Small molecule SWELL1 complex induction improves glycemic control and nonalcoholic fatty liver disease in murine Type 2 diabetes.

Type 2 diabetes is associated with insulin resistance, impaired pancreatic ß-cell insulin secretion, and nonalcoholic fatty liver disease. Tissue-specific SWELL1 ablation impairs insulin signaling in adipose, skeletal muscle, and endothelium, and impairs ß-cell insulin secretion and glycemic control. Here, we show that ICl,SWELL and SWELL1 protein are reduced in adipose and ß-cells in murine and human diabetes. Combining cryo-electron microscopy, molecular docking, medicinal chemistry, and functional studies, we define a structure activity relationship to rationally-design active derivatives of a SWELL1 channel inhibitor (DCPIB/SN-401), that bind the SWELL1 hexameric complex, restore SWELL1 protein, plasma membrane trafficking, signaling, glycemic control and islet insulin secretion via SWELL1-dependent mechanisms. In vivo, SN-401 restores glycemic control, reduces hepatic steatosis/injury, improves insulin-sensitivity and insulin secretion in murine diabetes. These findings demonstrate that SWELL1 channel modulators improve SWELL1-dependent systemic metabolism in Type 2 diabetes, representing a first-in-class therapeutic approach for diabetes and nonalcoholic fatty liver disease.

Association of gallbladder hyperkinesia with acalculous chronic cholecystitis: A case-control study.

BACKGROUND: This is the first case-control study investigating an association between gallbladder hyperkinesia and symptomatic acalculous chronic cholecystitis. METHODS: This retrospective study in a single academic center compared resolution of biliary pain in adults with gallbladder hyperkinesia, defined as a hepatobiliary iminodiacetic acid scan ejection fraction ≥80%, undergoing cholecystectomy (study group) with those treated medically without cholecystectomy (control group). Of 1,477 hepatobiliary iminodiacetic acid scans done between 2013 and 2018, a total of 296 adults without gallstones had an ejection fraction ≥80%, of whom 46 patients met predetermined eligibility criteria. Demographic data, hepatobiliary iminodiacetic acid scan ejection fraction, chronicity of pain, and resolution of pain were compared between groups. RESULTS: Demographics (mean ± standard deviation) in the control group (n = 25) and in the study group (n = 21) were, respectively, age 40 y ± 16 y and 39 y ± 14 y, body mass index 28.9 ± 5.2 and 29.1 ± 7.1 kg/m2, with 15 (60%) and 18 (86%) females in each. Resolution of pain after cholecystectomy occurred in 18 of 21 patients (86%); however, pain persisted in 20 of 25 patients (80%) treated medically after mean follow-up of 36 ± 28 months (range 10-120 months) (P < .01). Pain resolution with cholecystectomy was independent of demographic variables, hepatobiliary iminodiacetic acid scan ejection fraction, and chronicity of pain. The odds of pain resolution was 19.7 times greater with cholecystectomy than without (odds ratio, 19.7; 95% confidence interval, 4.34, 89.43; P < .01), and remained robust even with the odds adjusted for each covariate. Gallbladder histopathology confirmed chronic cholecystitis in all 21 cholecystectomy specimens. CONCLUSION: Symptomatic gallbladder hyperkinesia could be a new indication for cholecystectomy in adults.

Dataset on the performance of a three phase induction motor under balanced and unbalanced supply voltage conditions.

Three phase induction motors (TPIM) are extensively used for various applications in the industry for driving cranes, hoists, lifts, rolling mills, cooling fans, textile operations, and so forth. TPIM are designed to operate on balanced three phase power supply, but sometimes three phase supply line voltages to which the TPIM is connected may be unbalanced. In this data article, the operational data of a TPIM operating under changing voltage scenarios is profiled to determine the variations in the magnitude of the operational parameters of the motor. The magnitude of each of the line voltages was separately varied from the balanced state (0% unbalance) until 5% voltage unbalance condition was achieved, in line with the recommendations and guidelines of the National Electrical Manufactures Association. The motor parameters; both mechanical and electrical, at various slip values were collected in six sets for the 0%, 1%, 2%, 3%, 4%, and 5% unbalance voltage conditions. Frequency distributions and statistical analysis were carried out to identify the data pattern and data variation trends among the parameters in the dataset.

