 2 years compared to preoperative levels with a significant fall in haemoglobin levels. After OAGB-150, there was a significant fall in haemoglobin levels at 1 and 2 years but the increase in anaemia rate was only significant at 2 years. There was a significant increase in PTH levels and the number of abnormal values at 1 and 2 years with OAGB-200. With OAGB-150, PTH changes were significant at 2 years only. CONCLUSION: We found that both OAGB-200 and OAGB-150 are associated with a significant increase in anaemia and secondary hyperparathyroidism. Our findings should prompt the evaluation of supplementation protocols with higher dosages than we recommend for iron, folate and calcium. Consideration should also be given to evaluating shorter BPL lengths than 150 cm with OAGB.

Palmitoylation regulates plasma membrane-nuclear shuttling of R7BP, a novel membrane anchor for the RGS7 family.

The RGS7 (R7) family of RGS proteins bound to the divergent Gbeta subunit Gbeta5 is a crucial regulator of G protein-coupled receptor (GPCR) signaling in the visual and nervous systems. Here, we identify R7BP, a novel neuronally expressed protein that binds R7-Gbeta5 complexes and shuttles them between the plasma membrane and nucleus. Regional expression of R7BP, Gbeta5, and R7 isoforms in brain is highly coincident. R7BP is palmitoylated near its COOH terminus, which targets the protein to the plasma membrane. Depalmitoylation of R7BP translocates R7BP-R7-Gbeta5 complexes from the plasma membrane to the nucleus. Compared with nonpalmitoylated R7BP, palmitoylated R7BP greatly augments the ability of RGS7 to attenuate GPCR-mediated G protein-regulated inward rectifying potassium channel activation. Thus, by controlling plasma membrane nuclear-shuttling of R7BP-R7-Gbeta5 complexes, reversible palmitoylation of R7BP provides a novel mechanism that regulates GPCR signaling and potentially transduces signals directly from the plasma membrane to the nucleus.

One Anastomosis Gastric Bypass Performed with a 150-cm Biliopancreatic Limb Delivers Weight Loss Outcomes Similar to Those with a 200-cm Biliopancreatic Limb at 18 -24 Months.

BACKGROUND: It has been suggested that shortening the biliopancreatic limb (BPL) length with one anastomosis gastric bypass (OAGB) to 150 cm would reduce the revision rates for malnutrition. But, it remains unclear if this would not compromise the efficacy of this procedure. METHODS: We examined our prospectively maintained database to compare the outcomes of patients who had their OAGB performed with a 150-cm BPL with those performed with a 200-cm BPL. RESULTS: Medium-term weight loss data at 18-24 months was available for 343/398 (86.1% follow-up) patients. Of these, 225 had undergone OAGB-200 and 118 had undergone OAGB-150. The mean preoperative weight and body mass index were 141.6 ± 32.8 kg and 49.76 ± 8.6 kg/m2, respectively, in the OAGB-200 group compared with 133.7 ± 24.5 kg and 47.83 ± 7.2 kg/m2, respectively, in the OAGB-150 group. There was no significant difference in albumin and haemoglobin levels in the two groups at 18-month follow-up. The mean excess weight loss was 75.0% ± 20.1 in the OAGB-200 group and 74.0% ± 22.0 in the OAGB-150 group (p = 0.6714). A total of 89.7% (n = 202) patients achieved an excess weight loss (EWL) of ≥ 50.0% in the OAGB-200 group compared with 85.5% (n = 103) in the OAGB-150 group (p value = 0.4754). The mean total weight loss was 36.1% ± 9.2 in the OAGB-200 group compared with 34.0% ± 9.8 in the OAGB-150 group (p value = 0.0598). CONCLUSIONS: OAGB performed with a BPL of 150 cm delivers weight loss outcomes similar to that seen with a BPL of 200 cm.

Five-Year Outcomes with Stand-alone Primary Sleeve Gastrectomy.

