Downregulation of Setdb2 promotes alternative activation of macrophages via the PI3K/Akt pathway to attenuate NAFLD after sleeve gastrectomy.

Non-alcoholic fatty liver disease (NAFLD) stands as the most prevalent hepatic disorder, with bariatric surgery emerging as the most effective intervention for NAFLD remission. Sleeve gastrectomy (SG) has notably ascended as the predominant procedure due to its comparative simplicity and consistent surgical outcomes. Nonetheless, the underlying mechanisms remain unclear. In this study, we probed the therapeutic potential of SG for NAFLD induced by a high-fat diet (HFD) in mice, with a focus on its impact on liver lipid accumulation, macrophage polarization, and the role of the histone methyltransferase Setdb2. SG prompted significant weight loss, diminished liver size and liver-to-body weight ratio, and enhanced liver function, evidenced by reduced serum levels of triglycerides (TG), total cholesterol (T-CHO), alanine aminotransferase (ALT), and aspartate aminotransferase (AST). Histological examination confirmed a reduction in liver lipid accumulation. Additionally, flow cytometry unveiled an increased proportion of M2 macrophages and a decrease in Setdb2 expression was shown in the SG group, suggesting an association between Setdb2 levels and postsurgical macrophage polarization. Furthermore, the conditional knockout of Setdb2 in mice further mitigated HFD-induced steatosis and promoted the M2 macrophage phenotype. Mechanistically, Setdb2 knockout in bone marrow-derived macrophages (BMDMs) favored M2 polarization, with RNA sequencing and western blotting analyses corroborating the upregulation of the PI3K/Akt signaling pathway. The effects of Setdb2 on macrophage activation were nullified by the PI3K inhibitor LY294002, suggesting that Setdb2 facilitates alternative macrophage activation through the PI3K/Akt signaling pathway. These comprehensive findings underscore the potential of SG as a therapeutic intervention for NAFLD by regulating the critical function of Setdb2 in macrophage polarization and activation, thereby offering novel insights into NAFLD pathogenesis and therapeutic targets.

Olodaterol promotes thermogenesis in brown adipocytes via regulation of the ß2-AR/cAMP/PKA signaling pathway.

The escalating incidence of metabolic pathologies such as obesity and diabetes mellitus underscores the imperative for innovative therapeutics targeting lipid metabolism modulation. Within this context, augmenting thermogenic processes in adipose cells emerges as a viable therapeutic approach. Given the limitations of previous ß3-adrenergic receptor (ß3-AR) agonist treatments in human diseases, there is an increasing focus on therapies targeting the ß2-adrenergic receptor (ß2-AR). Olodaterol (OLO) is a potent ß2-AR agonist that is a potential novel pharmacological candidate in this area. Our study explores the role and underlying mechanisms of OLO in enhancing brown adipose thermogenesis, providing robust evidence from in vitro and in vivo studies. OLO demonstrated a dose-dependent enhancement of lipolysis, notably increasing the expression of Uncoupling Protein 1 (UCP1) and raising the rate of oxygen consumption in primary brown adipocytes. This suggests a significant increase in thermogenic potential and energy expenditure. The administration of OLO to murine models noticeably enhanced cold-induced nonshivering thermogenesis. OLO elevated UCP1 expression in the brown adipose tissue of mice. Furthermore, it promoted brown adipocyte thermogenesis by activating the ß2-AR/cAMP/PKA signaling cascades according to RNA sequencing, western blotting, and molecular docking analysis. This investigation underscores the therapeutic potential of OLO for metabolic ailments and sheds light on the intricate molecular dynamics of adipocyte thermogenesis, laying the groundwork for future targeted therapeutic interventions in human metabolic disorders.

Sleeve gastrectomy decreased hepatic lipid accumulation by inducing autophagy via AMPK/mTOR pathway.