Erratum: SWELL1 is a regulator of adipocyte size, insulin signalling and glucose homeostasis.

This corrects the article DOI: 10.1038/ncb3514.

SWELL1 is a regulator of adipocyte size, insulin signalling and glucose homeostasis.

Adipocytes undergo considerable volumetric expansion in the setting of obesity. It has been proposed that such marked increases in adipocyte size may be sensed via adipocyte-autonomous mechanisms to mediate size-dependent intracellular signalling. Here, we show that SWELL1 (LRRC8a), a member of the Leucine-Rich Repeat Containing protein family, is an essential component of a volume-sensitive ion channel (VRAC) in adipocytes. We find that SWELL1-mediated VRAC is augmented in hypertrophic murine and human adipocytes in the setting of obesity. SWELL1 regulates adipocyte insulin-PI3K-AKT2-GLUT4 signalling, glucose uptake and lipid content via SWELL1 C-terminal leucine-rich repeat domain interactions with GRB2/Cav1. Silencing GRB2 in SWELL1 KO adipocytes rescues insulin-pAKT2 signalling. In vivo, shRNA-mediated SWELL1 knockdown and adipose-targeted SWELL1 knockout reduce adiposity and adipocyte size in obese mice while impairing systemic glycaemia and insulin sensitivity. These studies identify SWELL1 as a cell-autonomous sensor of adipocyte size that regulates adipocyte growth, insulin sensitivity and glucose tolerance.

Isolation and Patch-Clamp of Primary Adipocytes.

The patch-clamp technique allows for the study of ion channel activity in the native adipocyte environment to better understand the contributions of ion channels to adipocyte signaling. Here, we describe methods for isolating primary mature adipocytes from both mouse and human white adipose tissues (subcutaneous and visceral). From the same preparation, we describe how to culture and differentiate preadipocytes isolated from the stromal vascular fraction. We then describe in detail patch-clamp methods, including both whole-cell and perforated-patch configurations.

Tratamiento del vitiligo con esencias florales de Bach: presentación de casos / Vitiligo treatment with Bach floral essences: Cases presentation

Se realiza una presentación de casos, de 2 pacientes en edades pediátricas con diagnóstico clínico de vitiligo. El objetivo del estudio fue exponer los resultados del tratamiento de esta dermatosis con esencias florales de Bach. Los pacientes estudiados fueron: RLT de 6 años, masculino, negro, remitido por lesiones en placas máculo- acrómicas, de 2 cm de diámetro, distribuidas en nuca y región lateral izquierda del cuello; el otro paciente OJTS, de 13 años, masculino, negro, que es remitido, por presentar lesiones en placas máculo-acrómicas, bordes precisos de 1 a 2 cm, de diámetro localizadas en región frontal y mejilla izquierda. Se les realizó interrogatorio, examen clínico general por el dermatólogo y el pediatra. Previo consentimiento informado se indicó tratamiento con esencias forales de Bach (Crab Apple, Willow y Walnut) y seguimiento posterior. Ambos niños llevan 5 años asintomáticos(AU)

It is made the case presentation of two pediatric-aged patients with clinical diagnosis of vitiligo. The aim of the study was exposing the results of this dermatosis treatment with Bach floral essences. The studied patients were: RLT, aged 6 years, male, black, remitted because of lesions in macula-achromatic plaques, of 2 cm diameter, located in nape and left lateral region of the neck; the other patient, OJTS, aged 13 years, male, black, is remitted for presenting lesions in macula-achromatic plaques, precise edges, ranging from 1 to 2 cm of diameter, located in frontal region and left cheek. The dermatologist and the pediatrician made questioning and clinical general examination. After obtaining the informed consent a treatment with Bach floral essences (Crab Apple, Willow, and walnut) and they were followed up. Both children are asymptomatic already for 5 years(AU)

Tratamiento del vitiligo con esencias florales de Bach. Presentación de casos / Vitiligo treatment with Bach floral essences. Cases presentation

