Renal sinus fat is associated with intrarenal hemodynamic abnormalities independent of visceral fat in patients with chronic kidney disease.

OBJECTIVE: Obesity is a risk factor of chronic kidney disease (CKD), contributing to the rising incidence of cardiometabolic diseases. Renal sinus fat (RSF) is an ectopic fat depot located at the renal cavity that could impair renal function and hemodynamic through compression of renal structures. The major purpose of this study was to explore the relationship between RSF accumulation and renal dysfunction in CKD patients. METHODS: We evaluated the associations between computed tomography measured RSF volume and key clinical and histologic parameters involved in renal function and hemodynamics in 132 well-characterized CKD patients who underwent renal biopsy (median age: 62 years; 63.6% men). RESULTS: RSF volume normalized by renal volume (RSF%) positively correlated with obesity-related traits such body mass index and visceral fat volume (VFV) (all P < 0.001) whereas it negatively correlated with estimated glomerular filtration rate (eGFR) (ρ = -0.42, P < 0.001) and 24-h urinary creatinine clearance (CCr) (ρ = -0.34, P < 0.001). Notably, we found robust positive correlations between RSF% and renal resistive index (RRI) measured by the Doppler ultrasound (ρ = 0.40, P < 0.001), and the histological severity of global glomerular sclerosis (ρ = 0.48, P < 0.001) and interstitial fibrosis and tubular atrophy (IFTA) (ρ = 0.35, P < 0.001). In the multivariate linear regression models, after accounting for potential confounders including VFV, RSF% remained significantly associated with CCr (ß = -0.26, P < 0.001), RRI (ß = 0.17, P = 0.022), global glomerular sclerosis (ß = 0.21, P = 0.002), and IFTA (ß = 0.17, P = 0.012). CONCLUSION: RSF accumulation is associated with renal dysfunction and hemodynamic abnormalities independent of visceral adiposity. Our results suggest that RSF may have a potential unique role in the pathogenesis of CKD.

Very-low-density lipoprotein triglyceride and free fatty acid plasma kinetics in women with high or low brown adipose tissue volume and overweight/obesity.

Although a high amount of brown adipose tissue (BAT) is associated with low plasma triglyceride concentration, the mechanism responsible for this relationship in people is not clear. Here, we evaluate the interrelationships among BAT, very-low-density lipoprotein triglyceride (VLDL-TG), and free fatty acid (FFA) plasma kinetics during thermoneutrality in women with overweight/obesity who had a low (<20 mL) or high (≥20 mL) volume of cold-activated BAT (assessed by using positron emission tomography in conjunction with 2-deoxy-2-[18F]-fluoro-glucose). We find that plasma TG and FFA concentrations are lower and VLDL-TG and FFA plasma clearance rates are faster in women with high BAT than low BAT volume, whereas VLDL-TG and FFA appearance rates in plasma are not different between the two groups. These findings demonstrate that women with high BAT volume have lower plasma TG and FFA concentrations than women with low BAT volumes because of increased VLDL-TG and FFA clearance rates. This study was registered at ClinicalTrials.gov (NCT02786251).

Antineutrophil cytoplasmic antibody-associated vasculitis predominantly manifesting tubulointerstitial nephritis: A case report.

The common histopathology of antineutrophil cytoplasmic antibody-associated vasculitis comprises pauci-immune crescentic glomerulonephritis with concomitant tubulointerstitial nephritis. Tubulointerstitial nephritis in the absence of glomerular involvement in patients with antineutrophil cytoplasmic antibody-associated vasculitis is uncommon. We report a case of antineutrophil cytoplasmic antibody-associated vasculitis-associated acute kidney injury manifesting as tubulointerstitial nephritis without glomerulonephritis. A 75-year-old woman with fever, cough, and myalgia developed kidney dysfunction with inflammatory reactions and tubular-type proteinuria, without glomerular hematuria. A kidney biopsy revealed tubulointerstitial nephritis with arteritis. We ruled out important underlying etiologies of tubulointerstitial nephritis, including infection, drug reactions, and autoimmune diseases. Since chest high-resolution computed tomography demonstrated mild interstitial pneumonia in bilateral lower lung fields, myeloperoxidase antineutrophil cytoplasmic antibody was measured and found to be positive. Therefore, we diagnosed the patient with antineutrophil cytoplasmic antibody-associated vasculitis-associated tubulointerstitial nephritis but not glomerulonephritis, and interstitial pneumonia. The patient's kidney function and symptoms markedly improved with prednisolone treatment. Clinicians should maintain high-level vigilance for antineutrophil cytoplasmic antibody-associated vasculitis as a possible underlying component of tubulointerstitial nephritis, particularly when kidney function deteriorates with tubulointerstitial injuries without glomerular features.