This study was designed to investigate the roles of autophagy in the attenuation of hepatic lipid accumulation after sleeve gastrectomy (SG). Thirty-two rats were divided into normal control, obesity group, sham group, and SG group. Then serum glucagon-like polypeptide-1 (GLP-1) and lipid accumulation were determined, followed by measuring the activity of autophagy based on immunohistochemistry (IHC) and Western blot analysis. Our data showed significant decrease in the lipid accumulation after SG compared with sham group. GLP-1 and autophagy showed significant increase in rats underwent SG compared with the sham group (P < 0.05). In vitro experiments were conducted to analyze the roles of GLP-1 in autophagy. We knock-downed the expression of Beclin-1 in HepG2, and then analyzed the expression of autophagy-related protein (i.e. LC3BII and LC3BI) and lipid droplet accumulation. In HepG2 cells, GLP-1 analog reduced lipid accumulation by activating autophagy through modulating the AMPK/mTOR signaling pathway. All these concluded that SG decreased hepatic lipid accumulation by inducing autophagy through modulating AMPK/mTOR pathway.

Laparoscopic versus open surgery for hepatic caudate lobectomy: a retrospective study.

BACKGROUND: This study was designed to investigate the feasibility and safety of laparoscopic hepatic caudate lobectomy (LHCL) for treating liver tumor by comparing with the open hepatic caudate lobectomy (OHCL). METHODS: In the LHCL group, we included 24 patients with liver tumor received LHCL in Qilu Hospital of the Shandong University from January 2014 to January 2019. Meanwhile, 24 matched liver tumor patients underwent OHCL in our hospital served as control. Then we compared the patient characteristics, intraoperative parameters, and postoperative outcomes between LHCL group and OHCL group. RESULTS: There were no significant differences in gender, age, degree of cirrhosis, tumor size, preoperative liver function, Child-Pugh grading, proportion of liver cirrhosis, and tumor size between LHCL group and OHCL group (P > 0.05). No death was reported in both groups. The length of incision in LHCL group was significantly lower than that in OHCL group (4.22 ± 1.14 cm vs. 22.46 ± 4.40 cm, P < 0.001). The intraoperative blood loss in LHCL group was significantly lower than that of OHCL group (116.82 ± 71.61 ml vs. 371.74 ± 579.35 ml, P = 0.047). The total operation time, Pringle maneuver occlusion time, and blocking rate in LHCL group showed no statistical difference compared with those of the OHCL group (P > 0.05). The VAS scores at postoperative 24 and 48 h showed no statistical differences between LHCL group and OHCL group (P > 0.05). Compared with the OHCL group, significant decrease was noticed in the proportion of patients with severe pain 48 h after surgery (0 vs. 4.25 ± 0.46, P < 0.001) and dezocine consumption (90.45 ± 45.77 mg vs. 131.6 ± 81.30 mg, P = 0.0448) in the LHCL group. CONCLUSION: LHCL is effective and feasible for treating liver tumor, which is featured by reducing intraoperative blood loss and serious pain.

Sleeve Gastrectomy Improves Hepatic Glucose Metabolism by Downregulating FBXO2 and Activating the PI3K-AKT Pathway.

Type 2 diabetes mellitus (T2DM), a chronic metabolic disease, is a public health concern that seriously endangers human health. Sleeve gastrectomy (SG) can relieve T2DM by improving glucose homeostasis and enhancing insulin sensitivity. However, its specific underlying mechanism remains elusive. SG and sham surgery were performed on mice fed a high-fat diet (HFD) for 16 weeks. Lipid metabolism was evaluated via histology and serum lipid analysis. Glucose metabolism was evaluated using the oral glucose tolerance test (OGTT) and insulin tolerance test (ITT). Compared with the sham group, the SG group displayed a reduction in liver lipid accumulation and glucose intolerance, and western blot analysis revealed that the AMPK and PI3K-AKT pathways were activated. Furthermore, transcription and translation levels of FBXO2 were reduced after SG. After liver-specific overexpression of FBXO2, the improvement in glucose metabolism observed following SG was blunted; however, the remission of fatty liver was not influenced by the over expression of FBXO2. Our study explores the mechanism of SG in relieving T2DM, indicating that FBXO2 is a noninvasive therapeutic target that warrants further investigation.

Central GLP-1 contributes to improved cognitive function and brain glucose uptake after duodenum-jejunum bypass on obese and diabetic rats.