Se realiza una presentación de casos, de 2 pacientes en edades pediátricas con diagnóstico clínico de vitiligo. El objetivo del estudio fue exponer los resultados del tratamiento de esta dermatosis con esencias florales de Bach. Los pacientes estudiados fueron: RLT de 6 años, masculino, negro, remitido por lesiones en placas máculo- acrómicas, de 2 cm de diámetro, distribuidas en nuca y región lateral izquierda del cuello; el otro paciente OJTS, de 13 años, masculino, negro, que es remitido, por presentar lesiones en placas máculo-acrómicas, bordes precisos de 1 a 2 cm, de diámetro localizadas en región frontal y mejilla izquierda. Se les realizó interrogatorio, examen clínico general por el dermatólogo y el pediatra. Previo consentimiento informado se indicó tratamiento con esencias forales de Bach (Crab Apple, Willow y Walnut) y seguimiento posterior. Ambos niños llevan 5 años asintomáticos.

It is made the case presentation of two pediatric-aged patients with clinical diagnosis of vitiligo. The aim of the study was exposing the results of this dermatosis treatment with Bach floral essences. The studied patients were: RLT, aged 6 years, male, black, remitted because of lesions in macula-achromatic plaques, of 2 cm diameter, located in nape and left lateral region of the neck; the other patient, OJTS, aged 13 years, male, black, is remitted for presenting lesions in macula-achromatic plaques, precise edges, ranging from 1 to 2 cm of diameter, located in frontal region and left cheek. The dermatologist and the pediatrician made questioning and clinical general examination. After obtaining the informed consent a treatment with Bach floral essences (Crab Apple, Willow, and walnut) and they were followed up. Both children are asymptomatic already for 5 years.

Scheduled intravenous acetaminophen reduces postoperative narcotic analgesic demand and requirement after laparoscopic Roux-en-Y gastric bypass.

BACKGROUND: Intravenous (i.v.) acetaminophen has the potential to reduce postoperative narcotic analgesic requirement but this has not been reported in bariatric surgery. As lower dosages could reduce undesirable narcotic side effects, we investigated the opioid-sparing effect of concomitant i.v. acetaminophen in bariatric surgery. METHODS: We performed a retrospective review of our electronic medical records of laparoscopic Roux-en-Y gastric bypasses (LRYGB) performed for severe obesity between 2011 and 2013. We identified 183 patients that received scheduled i.v. acetaminophen in addition to morphine sulfate (MSO4) patient-controlled analgesia (PCA). A cohort of 229 patients from the preceding 2 years who were treated with MSO4 PCA but not acetaminophen was used as a historical control. Patient demographic characteristics and narcotic use data were extracted from electronic medical records. Student's t test or linear regression was used as appropriate (P< .05). RESULTS: During the first 24-hour postoperative period after LRYGB, narcotic analgesic demand (total PCA demand including nondelivery of narcotic due to lock-out) was reduced by 25% with the concomitant use of i.v. acetaminophen (40.5 versus 30.9 average pushes; P<.05). During the same period, narcotic analgesic dosage requirement was cut down by 20% in the study group (average of 29.9 versus 24.1 mg of MSO4; P<.05). Linear regression analysis confirmed that these changes were independent of age, gender, and body mass index distribution, or type 2 diabetes mellitus. CONCLUSION: Scheduled i.v. acetaminophen reduces the demand for and the requirement of narcotic analgesia after LRYGB. We provide new evidence in support of the routine use of multimodal analgesia that includes scheduled i.v. acetaminophen in the initial 24-hour period after bariatric surgery.

The novel cytokine interleukin-33 activates acinar cell proinflammatory pathways and induces acute pancreatic inflammation in mice.