Comparison of Changes in Chest Wall Mechanics and Respiratory Timing Between Patient-Controlled Epidural Analgesia and Intravenous Patient-Controlled Analgesia After Laparoscopic Gastrectomy: A Randomized Controlled Trial.

BACKGROUND: Upper abdominal surgery is associated with postoperative diaphragmatic dysfunction. Whether patient-controlled epidural analgesia (PCEA) is superior to intravenous patient-controlled analgesia (IV-PCA) in preventing postoperative diaphragmatic dysfunction is still unclear in laparoscopic gastric surgery. METHODS: Sixteen patients undergoing laparoscopic gastrectomy randomly received either PCEA or IV-PCA. The primary outcomes were the change in chest wall mechanics and respiratory timing, measured by respiratory inductive plethysmography (Respitrace; Ambulatory Monitoring Inc., Ardsley, New York, United States) before and after surgery, and analyzed by a data acquisition system (PowerLab; ADInstruments, Dunedin, New Zealand). Inspiratory time (Ti), expiratory time (Te), total respiratory cycle time (Ttot), proportion of inspiratory time over total respiratory cycle time (Ti/Ttot), respiratory rate (RR), and abdominal contribution to tidal volume (AB/VT [%]) were calculated from the stored data. AB/VT, relative volume contribution of diaphragm to tidal breathing, represents an index of diaphragmatic function. Because the diaphragm is the main contributor to tidal volume, decreases in AB/VT indicate diaphragm dysfunction. Changes in outcomes over time between the two groups were analyzed using a linear mixed model, and two-sided p values < 0.05 were considered statistically significant. The secondary outcomes were postoperative pain score (visual analog scale (VAS)), bowel function recovery, and hospital stay duration. RESULTS: Postoperative AB/VT in the IV-PCA group was significantly decreased compared to preoperative levels. AB/VT in the PCEA group was significantly higher than the IV-PCA group on postoperative day (POD) 1. Change in AB/VT over time between the PCEA group and the IV-PCA group differed significantly (p = 0.01). A decrease of AB/VT during POD 1 to 3 was observed in the IV-PCA group but not in the PCEA group. As for respiratory timing, there were significant increases in RR with a reduction of Te and Ttot compared to preoperative levels on POD 1 in the PCEA group. There were significant decreases in RR and Ti/Ttot with an increase of Te and Ttot compared to preoperative levels on POD 1 in the IV-PCA group. There was a significant difference in the change of the Ttot over time between the two groups (p = 0.046). There were no significant differences in the changes of Te, Ti/Ttot, Ti, and RR over time between the two groups. There was no significant difference in VAS over time at rest and mobilization, recovery of bowel function, and hospital stay between the two groups. CONCLUSIONS: Continuous ropivacaine infusion with PCEA partially attenuated diaphragmatic dysfunction after laparoscopic gastrectomy, while pain relief by continuous intravenous administration of fentanyl could not attenuate diaphragmatic dysfunction. This suggests that PCEA might ameliorate postoperative diaphragmatic dysfunction after laparoscopic gastrectomy.

Silencing alanine transaminase 2 in diabetic liver attenuates hyperglycemia by reducing gluconeogenesis from amino acids.