The improvement of cognitive function following bariatric surgery has been highlighted, yet its underlying mechanisms remain elusive. Finding the improved brain glucose uptake of patients after Roux-en-Y gastric bypass (RYGB), duodenum-jejunum bypass (DJB), and sham surgery (Sham) were performed on obese and diabetic Wistar rats, and intracerebroventricular (ICV) injection of glucagon-like peptide-1 (GLP-1) analog liraglutide (Lira), antagonist exendin-(9-39) (Exe-9), and the viral-mediated GLP-1 receptor (Glp-1r) knockdown (KD) were applied on both groups to elucidate the role of GLP-1 in mediating cognitive function and brain glucose uptake assessed with the Morris water maze (MWM) and positron emission tomography (PET). Insulin and GLP-1 in serum and cerebral spinal fluid (CSF) were measured, and the expression of glucose uptake-related proteins including glucose transporter 1 (GLUT-1), GLUT-4, phospho-Akt substrate of 160kDa (pAS160), AS160, Rab10, Myosin-Va as well as the c-fos marker in the brain were examined. Along with augmented glucose homeostasis following DJB, central GLP-1 was correlated with the improved cognitive function and ameliorated brain glucose uptake, which was further confirmed by the enhancive role of Lira on both groups whereas the Exe-9 and Glp-1r KD were opposite. Known to activate insulin-signaling pathways, central GLP-1 contributes to improved cognitive function and brain glucose uptake after DJB.NEW & NOTEWORTHY The improvement of cognitive function following bariatric surgery has been highlighted while its mechanisms remain elusive. The brain glucose uptake of patients was improved after RYGB, and the DJB and sham surgery performed on obese and diabetic Wistar rats revealed that the elevated central GLP-1 contributes to the dramatic improvement of cognitive function, brain glucose uptake, transport, glucose sensing, and neuronal activation.

Downregulation of circular RNA circDOCK7 identified from diabetic rats after sleeve gastrectomy contributes to hepatocyte apoptosis through regulating miR-139-3p and MCM3.

Sleeve gastrectomy (SG) is the most widely used bariatric procedures globally, which could improve glucose and lipid metabolism dramatically. Circular RNAs (circRNAs) are being increasingly implicated in numerous pathophysiological processes. However, for diabetes mellitus (DM), the expression and function of circRNAs remain largely undetermined, in particular, whether circRNAs mediate the amelioration of DM observed after SG. Using a diabetic rat model, we subjected liver tissue from SG and sham-operated rats to RNA sequencing. Amongst the 103 differentially regulated circRNAs identified in diabetic rats after SG, we focused on circDOCK7, a highly expressed circRNA derived from the back-splicing of the DOCK7 gene. Silencing of circDOCK7 significantly inhibited cellular proliferation and induction of apoptosis in insulin-resistant rat hepatocytes. Further analysis indicated circDOCK7 harbored binding sites for miR-139-3p and regulated the expression of minichromosome maintenance 3 (MCM3) through sequestration of miR-139-3p. Our findings therefore demonstrate a novel regulatory pathway involving circDOCK7 that regulates cellular proliferation and apoptosis through increasing the expression of MCM3. Overall, our study establishes a list of specific circRNAs expressed in diabetic rat liver after SG including circDOCK7 which serve as potential biomarkers and treatment targets for DM patients.

Cystic Pancreatic Neuroendocrine Tumors Represent a Distinct Clinical Entity with Less Aggressive Biological Behaviors.