PURPOSE: Sleeve gastrectomy is now the commonest bariatric procedure worldwide, making it important to determine 5-year weight loss and micronutrient deficiency outcomes following primary, stand-alone sleeve gastrectomy (SG) with adequate follow-up. The purpose of this study was to evaluate weight loss, co-morbidity resolution, and haematological outcomes at 5 years with primary, stand-alone SG in our unit. MATERIALS AND METHODS: Baseline data were obtained from our prospectively maintained database and patients were invited for a 5-year follow-up. For those who could not attend, further information was obtained by telephoning them and contacting their general practitioners. RESULTS: A total of 92 patients (66 females) underwent primary SG at our centre in 2011. The median age was 46.0 years. The median weight and the body mass index (BMI) were 133.0 kg and 47.0 kg/m2 respectively. After 5 years, 7 (7.6%) patients had died due to unrelated causes and 11 (12.0%) had been converted to Roux-en-Y gastric bypass (RYGB). Of the remaining 74, we were able to obtain follow-up data on 64 (86.5%). Despite all efforts, 10 (13.5%) patients were lost to follow-up. The median total weight loss was 21.9% and median excess weight loss (EWL) was 48.0%. Patients developed a range of micronutrient deficiencies over the follow-up period. CONCLUSION: This study shows acceptable results with SG at 5 years in our unit, but a large number of patients experienced GORD and some patients needed additional micronutrient supplementation over and above our unit recommendation of a single multivitamin/mineral A-Z tablet daily.

Neuroscience of Addiction: Relevance to Prevention and Treatment.

Addiction, the most severe form of substance use disorder, is a chronic brain disorder molded by strong biosocial factors that has devastating consequences to individuals and to society. Our understanding of substance use disorder has advanced significantly over the last 3 decades in part due to major progress in genetics and neuroscience research and to the development of new technologies, including tools to interrogate molecular changes in specific neuronal populations in animal models of substance use disorder, as well as brain imaging devices to assess brain function and neurochemistry in humans. These advances have illuminated the neurobiological processes through which biological and sociocultural factors contribute to resilience against or vulnerability for drug use and addiction. The delineation of the neurocircuitry disrupted in addiction, which includes circuits that mediate reward and motivation, executive control, and emotional processing, has given us an understanding of the aberrant behaviors displayed by addicted individuals and has provided new targets for treatment. Most prominent are the disruptions of an individual's ability to prioritize behaviors that result in long-term benefit over those that provide short-term rewards and the increasing difficulty exerting control over these behaviors even when associated with catastrophic consequences. These advances in our understanding of brain development and of the role of genes and environment on brain structure and function have built a foundation on which to develop more effective tools to prevent and treat substance use disorder.

Forebrain glucocorticoid receptors modulate anxiety-associated locomotor activation and adrenal responsiveness.

Stress potently modulates anxiety- and depression-related behaviors. In response to stressors, the hypothalamic-pituitary-adrenal (HPA) axis is activated, resulting in the release of glucocorticoids from the adrenal cortex. These hormones act peripherally to restore homeostasis but also feed back to the CNS to control the intensity and duration of the stress response. Glucocorticoids act in limbic areas of the CNS to mediate the psychological and behavioral effects of stress. In this study, we investigate the effect of forebrain-specific disruption of the glucocorticoid receptor (GR) on stress- and anxiety-related behaviors. We demonstrate that mice with disruption of forebrain GR show alterations in stress-induced locomotor activation in a number of anxiety-related behavioral paradigms. These changes are associated with alterations in stress-induced HPA axis activation and, importantly, are not attenuated by chronic treatment with the tricyclic antidepressant imipramine. These data demonstrate the importance of forebrain GR in regulation of physiological and behavioral stress reactivity and suggest that distinct pathways regulate despair- and anxiety-related behaviors.

Conversion of Sleeve Gastrectomy to Roux-en-Y Gastric Bypass is Effective for Gastro-Oesophageal Reflux Disease but not for Further Weight Loss.