Hepatic gluconeogenesis from amino acids contributes significantly to diabetic hyperglycemia, but the molecular mechanisms involved are incompletely understood. Alanine transaminases (ALT1 and ALT2) catalyze the interconversion of alanine and pyruvate, which is required for gluconeogenesis from alanine. We find that ALT2 is overexpressed in the liver of diet-induced obese and db/db mice and that the expression of the gene encoding ALT2 (GPT2) is downregulated following bariatric surgery in people with obesity. The increased hepatic expression of Gpt2 in db/db liver is mediated by activating transcription factor 4, an endoplasmic reticulum stress-activated transcription factor. Hepatocyte-specific knockout of Gpt2 attenuates incorporation of 13C-alanine into newly synthesized glucose by hepatocytes. In vivo Gpt2 knockdown or knockout in liver has no effect on glucose concentrations in lean mice, but Gpt2 suppression alleviates hyperglycemia in db/db mice. These data suggest that ALT2 plays a significant role in hepatic gluconeogenesis from amino acids in diabetes.

Case report: Importance of early and continuous tocilizumab therapy in nephrotic syndrome associated with idiopathic multicentric Castleman disease: A case series.

Idiopathic multicentric Castleman disease (iMCD) is a systemic and polyclonal lymphoproliferative disease involving multiple organs, including the kidneys, due to the overproduction of interleukin-6 (IL-6). Recently, several reports have suggested that excessive IL-6 actions in iMCD could have a causal relationship with the development of diverse histopathological renal manifestations that cause nephrotic syndrome. However, the treatment for such cases remains unclear. We report a series of three cases of nephrotic syndrome due to iMCD that helps to delineate the importance of early and continuous therapy with the anti-interleukin-6 receptor antibody tocilizumab. First, treatment was suspended for infectious control, and the patient presented with nephrotic syndrome due to diffuse mesangial and endocapillary hypercellularity without immune deposits complicating acute kidney injury. Second, iMCD was treated with prednisolone alone. The patient suddenly developed nephrotic syndrome due to immune-complex glomerulonephritis, not otherwise specified, complicated with acute kidney injury. In the third case, nephrotic syndrome secondary to membranous glomerulonephritis was diagnosed, with a skin rash and IgE antibodies to tocilizumab, and was therefore treated with prednisolone alone. In contrast to the first two cases, the third progressed to end-stage renal disease on hemodialysis. Taken together, this series suggests that clinicians should maintain clinical vigilance for iMCD as a possible underlying component of nephrotic syndrome, since iMCD presents with a variety of renal pathologies. Prompt initiation and continuous administration of tocilizumab are likely key determinants of renal outcomes in such cases. In particular, when tocilizumab is suspended due to infection or in the perioperative period, consideration of its expeditious resumption should be made, taking into account both the withdrawal period and systemic conditions.

A case of spinal nerve neurotoxicity with ropivacaine after combined spinal and epidural anesthesia.

BACKGROUND: Neurotoxicity caused by a local anesthetic after regional anesthesia is a rare but serious problem for anesthesiologists. It is difficult to diagnose neurotoxicity from anesthetics because of the large number of possible diagnoses. In this case report, careful monitoring by neurological examinations helped to diagnose local neurotoxicity caused after epidural anesthesia. CASE DESCRIPTION: A 41-year-old pregnant woman who underwent emergency cesarean delivery under combined spinal-epidural anesthesia suffered left leg paralysis after surgery. Multiple neurological examinations (e.g., electromyography, nerve conduction study) revealed that the paralysis was induced by the neurotoxicity of ropivacaine. The neurological examinations were also useful to monitor the recovery process. CONCLUSIONS: This is the first clinical case report that describes the diagnosis of and recovery from local anesthesia-induced neurotoxicity monitored by electromyography and nerve conduction study. Neurological disorders caused by regional anesthetics should be carefully examined and diagnosed using these neurological examinations.

Retrolaminar versus epidural block for postoperative analgesia after minor video-assisted thoracic surgery: a retrospective, matched, non-inferiority study.