BACKGROUND: Pancreatic neuroendocrine tumors (pNETs) uncommonly present as cystic lesions. There is a gap in knowledge of their clinicopathological characteristics and biological behaviors. Previous reported studies remained inconsistent and controversial. The purpose of this study is to investigate the clinicopathological features of cystic pNET and determine if it represents a distinct clinical entity by comparing its characteristics with those of solid pNETs. METHODS: Patients with pNETs who underwent surgical resections from January 2014 to April 2019 at Qilu Hospital of Shandong University were reviewed retrospectively. Demographics, clinical characteristics, surgical data, and oncological as well as histological characteristics of cystic pNETs and their solid counterparts were collected and analyzed. RESULTS: A total of 122 patients were included in this study, and 10.7% (13/122) patients were cystic. There is no significant difference between cystic pNETs and solid pNETs in age (43.6 ± 15.8 versus 50.9 ± 14.5 y, P = 0.093) and sex distribution (P = 0.085). Cystic pNETs are more likely to be asymptomatic (61.5% versus 23.9%, P = 0.008) and nonfunctional (92.3% versus 52.7%, P = 0.006) than solid pNETs. However, the tumor size (4.8 ± 4.5 versus 2.8 ± 1.9 cm, P = 0.124), proportion of multiple endocrine neoplasia type 1 (92.3% versus 98.2%, P = 0.289), and tumor location (P = 0.154) are similar in both groups. Compared with solid pNETs, cystic pNETs have a lower Ki-67 index and incidence of liver metastasis, but the difference is not significant. CONCLUSIONS: Cystic pNETs are more likely to be nonfunctional and indolent and seem to exhibit less aggressive biological behaviors than solid pNETs. Conservative approach should be considered for certain selected patients.

Positive Thyroid Peroxidase Antibody and Thyroglobulin Antibody are Associated With Better Clinicopathologic Features of Papillary Thyroid Cancer.

OBJECTIVE: To compare the thyroid autoantibody status of patients with papillary thyroid cancer (PTC) and benign nodular goiter as well as possible associations between thyroid autoantibodies and clinicopathologic features of PTC. METHODS: A total of 3934 participants who underwent thyroidectomy were enrolled in this retrospective study. Patients were divided into PTC and benign nodule groups according to pathological diagnosis. Based on the preoperative serum antibody results, PTC patients were divided into thyroid peroxidase antibody (TPOAb)-positive, thyroglobulin antibody (TgAb)-positive, dual TPOAb- and TgAb-positive, or antibody-negative groups. RESULTS: Of the 3934 enrolled patients, 2926 (74.4%) were diagnosed with PTC. Multivariate regression analyses suggested that high thyroid-stimulating hormone levels (adjusted odds ratio [OR] = 1.732, 95% CI [1.485-2.021], P < .001), positive TgAb (adjusted OR = 1.768, 95% CI [1.436-2.178], P < .001), and positive TPOAb (adjusted OR = 1.452, 95% CI [1.148-1.836], P = .002) were independent risk factors for predicting malignancy of thyroid nodules. Multinomial multiple logistic regression analyses indicated that positive TPOAb alone was an independent predictor of less central lymph node metastasis in PTC patients (adjusted OR = 0.643, 95% CI [0.448-0.923], P = .017), whereas positive TgAb alone was significantly associated with less extrathyroidal extension (adjusted OR = 0.778, 95% CI [0.622-0.974], P = .028). PTC patients with dual-positive TPOAb and TgAb displayed a decreased incidence of extrathyroidal extension (adjusted OR = 0.767, 95% CI [0.623-0.944], P = .012) and central lymph node metastasis (adjusted OR = 0.784, 95% CI [0.624-0.986], P = .037). CONCLUSION: Although preoperative positive TPOAb and TgAb are independent predictive markers for PTC, they are also associated with better clinicopathologic features of PTC.

[Progress in diagnosis and treatment of chylous leakage following pancreatic resection].

Compared with other postoperative complications following pancreatic resection, chylous leakage is rare in clinical, which could lead to serious morbidity, including malnutrition,immunosuppression and abdominal infection. The main risk factors for chylous leakage after pancreatic resection are the injury of cisterna chyli or lymphatic vessels caused by intraoperative lymph node dissection and early enteral nutrition. The clinical features of chylous leakage are not specific, and the diagnosis mainly depends on the composition analysis of the drainage fluid. The diagnostic criteria generally adopt the expert consensus of the international Study Group on Pancreatic Surgery,but it is only applicable to isolated chylous leakage and there is still no widely accepted diagnostic criteria in most complex cases. Abdominal fluid analysis and abdominal CT scan are the most applied diagnostic methods for chylous leakage after pancreatic resection,while lymphangiography can not only identify the site of leakage,but also has therapeutic value. For its treatment,the"step-up"treatment strategy is typically applied in most patients. Conservative treatments, including drainage,proper diet and applying octreotide, can benefit most patients. Surgical treatment is not commonly used,and its therapeutic value needs to be further verified. Optimizing perioperative management measures and personalized treatment strategies for different patients can effectively prevent postoperative chylous leakage and maximize the clinical benefits of patients who received pancreatic resection.