BACKGROUND: Acute pancreatitis is potentially fatal but treatment options are limited as disease pathogenesis is poorly understood. IL-33, a novel IL-1 cytokine family member, plays a role in various inflammatory conditions but its role in acute pancreatitis is not well understood. Specifically, whether pancreatic acinar cells produce IL-33 when stressed or respond to IL-33 stimulation, and whether IL-33 exacerbates acute pancreatic inflammation is unknown. METHODS/RESULTS: In duct ligation-induced acute pancreatitis in mice and rats, we found that (a) IL-33 concentration was increased in the pancreas; (b) mast cells, which secrete and also respond to IL-33, showed degranulation in the pancreas and lung; (c) plasma histamine and pancreatic substance P concentrations were increased; and (d) pancreatic and pulmonary proinflammatory cytokine concentrations were increased. In isolated mouse pancreatic acinar cells, TNF-α stimulation increased IL-33 release while IL-33 stimulation increased proinflammatory cytokine release, both involving the ERK MAP kinase pathway; the flavonoid luteolin inhibited IL-33-stimulated IL-6 and CCL2/MCP-1 release. In mice without duct ligation, exogenous IL-33 administration induced pancreatic inflammation without mast cell degranulation or jejunal inflammation; pancreatic changes included multifocal edema and perivascular infiltration by neutrophils and some macrophages. ERK MAP kinase (but not p38 or JNK) and NF-kB subunit p65 were activated in the pancreas of mice receiving exogenous IL-33, and acinar cells isolated from the pancreas of these mice showed increased spontaneous cytokine release (IL-6, CXCL2/MIP-2α). Also, IL-33 activated ERK in human pancreatic tissue. SIGNIFICANCE: As exogenous IL-33 does not induce jejunal inflammation in the same mice in which it induces pancreatic inflammation, we have discovered a potential role for an IL-33/acinar cell axis in the recruitment of neutrophils and macrophages and the exacerbation of acute pancreatic inflammation. CONCLUSION: IL-33 is induced in acute pancreatitis, activates acinar cell proinflammatory pathways and exacerbates acute pancreatic inflammation.

Roux-en-Y gastric bypass achieves substantial resolution of migraine headache in the severely obese: 9-year experience in 81 patients.

BACKGROUND: Although migraine headache (MH) is more severe in the obese, the risk of developing MH in the obese population is controversial. The effect of surgical weight loss on morbidly obese patients with MH provides a unique opportunity to evaluate this potential association. METHODS: We analyzed the data from 702 morbidly obese patients who underwent Roux-en-Y gastric bypass (RYGB) from 2000 to 2009. We identified patients with physician-diagnosed MH taking antimigraine medication. RESULTS: The data are presented as the mean ± SEM, with the range in parentheses. Of the 102 patients with preoperative MH, 21 were excluded because they had <12-month follow-up data and 81 were followed up for 38.6 ± 3 months (range 12-123). Of the 81 patients, 90% were women. Their body mass index was 48 ± 1 kg/m(2) (range 37-85), and their age was 40 ± 1 years (range 18-62). After surgical weight loss, clinical improvement in MH was seen in 89% of patients within 5.6 ± .9 months (range 1-36; P < .01, chi-square test), with 57 reporting total resolution and 15 reporting partial resolution (9 experienced no change). Using logistic regression analysis, we showed that the improvement in MH after RYGB was independent of the improvement in migraine-associated co-morbidities, such as sleep apnea, menstrual dysfunction, depression, and anxiety. We also compared patients who developed MH after obesity onset with those who had MH before obesity. The MH after obesity onset group included 51 patients, of whom 48 showed clinical improvement (41 complete, 7 partial, and 3 no improvement). The MH before obesity group included 24 patients, of whom 18 showed clinical improvement (11 complete, 7 partial, and 6 no improvement). The MH after obesity group showed a greater rate of complete resolution of MH after RYGB than did the MH before obesity group (P < .01; chi-square test). CONCLUSIONS: Weight loss after RYGB substantially resolves MH, especially when obesity onset precedes MH onset. It remains to be determined whether RYGB-induced endocrine alterations or a reduction in adipokine burden contribute to migraine improvement.