BACKGROUND: The role of thoracic epidural analgesia (TEA) for postoperative analgesia after video-assisted thoracic surgery (VATS) is still controversial. Some studies have reported the efficacy of ultrasound-guided retrolaminar block (RLB) for the postoperative management of pain after chest wall surgery. The purpose of this study was to compare the postoperative analgesic efficacy and adverse effects of ultrasound-guided RLB with those of TEA in patients undergoing minor VATS procedures. METHODS: A total of 192 relevant records of patients were enrolled in this study. We reviewed electronic medical records of patients undergoing minor VATS procedures under general anesthesia. The primary outcome was the median differences in the numerical rating scale (NRS) scores during rest between the groups at the morning of postoperative day 1 (POD 1m). A propensity-matched analysis incorporating preoperative variables was used to compare the efficacy of postoperative analgesia in two groups. RESULTS: Overall, 94 patients were identified for analysis. Propensity score matching resulted in 47 patients in each group. There were no significant differences in the NRS scores between the two groups. The median differences in NRS scores during rest between the two groups at POD 1m were under 1, which indicates non-inferiority of RLB. There were no significant differences in the incidence of adverse effects and rescue dose of analgesic consumption between the two groups. CONCLUSIONS: The analgesic effects of continuous ultrasound-guided RLB were non inferior to those of TEA for minor VATS procedures.

A critical role of hepatic GABA in the metabolic dysfunction and hyperphagia of obesity.

Hepatic lipid accumulation is a hallmark of type II diabetes (T2D) associated with hyperinsulinemia, insulin resistance, and hyperphagia. Hepatic synthesis of GABA, catalyzed by GABA-transaminase (GABA-T), is upregulated in obese mice. To assess the role of hepatic GABA production in obesity-induced metabolic and energy dysregulation, we treated mice with two pharmacologic GABA-T inhibitors and knocked down hepatic GABA-T expression using an antisense oligonucleotide. Hepatic GABA-T inhibition and knockdown decreased basal hyperinsulinemia and hyperglycemia and improved glucose intolerance. GABA-T knockdown improved insulin sensitivity assessed by hyperinsulinemic-euglycemic clamps in obese mice. Hepatic GABA-T knockdown also decreased food intake and induced weight loss without altering energy expenditure in obese mice. Data from people with obesity support the notion that hepatic GABA production and transport are associated with serum insulin, homeostatic model assessment for insulin resistance (HOMA-IR), T2D, and BMI. These results support a key role for hepatocyte GABA production in the dysfunctional glucoregulation and feeding behavior associated with obesity.

Associations Among Adipose Tissue Immunology, Inflammation, Exosomes and Insulin Sensitivity in People With Obesity and Nonalcoholic Fatty Liver Disease.

BACKGROUND AND AIMS: Insulin resistance is a key factor in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). We evaluated the importance of subcutaneous abdominal adipose tissue (SAAT) inflammation and both plasma and SAAT-derived exosomes in regulating insulin sensitivity in people with obesity and NAFLD. METHODS: Adipose tissue inflammation (macrophage and T-cell content and expression of proinflammatory cytokines), liver and whole-body insulin sensitivity (assessed using a hyperinsulinemic-euglycemic clamp and glucose tracer infusion), and 24-hour serial plasma cytokine concentrations were evaluated in 3 groups stratified by adiposity and intrahepatic triglyceride (IHTG) content: (1) lean with normal IHTG content (LEAN; N = 14); (2) obese with normal IHTG content (OB-NL; N = 28); and (3) obese with NAFLD (OB-NAFLD; N = 28). The effect of plasma and SAAT-derived exosomes on insulin-stimulated Akt phosphorylation in human skeletal muscle myotubes and mouse primary hepatocytes was assessed in a subset of participants. RESULTS: Proinflammatory macrophages, proinflammatory CD4 and CD8 T-cell populations, and gene expression of several cytokines in SAAT were greater in the OB-NAFLD than the OB-NL and LEAN groups. However, with the exception of PAI-1, which was greater in the OB-NAFLD than the LEAN and OB-NL groups, 24-hour plasma cytokine concentration areas-under-the-curve were not different between groups. The percentage of proinflammatory macrophages and plasma PAI-1 concentration areas-under-the-curve were inversely correlated with both hepatic and whole-body insulin sensitivity. Compared with exosomes from OB-NL participants, plasma and SAAT-derived exosomes from the OB-NAFLD group decreased insulin signaling in myotubes and hepatocytes. CONCLUSIONS: Systemic insulin resistance in people with obesity and NAFLD is associated with increased plasma PAI-1 concentrations and both plasma and SAAT-derived exosomes. ClinicalTrials.gov number: NCT02706262 (https://clinicaltrials.gov/ct2/show/NCT02706262).