Sleeve gastrectomy ameliorates alveolar structures and surfactant protein expression in lungs of obese and diabetic rats.

BACKGROUND: Bariatric surgeries have been shown to be effective in reversing damaged pulmonary function in individuals suffering from obesity and type 2 diabetes mellitus, whereas its underlying mechanisms remain largely unknown. METHODS: Sleeve gastrectomy (SG) was performed on obese and diabetic Wistar rats, and their pulmonary function and lung tissues were compared to sham-operated (SH) obese and diabetic rats, and age-matched healthy controls (C) to explore the improvements in microstructures and expression of surfactant protein (SP)-A and -C at postoperative 4th, 8th, and 12th week. RESULT: Apart from the profound metabolic changes and improvement in pulmonary function, lung volume was restored along with an improved diffusion capacity noted by thinned capillary basement membrane and decreased harmonic mean length of diffusion barrier in SG rats. The digital slices of light microscope showed the general changes brought on by the SG, including normalized basic structures, ameliorated inflammatory status, as well as reduced lipid deposition, where the hydroxyproline (HYP), triglyceride (TG) assays, and electron microscope further suggested that the improvement in alveolar structures lies in reduced collagen fibers, lipids and septal tissues, increased capillary blood, and normalized alveolar type 2 (AT2) cells. Besides, disrupted SP-A and SP-C expression were also normalized after SG. CONCLUSION: The improvement of lung function after SG is related to the ameliorated alveolar structures, and surface protein expression induced by weight loss and improved glucose metabolism.

Effect of Sleeve Gastrectomy on Glycometabolism via Forkhead Box O1 (FoxO1)/Lipocalin-2 (LCN2) Pathway.

BACKGROUND The mechanism by which sleeve gastrectomy (SG) improves glycometabolism has remained unclear so far. Increasing evidence has demonstrated that bone is a regulator of glucose metabolism, and osteoblast-derived forkhead box O1 (FoxO1) and lipocalin-2 (LCN2) are regulators of energy metabolism. The aim of this study was to investigate whether the FOXO1/LCN2 signaling pathway is involved in the anti-diabetic effect of SG. MATERIAL AND METHODS Insulin resistance was induced in Wistar rats, which were then intraperitoneally injected with streptozotocin to induce a type 2 diabetic state. Levels of fasting blood glucose, serum insulin, HbA1c, and LCN2 were analyzed at corresponding time points after SG and sham surgeries. The expressions of FOXO1, LCN2, and the melanocortin 4 receptor (MC4R) in bone and hypothalamus were detected by immunofluorescence. FOXO1 siRNA was applied to downregulate FOXO1 expression in osteoblasts of rats. The influence of FOXO1 gene on expression of LCN2 was investigated in cultured osteoblasts by western blot and PCR. RESULTS Glucose metabolism in the SG group was significantly improved. The LCN2 expression in bone in the SG group was higher than that in the sham group, whereas FOXO1 expression in the SG group was lower than that in the sham group. The binding rate of LCN2 and MC4R in the hypothalamus was also higher in the SG group compared with that in the sham group. The downregulation of FOXO1 expression in osteoblasts was accompanied by upregulation of LCN2 expression. CONCLUSIONS These results suggest that the FOXO1/LCN2 signaling pathway participates in the anti-diabetic effect of SG.

Laparoscopic gastrectomy for early gastric cancer and the risk factors of lymph node metastasis.

