Mast cell corticotropin-releasing factor subtype 2 suppresses mast cell degranulation and limits the severity of anaphylaxis and stress-induced intestinal permeability.

BACKGROUND: Psychological stress and heightened mast cell (MC) activation are linked with important immunologic disorders, including allergy, anaphylaxis, asthma, and functional bowel diseases, but the mechanisms remain poorly defined. We have previously demonstrated that activation of the corticotropin-releasing factor (CRF) system potentiates MC degranulation responses during IgE-mediated anaphylaxis and psychological stress through corticotropin-releasing factor receptor subtype 1 (CRF1) expressed on MCs. OBJECTIVE: In this study we investigated the role of corticotropin-releasing factor receptor subtype 2 (CRF2) as a modulator of stress-induced MC degranulation and associated disease pathophysiology. METHODS: In vitro MC degranulation assays were performed with bone marrow-derived mast cells (BMMCs) derived from wild-type (WT) and CRF2-deficient (CRF2-/-) mice and RBL-2H3 MCs transfected with CRF2-overexpressing plasmid or CRF2 small interfering RNA. In vivo MC responses and associated pathophysiology in IgE-mediated passive systemic anaphylaxis and acute psychological restraint stress were measured in WT, CRF2-/-, and MC-deficient KitW-sh/W-sh knock-in mice. RESULTS: Compared with WT mice, CRF2-/- mice exhibited greater serum histamine levels and exacerbated IgE-mediated anaphylaxis and colonic permeability. In addition, CRF2-/- mice exhibited increased serum histamine levels and colonic permeability after acute restraint stress. Experiments with BMMCs and RBL-2H3 MCs demonstrated that CRF2 expressed on MCs suppresses store-operated Ca2+ entry signaling and MC degranulation induced by diverse MC stimuli. Experiments with MC-deficient KitW-sh/W-sh mice systemically engrafted with WT and CRF2-/- BMMCs demonstrated the functional importance of MC CRF2 in modulating stress-induced pathophysiology. CONCLUSIONS: MC CRF2 is a negative global modulator of stimuli-induced MC degranulation and limits the severity of IgE-mediated anaphylaxis and stress-related disease pathogenesis.

Systems innovation model: an integrated interdisciplinary team approach pre- and post-bariatric surgery at a veterans affairs (VA) medical center.

BACKGROUND: Provision of bariatric surgery in the Veterans Health Administration must account for obese veterans' co-morbidity burden and the geographically dispersed location of patients relative to Veterans Affairs (VA) bariatric centers. OBJECTIVES: To evaluate a collaborative, integrated, interdisciplinary bariatric team of surgeons, bariatricians, psychologists, dieticians, and physical therapists working in a hub-and-spokes care model, for pre- and post-bariatric surgery assessment and management. METHODS: This is a description of an interdisciplinary clinic and bariatric program at a VA healthcare system and a report on program evaluation findings. Retrospective data of a prospective database was abstracted. For program evaluation, we abstracted charts to characterize patient data and conducted a patient survey. RESULTS: Since 2009, 181 veterans have undergone bariatric surgery. Referrals came from 7 western U.S. states. Mean preoperative body mass index was 46 kg/m2 (maximum 71). Mean age was 53 years, with 33% aged>60 years; 79% were male. Medical co-morbidity included diabetes (70%), hypertension (85%), and lower back or extremity joint pain (84%). A psychiatric diagnosis was present in 58%. At 12 months, follow-up was 81% and percent excess body mass index loss was 50.5%. Among 54 sequential clinic patients completing anonymous surveys, overall satisfaction with the interdisciplinary team approach and improved quality of life were high (98% and 94%, respectively). CONCLUSION: The integrated, interdisciplinary team approach using a hub-and-spokes model is well suited to the VA bariatric surgery population, with its heavy burden of medical and mental health co-morbidity and its system of geographically dispersed patients receiving treatment at specialty centers. As the VA seeks to expand the use of bariatric surgery as an option for obese veterans, interdisciplinary models crafted to address case complexity, care coordination, and long-term outcomes should be part of policy planning efforts.

Osteoarthritis in veterans undergoing bariatric surgery is associated with decreased excess weight loss: 5-year outcomes.