Removal of Epididymal Visceral Adipose Tissue Prevents Obesity-Induced Multi-organ Insulin Resistance in Male Mice.

Obesity is associated with insulin resistance, an important risk factor of type 2 diabetes, atherogenic dyslipidemia, and nonalcoholic fatty liver disease. The major purpose of this study was to test hypothesize that prophylactic removal of epididymal visceral adipose tissue (VAT) prevents obesity-induced multi-organ (liver, skeletal muscle, adipose tissue) insulin resistance. Accordingly, we surgically removed epididymal VAT pads from adult C57BL/6J mice and evaluated in vivo and cellular metabolic pathways involved in glucose and lipid metabolism following chronic high-fat diet (HFD) feeding. We found that VAT removal decreases HFD-induced body weight gain while increasing subcutaneous adipose tissue (SAT) mass. Strikingly, VAT removal prevents obesity-induced insulin resistance and hyperinsulinemia and markedly enhances insulin-stimulated AKT-phosphorylation at serine-473 (Ser473) and threonine-308 (Thr308) sites in SAT, liver, and skeletal muscle. VAT removal leads to decreases in plasma lipid concentrations and hepatic triglyceride (TG) content. In addition, VAT removal increases circulating adiponectin, a key insulin-sensitizing adipokine, whereas it decreases circulating interleukin 6, a pro-inflammatory adipokine. Consistent with these findings, VAT removal increases adenosine monophosphate-activated protein kinase C phosphorylation, a major downstream target of adiponectin signaling. Data obtained from RNA sequencing suggest that VAT removal prevents obesity-induced oxidative stress and inflammation in liver and SAT, respectively. Taken together, these findings highlight the metabolic benefits and possible action mechanisms of prophylactic VAT removal on obesity-induced insulin resistance and hepatosteatosis. Our results also provide important insight into understanding the extraordinary capability of adipose tissue to influence whole-body glucose and lipid metabolism as an active endocrine organ.

Importance of Adipose Tissue NAD+ Biology in Regulating Metabolic Flexibility.

Nicotinamide adenine dinucleotide (NAD+) is an essential coenzyme that regulates cellular energy metabolism in many cell types. The major purpose of the present study was to test the hypothesis that NAD+ in white adipose tissue (WAT) is a regulator of whole-body metabolic flexibility in response to changes in insulin sensitivity and with respect to substrate availability and use during feeding and fasting conditions. To this end, we first evaluated the relationship between WAT NAD+ concentration and metabolic flexibility in mice and humans. We found that WAT NAD+ concentration was increased in mice after calorie restriction and exercise, 2 enhancers of metabolic flexibility. Bariatric surgery-induced 20% weight loss increased plasma adiponectin concentration, skeletal muscle insulin sensitivity, and WAT NAD+ concentration in people with obesity. We next analyzed adipocyte-specific nicotinamide phosphoribosyltransferase (Nampt) knockout (ANKO) mice, which have markedly decreased NAD+ concentrations in WAT. ANKO mice oxidized more glucose during the light period and after fasting than control mice. In contrast, the normal postprandial stimulation of glucose oxidation and suppression of fat oxidation were impaired in ANKO mice. Data obtained from RNA-sequencing of WAT suggest that loss of NAMPT increases inflammation, and impairs insulin sensitivity, glucose oxidation, lipolysis, branched-chain amino acid catabolism, and mitochondrial function in WAT, which are features of metabolic inflexibility. These results demonstrate a novel function of WAT NAMPT-mediated NAD+ biosynthesis in regulating whole-body metabolic flexibility, and provide new insights into the role of adipose tissue NAD+ biology in metabolic health.

Effects of Diet versus Gastric Bypass on Metabolic Function in Diabetes.