Objective: Lymph node metastasis (LNM) is one of the important prognostic factors of early gastric cancer (EGC). Moreover, LNM is also important when choosing therapeutic intervention for EGC patients. The purpose of this study is to explore the risk factors of LNM in EGC and to discuss the corresponding treatment. Design: We retrospectively reviewed the medical records of 253 patients with EGC who underwent surgical therapy in our department between 2012 and 2015. Univariate analysis and Multivariate Cox regression were used to evaluate the independent risk factors of LNM. Results: LNM was present in 38 cases among 253 patients (15%). Univariate analysis showed an obvious correlation between LNM and tumour location, tumour size, depth of invasion, morphological classification, gross type of the lesion and venous invasion. Multivariate analysis indicated that poorly differentiated carcinoma, submucosal cancer, tumour size ≥2 cm and venous invasion were the independent risk factors for LNM. Conclusion: Tumour size, depth of invasion, morphological classification and blood vessel invasion were predictive risk factors for LNM in EGC. We propose that EGC patients with those risk factors should be accepted gastrectomy with LN dissection.

Comparative study of laparoscopic radical gastrectomy and open radical gastrectomy.

INTRODUCTION: At present, the main treatment of gastric cancer is surgical resection combined with radiotherapy and chemotherapy, the most important part of which is radical gastrectomy. Laparoscopic radical gastrectomy for advanced gastric cancer is difficult to operate, and whether it can achieve the same curative effect with the laparotomy is still controversial. MATERIALS AND METHODS: This study retrospectively analysed the clinical data of 269 gastric cancer patients surgically treated by our medical team from May 2011 to December 2015 for comparative analysis of the clinical efficacy of laparoscopic-assisted radical gastrectomy and traditional open radical gastrectomy. RESULTS: The laparoscopic surgery group had longer duration of surgery, less intra-operative blood loss, shorter post-operative exhaust time, shorter post-operative hospital stay and shorter timing of drain removal. The average number of harvested lymph nodes in the laparoscopic surgery group was 22.9 ± 9.5 per case. And in the laparotomy group the average number was 23.3 ± 9.9 per case. The difference had no statistical significance. With the increase of the number of laparoscopic surgical procedures, the amount of intra-operative blood loss gradually decreases, and the duration of surgery is gradually reduced. CONCLUSION: Laparoscopic radical gastrectomy is superior to open surgery in the aspects of intra-operative blood loss, post-operative exhaust time, post-operative hospital stay and timing of drain removal. With the number of laparoscopic radical gastrectomy cases increased, the duration of surgery is shortened and the amount of intra-operative blood loss will decrease.

Endovascular treatment of spontaneous renal artery dissection.

OBJECTIVE: This study aimed to assess the outcomes of patients with spontaneous renal artery dissection (SRAD) after endovascular repair. METHODS: We performed a retrospective review of SRAD patients after endovascular treatment between January 2007 and August 2018. Demographic, clinical, ancillary testing, treatment, and outcome data were collected and analyzed. RESULTS: Fourteen patients (12 men and 2 women) with a mean age of 47 years were included in this study. All the patients had hypertension, either new onset (78.6%) or pre-existent (21.4%). Sudden flank pain was the most common symptom. Fourteen patients had 15 affected renal arteries. Endovascular repair was successfully performed in 14 arteries. The technical success rate of endovascular repair was 93.3% (14/15), with no postoperative death. Endovascular repair significantly improved hypertension and renal function, and these improvements persisted during the follow-up period. The effective rate of endovascular repair for improving or curing hypertension was 85.7%. Follow-up imaging showed no sign of stent stenosis or occlusion in those patients who received endovascular repair. CONCLUSIONS: Endovascular repair is safe, feasible, and effective for SRAD treatment and should be a promising alternative to open revascularization.

Obesity and pancreatic cancer: An update of epidemiological evidence and molecular mechanisms.

Despite advances in therapy and achievements in translational research, pancreatic cancer (PC) remains an invariably fatal malignancy. Risk factors that affect the incidence of PC include diabetes, smoking, obesity, chronic pancreatitis, and diet. The growing worldwide obesity epidemic is associated with an increased risk of the most common cancers, including PC. Chronic inflammation, hormonal effects, circulating adipokines, and adipocyte-mediated inflammatory and immunosuppressive microenvironment are involved in the association of obesity with PC. Herein, we systematically review the epidemiology of PC and the biological mechanisms that may account for this association. Included in this review is a discussion of adipokine-mediated inflammation, lipid metabolism, and the interactions of adipocytes with cancer cells. We consider the influence of bariatric surgery on the risk of PC risk as well as potential molecular targets of therapy. Our review leads us to conclude that targeting adipose tissue to achieve weight loss may represent a new therapeutic strategy for preventing and treating PC.