BACKGROUND: Obesity exacerbates pre-existing musculoskeletal disease and joint pain. This may limit physical activity in obese individuals. OBJECTIVES: We sought to identify the disease burden and impact of osteoarthritis of the lumbar back, hip, knee, and ankle in veterans undergoing bariatric surgery. SETTING: Veterans Affairs medical center. METHODS: Retrospective review of a prospective bariatric database of operations performed at a single Veterans Affairs medical center. Patients with osteoarthritis of the lumbar spine, hip, knee, or ankle were identified and diagnosis confirmed by electronic health record review of prior radiographic reports. Analysis was performed using χ2 test for continuous variables. Student's t test and one-way analysis of variance were used to compare qualitative variables. RESULTS: Of 254 bariatric surgical patients, 83.9% had preoperative musculoskeletal pain before bariatric surgery and 59.1% had a confirmed diagnosis of osteoarthritis of the lumbar spine, hips, knees, and/or ankles. Follow-up rate was 97.4%, 85.4%, and 82.6% at 1, 3, and 5 years respectively. Of patients with osteoarthritis, 58.6% had knee involvement and 46% had multiple sites involved. In the cohort without osteoarthritis, percent excess body mass index loss was 66.9% at 1 year versus 58.5% in the cohort with osteoarthritis (P = .009), 66.1% versus 51.9% (P = .001) at 3 years, and 64.3% versus 50.1% (P = .002) after 5 years. Percent total weight loss was 28.4% versus 25.2%, 28.0% versus 22.8%, and 27.1% versus 22.4%, respectively, at 1, 3, and 5 years. CONCLUSIONS: Osteoarthritis is common among veterans undergoing bariatric surgery. It is associated with significantly less weight loss compared to veterans who do not have osteoarthritis, up to 5 years after bariatric surgery.

Urgent and Elective Robotic Single-Site Cholecystectomy: Analysis and Learning Curve of 150 Consecutive Cases.

BACKGROUND: The use of robotic single-site cholecystectomy has increased exponentially. There are few reports describing the safety, efficacy, and operative learning curve of robotic single-site cholecystectomy either in the community setting or with nonelective surgery. MATERIALS AND METHODS: We performed a retrospective review of a prospective database of our initial experience with robotic single-site cholecystectomy. Demographics and perioperative outcomes were evaluated for both urgent and elective cholecystectomy. Cumulative sum analysis was performed to determine the surgeon's learning curve. RESULTS: One hundred fifty patients underwent robotic single-site cholecystectomy. Seventy-four (49.3%) patients underwent urgent robotic single-site cholecystectomy, and 76 (50.7%) underwent elective robotic single-site cholecystectomy. Mean total operative time for robotic single-site cholecystectomy was 83.3 ± 2.7 minutes. Mean operative time for the urgent cohort was significantly longer than for the elective cohort (95.0 ± 4.4 versus 71.9 ± 2.6 minutes; P < .001). There was one conversion in the urgent cohort and none in the elective cohort. There was one bile duct injury (0.7%) in the urgent cohort. Perioperative complications occurred in 8.7% of patients, and most consisted of superficial surgical-site infections. There were no incisional hernias detected. The surgeon's learning curve, inclusive of urgent and elective cases, was 48 operations. CONCLUSIONS: Robotic single-site cholecystectomy can be performed safely and effectively in both elective and urgent cholecystectomy with a reasonable learning curve and acceptable perioperative outcomes.

Corticotropin-releasing factor receptor 2 mediates sex-specific cellular stress responses.

Although females suffer twice as much as males from stress-related disorders, sex-specific participating and pathogenic cellular stress mechanisms remain uncharacterized. Using corticotropin-releasing factor receptor 2-deficient (Crhr2-/-) and wild-type (WT) mice, we show that CRF receptor type 2 (CRF2) and its high-affinity ligand, urocortin 1 (Ucn1), are key mediators of the endoplasmic reticulum (ER) stress response in a murine model of acute pancreatic inflammation. Ucn1 was expressed de novo in acinar cells of male, but not female WT mice during acute inflammation. Upon insult, acinar Ucn1 induction was markedly attenuated in male but not female Crhr2-/- mice. Crhr2-/- mice of both sexes show exacerbated acinar cell inflammation and necrosis. Electron microscopy showed mild ER damage in WT male mice and markedly distorted ER structure in Crhr2-/- male mice during pancreatitis. WT and Crhr2-/- female mice showed similarly distorted ER ultrastructure that was less severe than distortion seen in Crhr2-/- male mice. Damage in ER structure was accompanied by increased ubiquitination, peIF2, and mistargeted localization of vimentin in WT mice that was further exacerbated in Crhr2-/- mice of both sexes during pancreatitis. Exogenous Ucn1 rescued many aspects of histological damage and cellular stress response, including restoration of ER structure in male WT and Crhr2-/- mice, but not in females. Instead, females often showed increased damage. Thus, specific cellular pathways involved in coping and resolution seem to be distinct to each sex. Our results demonstrate the importance of identifying sex-specific pathogenic mechanisms and their value in designing effective therapeutics.