BACKGROUND: Some studies have suggested that in people with type 2 diabetes, Roux-en-Y gastric bypass has therapeutic effects on metabolic function that are independent of weight loss. METHODS: We evaluated metabolic regulators of glucose homeostasis before and after matched (approximately 18%) weight loss induced by gastric bypass (surgery group) or diet alone (diet group) in 22 patients with obesity and diabetes. The primary outcome was the change in hepatic insulin sensitivity, assessed by infusion of insulin at low rates (stages 1 and 2 of a 3-stage hyperinsulinemic euglycemic pancreatic clamp). Secondary outcomes were changes in muscle insulin sensitivity, beta-cell function, and 24-hour plasma glucose and insulin profiles. RESULTS: Weight loss was associated with increases in mean suppression of glucose production from baseline, by 7.04 µmol per kilogram of fat-free mass per minute (95% confidence interval [CI], 4.74 to 9.33) in the diet group and by 7.02 µmol per kilogram of fat-free mass per minute (95% CI, 3.21 to 10.84) in the surgery group during clamp stage 1, and by 5.39 (95% CI, 2.44 to 8.34) and 5.37 (95% CI, 2.41 to 8.33) µmol per kilogram of fat-free mass per minute in the two groups, respectively, during clamp stage 2; there were no significant differences between the groups. Weight loss was associated with increased insulin-stimulated glucose disposal, from 30.5±15.9 to 61.6±13.0 µmol per kilogram of fat-free mass per minute in the diet group and from 29.4±12.6 to 54.5±10.4 µmol per kilogram of fat-free mass per minute in the surgery group; there was no significant difference between the groups. Weight loss increased beta-cell function (insulin secretion relative to insulin sensitivity) by 1.83 units (95% CI, 1.22 to 2.44) in the diet group and by 1.11 units (95% CI, 0.08 to 2.15) in the surgery group, with no significant difference between the groups, and it decreased the areas under the curve for 24-hour plasma glucose and insulin levels in both groups, with no significant difference between the groups. No major complications occurred in either group. CONCLUSIONS: In this study involving patients with obesity and type 2 diabetes, the metabolic benefits of gastric bypass surgery and diet were similar and were apparently related to weight loss itself, with no evident clinically important effects independent of weight loss. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT02207777.).

Inhibition of Grb14, a negative modulator of insulin signaling, improves glucose homeostasis without causing cardiac dysfunction.

Insulin resistance increases patients' risk of developing type 2 diabetes (T2D), non-alcoholic steatohepatitis (NASH) and a host of other comorbidities including cardiovascular disease and cancer. At the molecular level, insulin exerts its function through the insulin receptor (IR), a transmembrane receptor tyrosine kinase. Data from human genetic studies have shown that Grb14 functions as a negative modulator of IR activity, and the germline Grb14-knockout (KO) mice have improved insulin signaling in liver and skeletal muscle. Here, we show that Grb14 knockdown in liver, white adipose tissues, and heart with an AAV-shRNA (Grb14-shRNA) improves glucose homeostasis in diet-induced obese (DIO) mice. A previous report has shown that germline deletion of Grb14 in mice results in cardiac hypertrophy and impaired systolic function, which could severely limit the therapeutic potential of targeting Grb14. In this report, we demonstrate that there are no significant changes in cardiac function as measured by echocardiography in the Grb14-knockdown mice fed a high-fat diet for a period of four months. While additional studies are needed to further confirm the efficacy and to de-risk potential negative cardiac effects in preclinical models, our data support the therapeutic strategy of inhibiting Grb14 to treat diabetes and related conditions.

Loss of ARID1A induces a stemness gene ALDH1A1 expression with histone acetylation in the malignant subtype of cholangiocarcinoma.