Cystic pancreatic neuroendocrine tumors: A distinctive subgroup with indolent biological behavior? A systematic review and meta-analysis.

BACKGROUND/OBJECTIVES: The clinicopathological features and biological behaviors of cystic pancreatic neuroendocrine tumors (pNETs) are unclear and controversial. Here we performed a systematic review and meta-analysis to investigate the unique characteristics of cystic pNETs, to determine whether they represent a distinct clinical entity. METHODS: We selected comparative studies published since January 2000 that explore the differences between clinicopathological features of cystic and solid pNETs. Demographic information, pathological characteristics, and survival information were analyzed. RESULT: The 12 selected studies comprised 355 and 1530 patients diagnosed with cystic and solid pNETs, respectively. Compared with solid pNETs, cystic pNETs were less likely to be functional (odds ratio, OR = 0.31, 95% confidence interval (CI) 0.19-0.50, p < 0.00001), more likely to affect males (OR = 1.56, 95% CI 1.22-2.00, p = 0.0005), and significantly associated with multiple endocrine neoplasia type 1 (OR = 2.71). Cystic pNETs were more likely to present with G1 and G2 rather than G3 (OR = 1.66). Cystic pNETs were associated with less frequent distant organs and lymph node metastasis, microvascular invasion, perineural invasion, and a low Ki-67 index and mitotic count. There were no significant differences between 5- and 10-year overall survival. However, the 5-year disease-free survival (DFS) and 10-year DFS rate of patients with cystic pNETs was significantly higher compared with those with solid pNETs (94.6% vs 83.5%, OR = 3.00; 92.7% vs 63.6%, OR = 5.92, respectively). CONCLUSIONS: Cystic pNETs represent a distinct subgroup of pNETs that present with an indolent biological behavior, and patients experience better DFS. Observation and surveillance should be considered in some selected cases.

Diagnosis and Treatment of Aortic Saddle Embolism.

BACKGROUND: Acute aortic occlusion is a rare but life-threatening medical condition that can result from aortic saddle embolism, thrombosis of an atherosclerotic aorta, or aortic dissection. Herein are described the diagnostic and therapeutic characteristics for a series of patients with aortic saddle embolism. METHODS: A retrospective review of medical records was performed for patients receiving treatment for aortic saddle embolism at a university hospital in China between January 2001 and September 2017. Demographic, clinical, ancillary testing, treatment, and outcome data were collected and analyzed. RESULTS: Eighteen patients (10 women and 8 men) with a mean age of 53.8 years were included. The most commonly associated cardiac diseases were atrial fibrillation or atrial flutter (89%); rheumatic heart disease, valvular heart disease, or both (72%); and congestive heart failure (56%). Rest pain was present in all patients, and sensory or motor deficits were present in 12 patients (67%). Computed tomography (CT) angiography was performed for all patients. Seventeen patients (94%) presented with aortic embolism below the renal arteries. Fifteen patients (83%) underwent bilateral transfemoral embolectomy, and 3 patients (17%) received no intervention. Fasciotomy was performed for 9 patients in 14 limbs. The overall mortality rate was 33%, with a postprocedure mortality rate of 20%. Major morbidity occurred in 60% of patients. Six lower extremities were amputated in 4 patients, and acute renal failure developed in 4 patients. The incidence of postembolectomy internal iliac artery embolism was 58% (11 of 19 iliac arteries), and pelvic ischemia developed in 1 young patient. CONCLUSIONS: Aortic saddle embolism is uncommon but associated with high morbidity and mortality. CT angiography is recommended for diagnosis, and bilateral transfemoral embolectomy is the preferred treatment. Postembolectomy internal iliac artery embolism was common, and prevention of pelvic ischemia should be considered for young patients.

Bile acid profiles within the enterohepatic circulation in a diabetic rat model after bariatric surgeries.