INTRODUCTION: Inadequate weight loss (IWL)/weight regain (WR) and gastro-esophageal reflux disease (GERD), unresponsive to medical management, are two most common indications for conversion of sleeve gastrectomy (SG) to Roux-en-Y gastric bypass (RYGB). This study reports detailed outcomes of conversion of SG to RYGB for these two indications separately. METHODS: We interrogated our prospectively maintained database to identify patients who underwent a conversion of their SG to RYGB in our unit. Outcomes in patients converted for IWL/WR and those converted for GERD were evaluated separately. RESULTS: We carried out 22 SG to RYGB in our unit between Aug 2012 and April 2015 with a mean follow-up of 16 months. Indication for conversion was GERD in 10/22 (45.5%) patients and IWL/WR in 11/22 (50.0%) patients. Patients undergoing conversion for GERD were significantly lighter (BMI 30.5) than those converted for IWL/WR (BMI 43.3) at the time of conversion. The conversion was very effective for GERD with 100% patients reporting improvement in symptoms, and 80% patients were able to stop their antacid medications. IWL/WR group achieved a further BMI drop of 2.5 points 2 years after surgery (final BMI 40.8) in comparison with 2.0 points BMI drop achieved by the GERD group (final BMI 28.5). CONCLUSION: This study demonstrates that conversion of SG to RYGB is effective for GERD symptoms but not for further weight loss, which was modest in both groups. Future studies need to examine the best revisional procedure for IWL/WR after SG.

Management of Super-super Obese Patients: Comparison Between Mini (One Anastomosis) Gastric Bypass and Sleeve Gastrectomy.

Management of super-super obese patients poses a particular challenge for bariatric surgeons. Many staged algorithms exist for these patients. Essentially all of these involve a lower-risk procedure like sleeve gastrectomy first before a definitive second-stage procedure like gastric bypass or duodenal switch. This study compares our results with 19 mini (one anastomosis) gastric bypass and 56 sleeve gastrectomy in super-super obese patients. Sleeve gastrectomy patients were significantly older. There was no mortality or major complication in either group. There was no minor complication in mini (one anastomosis) gastric bypass group compared to two in the sleeve gastrectomy group. Mini (one anastomsosis) gastric bypass patients experienced significantly higher weight loss compared to sleeve gastrectomy patients at 6 months, 1 year, and 2 years after surgery.

A retrospective comparison of early results of conversion of failed gastric banding to sleeve gastrectomy or gastric bypass.

BACKGROUND: Laparoscopic adjustable gastric banding (LAGB) is associated with high long-term failure rates requiring conversion to alternative procedures. Operative conversion to laparoscopic sleeve gastrectomy (LSG) or laparoscopic Roux-en-Y gastric (LRYGB) bypass is associated with higher complication rates than primary procedures. OBJECTIVES: To compare results for converting failed LAGB to LSG versus LRYGB. SETTING: University Hospital, United Kingdom, National Health Service. METHODS: All patients undergoing conversion of LAGB to LRYGB and LSG from July 2006 to September 2012 were included. A retrospective analysis of our prospectively maintained database was performed to identify differences in death rates, complication rates, length of hospital stay, and weight loss. Within this study LRYGB was the preferred choice for conversion and LSG was only considered in the presence of significant intraabdominal adhesions, because of patient choice, or in patients with contraindications to LRYGB. RESULTS: Eighty-nine patients with failed LAGB underwent conversional surgery within this period. Of these, 64 patients underwent conversion to LRYGB and 25 underwent conversion to LSG. There was no statistical difference in percentage of excess weight loss at 1 or 2 years after conversional surgery to LSG or LRYGB. Conversion to LRYGB was carried out as a single procedure in 51/64 (80%) compared with 10/25 (40%) for conversion to LSG (P = .003). One postoperative complication occurred requiring reoperation after conversion to LRYGB. CONCLUSION: There was no difference in complication rates, hospital stay, and early weight loss when converting failed LAGB to LRYGB or LSG. Both procedures are appropriate for conversion from LAGB, although a staged approach is often needed, especially for LSG.