Roux-en-Y gastric bypass ameliorates polycystic ovary syndrome and dramatically improves conception rates: a 9-year analysis.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a common cause of infertility, especially in the morbidly obese. We evaluated the long-term effects of Roux-en-Y gastric bypass on PCOS and infertility. METHODS: A total of 566 morbidly obese women underwent Roux-en-Y gastric bypass from 2000 to 2009. A total of 31 patients (5.5%) had a history of PCOS. Of the 31 patients, 6 were postmenopausal and 5 lost to follow-up and were excluded. Telephone interviews were conducted with the 20 eligible patients. RESULTS: The mean age and body mass index was 32 ± 5.8 years (range 22-42) and 52.8 ± 9.08 kg/m(2) (range 37-76) before surgery. All 20 patients had ≥ 2 of 3 diagnostic criteria for PCOS, including clinical or biochemical evidence of hyperandrogenism, anovulation, or polycystic ovaries. Of these, 85% had oligomenorrhea, 70% had hirsutism, and 45% had type 2 diabetes mellitus with medication. Before surgery, 8 patients conceived with or without hormonal treatment, 2 did not desire pregnancy, and 10 did not conceive. The mean follow-up was 46.7 months. After surgical weight loss, menstruation was corrected in 82%, hirsutism had resolved in 29%, and 77.8% of those with diabetes had complete remission. Of the 10 patients who did not conceive before surgery, 4 no longer desired pregnancy, and the remaining 6 patients had become pregnant within 3 years of surgery-5 without any hormonal treatment and 1 with in utero insemination. CONCLUSION: Surgical weight loss after Roux-en-Y gastric bypass achieves excellent amelioration of PCOS manifestations and the postoperative conception rate in infertile PCOS subjects desiring pregnancy was 100%.

Systemic inflammation with multiorgan dysfunction is the cause of death in murine ligation-induced acute pancreatitis.

BACKGROUND: We have previously shown that distal pancreatic duct ligation-induced acute pancreatitis in mice is associated with substantial mortality. METHODS: We examined the cause of death in duct ligation-induced acute pancreatitis in mice by serial examination of multiple parameters in three experimental groups: distal pancreatic duct ligation (PD), bile duct ligation alone (BD), and sham operation (S). RESULTS: BD and S had no mortality, while PD had 94% mortality with most deaths between days 2 and 4. Characteristics of mice with acute pancreatitis included (ANOVA; p < 0.05): extracellular regulated kinase activation in the pancreas and lung; pancreatic neutrophil infiltration and acinar cell necrosis maximal on day 2; increased plasma cytokine and aspartate aminotransferase levels and bronchoalveolar lavage fluid neutrophil count and cytokine levels, peaked on day 3; hypotension and bradycardia were worst on day 4; pulmonary neutrophil infiltration and plasma creatinine level peaked on day 4. Liver injury evidenced by raised aspartate serum transaminase after hepatic obstruction was exacerbated by PD. CONCLUSIONS: Systemic inflammation with multiorgan dysfunction causes death in pancreatic duct ligation-induced acute pancreatitis in mice. This experimental model is a suitable experimental analogy of "early severe gallstone pancreatitis" to investigate disease pathogenesis and to evaluate novel therapeutic strategies.

Physical activity patterns in morbidly obese and normal-weight women.

OBJECTIVE: To compare physical activity patterns between morbidly obese and normal-weight women. METHODS: Daily physical activity of 18 morbidly obese and 7 normal-weight women aged 30-58 years was measured for 2 days using the Intelligent Device for Energy Expenditure and Activity (IDEEA) device. RESULTS: The obese group spent about 2 hr/day less standing and 30 min/day less walking than did the normal-weight group. Time spent standing (standing time) was positively associated with time spent walking (walking time). Age- and walking time-adjusted standing time did not differ according to weight status. CONCLUSION: Promoting standing may be a strategy to increase walking.

Resolution of hyperlipidemia follows surgical weight loss in patients undergoing Roux-en-Y gastric bypass surgery: a 6-year analysis of data.

BACKGROUND: Hyperlipidemia is a known risk factor for the development of atherosclerosis and coronary artery disease in morbidly obese individuals. The aim of our study was to review the trends in the serum lipid profiles of patients undergoing Roux-en-Y gastric bypass at our institution. METHODS: A retrospective 6-year analysis of data of patients undergoing Roux-en-Y gastric bypass was performed. The indicators of resolution of hyperlipidemia were reviewed for 6 months and then annually for 6 consecutive years. Hyperlipidemia was defined according to the American Heart Association and National Cholesterol Education Program Adult Treatment Panel III guidelines. The changes in the lipid profile of the patients with subnormal levels of high-density lipoprotein (HDL) cholesterol and total cholesterol/HDL cholesterol risk ratio were also examined. RESULTS: A total of 94 patients were diagnosed with hyperlipidemia, of whom 23 were receiving clinical treatment. The mean patient age was 39 ± 9 years, and the mean body mass index was 50 ± 9.6 kg/m(2), with a female predominance. The mean baseline serum levels were as follows: total cholesterol 220 ± 42.2 mg/dL, triglycerides 212 ± 123.5 mg/dL, low-density lipoprotein cholesterol 135 ± 34.2 mg/dL, and HDL cholesterol 51 ± 12 mg/dL. The optimization of serum total cholesterol, triglycerides, and low-density lipoprotein cholesterol profiles was seen in all patients within 6 months after surgery. The HDL cholesterol levels improved more slowly, reaching desirable levels within 12 months after surgery. All patients taking lipid-lowering agents no longer required the medication at the end of the study period. CONCLUSION: Roux-en-Y gastric bypass provides an effective remission of hyperlipidemia in morbidly obese patients, with most patients no longer requiring lipid-lowering agents within 6 months after surgery. The improvement in overall lipid profiles continued during follow-up after surgery.