Genomic analyses have recently discovered the malignant subtype of human intrahepatic cholangiocarcinoma (ICC) characterized by frequent mutations of chromatin remodeling gene ARID1A; however, the biological and molecular functions still remain obscure. We here examined the clinical and biological significances of ARID1A deficiency in human ICC. Immunohistochemical analysis demonstrated that the loss of ARID1A was an independent prognostic factor for overall survival of ICC patients (P = 0.023). We established ARID1A-knockout (KO) cells by using the CRISPR/Cas9 system from two human cholangiocarcinoma cell lines. ARID1A-KO cells exhibited significantly enhanced migration, invasion, and sphere formation activity. Microarray analysis revealed that ALDH1A1, a stemness gene, was the most significantly elevated genes in ARID1A-KO cells. In addition, ALDH enzymatic activity as a hallmark of cancer stem cells was markedly high in the KO cells. ARID1A and histone deacetylase 1 were directly recruited to the ALDH1A1 promoter region in cholangiocarcinoma cells with undetectable ALDH1A1 expression by chromatin immunoprecipitation assay. The histone H3K27 acetylation level at the ALDH1A1 promoter region was increased in cells when ARID1A was disrupted (P < 0.01). Clinically, inverse correlation between ARID1A and ALDH1A1 expression was also identified in primary ICC (P = 0.018), and ARID1A-negative and ALDH1A1-positve ICCs showed worse prognosis than only ARID1A-negative cases (P = 0.002). In conclusion, ARID1A may function as a tumor suppressor in ICC through transcriptional downregulation of ALDH1A1 expression with decreasing histone H3K27 acetylation. Our studies provide the basis for the development of new epigenetic approaches to ARID1A-negative ICC. Immunohistochemical loss of ARID1A is an independent prognostic factor in intrahepatic cholangiocarcinoma patients. ARID1A recruits HDAC1 to the promoter region of ALDH1A1, a stemness gene, and epigenetically suppresses ALDH1A1 expression with decreasing histone H3K27 acetylation in cholangiocarcinoma cells.

The Clinical Implications of Peripancreatic Fluid Collection After Distal Pancreatectomy.

OBJECTIVES: Pancreatic fistula after distal pancreatectomy (DP) remains an unsolved problem, and postoperative CT imaging often demonstrates fluid collection (FC) around the pancreatic remnant. This study sought to clarify the clinical implications of FC. METHODS: This study enrolled 146 patients who underwent DP. FC was defined as a cyst-like lesion ≥ 10 mm in diameter on CT imaging at postoperative day (POD) 7. FC size, irregularity of FC margin, and air bubbles in FC were investigated. In addition, clinical data were retrospectively collected, and useful predictive factors for postoperative pancreatic fistula (POPF) were analyzed. RESULTS: Clinically relevant POPF was observed in 26 patients (17.8%), and FC was detected in 136 patients (94.4%). Multivariate analysis identified FC size and drain amylase levels on POD3 as significant risk factors for POPF. Cutoff values were determined by ROC analyses, and the levels of the FC size and drain amylase on POD3 were determined as 41 mm and 1026 IU/L, respectively. The sensitivity and specificity of FC diameters > 41 mm were 76.9% and 75.0%, respectively, while those of drain amylase levels > 1026 IU on POD3 were 73.1% and 75.8%, respectively. CONCLUSIONS: While treating some FCs after DP was necessary for the management of POPF, others did not require any intervention since most of them spontaneously disappeared. FC size and drain amylase levels on POD3 were found to be significantly associated with POPF and could potentially help to determine appropriate treatment.

Loss of lipin 1-mediated phosphatidic acid phosphohydrolase activity in muscle leads to skeletal myopathy in mice.

Lipin 1 regulates glycerolipid homeostasis by acting as a phosphatidic acid phosphohydrolase (PAP) enzyme in the triglyceride-synthesis pathway and by regulating transcription factor activity. Mutations in human lipin 1 are a common cause of recurrent rhabdomyolysis in children. Mice with constitutive whole-body lipin 1 deficiency have been used to examine mechanisms connecting lipin 1 deficiency to myocyte injury. However, that mouse model is confounded by lipodystrophy not phenocopied in people. Herein, 2 muscle-specific mouse models were studied: 1) Lpin1 exon 3 and 4 deletion, resulting in a hypomorphic protein without PAP activity, but which preserved transcriptional coregulatory function; and 2) Lpin1 exon 7 deletion, resulting in total protein loss. In both models, skeletal muscles exhibited a chronic myopathy with ongoing muscle fiber necrosis and regeneration and accumulation of phosphatidic acid and, paradoxically, diacylglycerol. Additionally, lipin 1-deficient mice had abundant, but abnormal, mitochondria likely because of impaired autophagy. Finally, these mice exhibited increased plasma creatine kinase following exhaustive exercise when unfed. These data suggest that mice lacking lipin 1-mediated PAP activity in skeletal muscle may serve as a model for determining the mechanisms by which lipin 1 deficiency leads to myocyte injury and for testing potential therapeutic approaches.-Schweitzer, G. G., Collier, S. L., Chen, Z., McCommis, K. S., Pittman, S. K., Yoshino, J., Matkovich, S. J., Hsu, F.-F., Chrast, R., Eaton, J. M., Harris, T. E., Weihl, C. C., Finck, B. N. Loss of lipin 1-mediated phosphatidic acid phosphohydrolase activity in muscle leads to skeletal myopathy in mice.