Bile acids (BAs), which are synthesized in the liver and cycled in the enterohepatic circulation, have been recognized as signaling molecules by activating their receptors in the intestine and liver. Serum taurine-conjugated BAs have been shown to be elevated after bariatric surgeries although the postoperative BA profiles within the enterohepatic circulation have not been investigated. Clarification of these profiles could help explain the mechanisms by which bariatric surgery leads to BA profile alterations and subsequent metabolic effects. We performed duodenal-jejunal bypass (DJB), sleeve gastrectomy (SG), and sham procedures in an obese diabetic rat model induced by high-fat diet and streptozotocin. The weight loss and antidiabetic effects were evaluated postsurgery. BA profiles in the systemic serum and within the enterohepatic circulation were analyzed, together with the expression of related BA transporters and enzymes at week 12 after surgery. Compared with sham, SG induced sustained weight loss, and both DJB and SG significantly improved glucose tolerance and insulin sensitivity with enhanced glucagon-like peptide 1 secretion. Similar to changes in the serum, BAs, especially taurine-conjugated species, were also elevated in the enterohepatic circulation (bile and portal vein) after DJB and SG. In addition, the expression of key BA transporters and conjugational enzymes was elevated postoperatively, whereas the enzymes responsible for BA synthesis were decreased. In conclusion, DJB and SG elevated BA levels in the systemic serum and enterohepatic circulation, especially taurine-conjugated species, which likely indicates increased ileal reabsorption and hepatic conjugation rather than synthesis. NEW & NOTEWORTHY Bile acids (BAs) have been implicated as potential mediators of the weight-independent effects of bariatric surgery. For the first time, we discovered that duodenal-jejunal bypass and sleeve gastrectomy elevated BAs, particularly the taurine-conjugated species in the enterohepatic circulation, likely through the promotion of ileal reabsorption and hepatic conjugation rather than BA synthesis. These findings will improve our understanding of BA metabolism after bariatric surgery and their subsequent metabolic effects.

Heterotrimeric G Stimulatory Protein α Subunit Is Required for Intestinal Smooth Muscle Contraction in Mice.

BACKGROUND & AIMS: The α subunit of the heterotrimeric G stimulatory protein (Gsa), encoded by the guanine nucleotide binding protein, α-stimulating gene (Gnas, in mice), is expressed ubiquitously and mediates receptor-stimulated production of cyclic adenosine monophosphate and activation of the protein kinase A signaling pathway. We investigated the roles of Gsa in vivo in smooth muscle cells of mice. METHODS: We performed studies of mice with Cre recombinase-mediated disruption of Gnas in smooth muscle cells (GsaSMKO and SM22-CreERT2, induced in adult mice by tamoxifen). Intestinal tissues were collected for histologic, biochemical, molecular, cell biology, and physiology analyses. Intestinal function was assessed in mice using the whole-gut transit time test. We compared gene expression patterns of intestinal smooth muscle from mice with vs without disruption of Gnas. Biopsy specimens from ileum of patients with chronic intestinal pseudo-obstruction and age-matched control biopsies were analyzed by immunohistochemistry. RESULTS: Disruption of Gnas in smooth muscle of mice reduced intestinal motility and led to death within 4 weeks. Tamoxifen-induced disruption of Gnas in adult mice impaired contraction of intestinal smooth muscle and peristalsis. More than 80% of these died within 3 months of tamoxifen exposure, with features of intestinal pseudo-obstruction characterized by chronic intestinal dilation and dysmotility. Gsa deficiency reduced intestinal levels of cyclic adenosine monophosphate and transcriptional activity of the cyclic adenosine monophosphate response element binding protein 1 (CREB1); this resulted in decreased expression of the forkhead box F1 gene (Foxf1) and protein, and contractile proteins, such as myosin heavy chain 11; actin, α2, smooth muscle, aorta; calponin 1; and myosin light chain kinase. We found decreased levels of Gsa, FOXF1, CREB1, and phosphorylated CREB1 proteins in intestinal muscle layers of patients with chronic intestinal pseudo-obstruction, compared with tissues from controls. CONCLUSIONS: Gsa is required for intestinal smooth muscle contraction in mice, and its levels are reduced in ileum biopsies of patients with chronic intestinal pseudo-obstruction. Mice with disruption of Gnas might be used to study human chronic intestinal pseudo-obstruction.