A novel model of severe gallstone pancreatitis: murine pancreatic duct ligation results in systemic inflammation and substantial mortality.

BACKGROUND: Suitable experimental models of gallstone pancreatitis with systemic inflammation and mortality are limited. We developed a novel murine model of duct-ligation-induced acute pancreatitis associated with multiorgan dysfunction and severe mortality. METHODS: Laparotomy was done on C57/BL6 mice followed by pancreatic duct (PD) ligation, bile duct (BD) ligation without PD ligation, or sham operation. RESULTS: Only mice with PD ligation developed acute pancreatitis and had 100% mortality. Pulmonary compliance was significantly reduced after PD ligation but not BD ligation. Bronchoalveolar lavage fluid neutrophil count and interleukin-1ß concentration, and the plasma creatinine level, were significantly elevated with PD ligation but not BD ligation. Pancreatic nuclear factor κB (p65) and activator protein 1 (c-Jun) were activated within 1 h of PD ligation. CONCLUSION: PD-ligation-induced acute pancreatitis in mice is associated with systemic inflammation, acute lung injury, multiorgan dysfunction and death. The development of this novel model is an exciting and notable advance in the field.

Validation of a novel physical activity assessment device in morbidly obese females.

Assessment of physical activity in morbidly obese subjects is important especially in bariatric surgery. We examined the validity of Intelligent Device for Energy Expenditure and Activity (IDEEA) for measuring physical activity and sedentary behavior in morbidly obese women. Activity types, gait counts, and speed detected by the IDEEA monitor were compared to those reported by an observer. The IDEEA monitor detected activity types and gait counts with relatively high accuracy, although slightly lower in extremely obese women than in normal weight controls. The IDEEA monitor accurately estimated gait speeds in both groups. Since gait speed predicts energy expenditure more accurately than gait counts, it is of greater clinical relevance. Reliability of the IDEEA monitor was excellent. The IDEEA monitor is a valid instrument for measuring physical activity and sedentary behavior in extremely obese women, and therefore has potential applications in bariatric surgery both in preoperative evaluation and long-term follow-up.

Dominant negative p38 mitogen-activated protein kinase expression inhibits NF-kappaB activation in AR42J cells.

BACKGROUND: The role of the p38 mitogen-activated protein (MAP) kinase in acute pancreatitis pathogenesis is controversial. We hypothesize that p38 plays a role in regulating NF-kappaB activation in exocrine pancreatic cells. METHODS: AR42J cells incorporating an NF-kappaB-responsive luciferase reporter, with and without adenoviral transduction of DNp38, were stimulated with cholecystokinin (CCK) or tumor necrosis factor-alpha (TNF-alpha) prior to measuring NF-kappaB activation. RESULTS: CCK- or TNF-alpha-stimulated NF-kappaB-dependent gene transcription (luciferase assay) was substantially subdued by DNp38 expression. These findings were confirmed by electrophoretic mobility shift assay. Nuclear translocation of the p65 NF-kappaB subunit following agonist stimulation was evident (supershift). Characterization studies showed excellent adenoviral infection efficiency and cell viability in our AR42J cell model. Agonist-stimulated dose- and time-dependent p38 activation, with inhibition by DNp38 expression, was also confirmed. CONCLUSION: The p38 MAP kinase regulates NF-kappaB pathway activation in exocrine pancreatic cells, and thus potentially plays a role in the mechanism of acute pancreatitis pathogenesis..