Percutaneous muscle biopsy-induced tissue injury causes local endoplasmic reticulum stress.

Endoplasmic reticulum (ER) stress is likely involved in the pathogenesis of metabolic dysfunction in people with obesity and diabetes. Although tissue biopsy is often used to evaluate the presence and severity of ER stress, it is not known whether acute tissue injury-induced by percutaneous muscle biopsy causes ER stress and its potential downstream effects on markers of inflammation and metabolic function. In this study, we tested the hypothesis that percutaneous biopsy-induced tissue injury causes ER stress and alters inflammatory and metabolic pathways in skeletal muscle. Vastus lateralis muscle tissue was obtained by percutaneous biopsy at 0600 h and 12 h later from either the contralateral leg (Group 1, n = 6) or at the same site as the initial biopsy (Group 2, n = 6) in women who were overweight. Muscle gene expression of selected markers of ER stress, inflammation, and regulators of glucose and lipid metabolism were determined. Compared with Group 1, muscle gene expression in the second biopsy sample obtained in Group 2 demonstrated marked increases in markers of ER stress (GRP78, XBP1, ATF6) and inflammation (IL6, TNF), and alterations in metabolic regulators (decreased expression of GLUT4 and PPARGC1A and increased expression of FASN). Our results suggest that acute tissue injury induced by percutaneous muscle biopsy causes an integrated local response that involves an induction of ER stress and alterations in markers of inflammation and regulators of glucose and lipid metabolism.

Effectiveness of arginine vasopressin for the management of refractory hemorrhagic shock in a patient with autonomic dysreflexia caused by spinal cord injury.

BACKGROUND: Arginine vasopressin has been used for the management of refractory vasodilatory shock. However, it is still unclear whether arginine vasopressin is useful for hypotension in patients with spinal cord injury. CASE DESCRIPTION: A 78-year-old man with autonomic dysreflexia and paralysis below the level corresponding to Th2 due to spinal cord injury previously underwent cholecystectomy. During the surgery, accidental hemorrhage led him to refractory hemorrhagic shock unresponsive to fluid resuscitation and catecholamine. Lasting hypotension was improved with arginine vasopressin. CONCLUSION: We described a rare case report on the use of arginine vasopressin for management of refractory hemorrhagic shock in a patient with autonomic dysreflexia.

Swallowing action immediately before intravenous fentanyl at induction of anesthesia prevents fentanyl-induced coughing: a randomized controlled study.

PURPOSE: Fentanyl is a strong µ-opioid analgesic which attenuates the stimulation of surgical invasion and tracheal intubation. However, intravenous fentanyl often induces coughing [fentanyl-induced coughing (FIC)] during induction of anesthesia. We found that the swallowing action, when requested at induction of anesthesia, attenuated FIC. In the current study, we investigated the relationship between the occurrence of FIC and the swallowing action. METHODS: The study included American Society of Anesthesiologists physical status I or II patients, aged 20-64 years, who were undergoing elective surgery. They were divided into two groups-one group was urged to perform the swallowing action immediately before intravenous fentanyl (S group), and the other group performed no swallowing action (non-S group). The patients first received intravenous fentanyl and were observed for 90 s. Each patient's background, dose of fentanyl and occurrence of coughing were investigated from their records and a motion picture recording. The incidence of FIC was evaluated by chi-squared test, and severity was tested by Wilcoxon rank-sum test. P < 0.05 was considered statistically significant. RESULTS: The incidence of FIC in the S group and non-S group was 14.0 and 40.4%, respectively. The risk of FIC was reduced in the S group by 75%; risk ratio (95% confidence interval) was 0.35 (0.20, 0.60). The number of coughs in the S group were less than in the non-S group (P < 0.001). CONCLUSION: The swallowing action immediately before intravenous fentanyl may be a simple and clinically feasible method for preventing FIC effectively. Clinical trial number: UMIN000012086 ( https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&type=summary&recptno=Rn000014126&language=J ).