Does bariatric surgery improve adipose tissue function?

Bariatric surgery is currently the most effective treatment for obesity. Not only do these types of surgeries produce significant weight loss but also they improve insulin sensitivity and whole body metabolic function. The aim of this review is to explore how altered physiology of adipose tissue may contribute to the potent metabolic effects of some of these procedures. This includes specific effects on various fat depots, the function of individual adipocytes and the interaction between adipose tissue and other key metabolic tissues. Besides a dramatic loss of fat mass, bariatric surgery shifts the distribution of fat from visceral to the subcutaneous compartment favoring metabolic improvement. The sensitivity towards lipolysis controlled by insulin and catecholamines is improved, adipokine secretion is altered and local adipose inflammation as well as systemic inflammatory markers decreases. Some of these changes have been shown to be weight loss independent, and novel hypothesis for these effects includes include changes in bile acid metabolism, gut microbiota and central regulation of metabolism. In conclusion bariatric surgery is capable of improving aspects of adipose tissue function and do so in some cases in ways that are not entirely explained by the potent effect of surgery. © 2016 World Obesity.

Recombinant vascular endothelial growth factor165 gene therapy improves anastomotic healing in an animal model of ischemic esophagogastrostomy.

Proper anastomotic healing is dependent upon many factors including adequate blood flow to healing tissue. The aim of this study was to investigate the impact of vascular endothelial growth factor (VEGF(165)) transfection on anastomotic healing in an ischemic gastrointestinal anastomosis model. Utilizing an established opossum model of esophagogastrectomy followed by esophageal-gastric anastomosis, the gastric fundus was transfected with recombinant human vascular endothelial growth factor via direct injection of a plasmid-based nonviral delivery system. Twenty-nine animals were divided into three groups: two concentrations of VEGF and a control group. Outcomes included VEGF mRNA transcript levels, neovascularization, tissue blood flow, and anastomotic bursting pressure. To determine whether local injection resulted in a systemic effect, distant tissues were evaluated for VEGF transcript levels. Successful gene transfection was demonstrated by quantitative polymerase chain reaction analysis of anastomotic tissue, with significantly higher VEGF mRNA expression in treated animals compared to controls. At the gastric side of the anastomosis, there was significantly increased neovascularization, blood flow, and bursting pressure in experimental animals compared to controls. There were no differences in outcome measures between low- and high-dose VEGF groups; however, the high-dose group demonstrated increased VEGF mRNA expression across the anastomosis. VEGF production was not increased at distant sites in treated animals. In this animal model, VEGF gene therapy increased VEGF transcription at a healing gastrointestinal anastomosis without systemic VEGF upregulation. This treatment led to improved healing and strength of the acutely ischemic anastomosis. These findings suggest that VEGF gene therapy has the potential to reduce anastomotic morbidity and improve surgical outcomes in a wide array of patients.

Hypoxia-induced inflammatory cytokine secretion in human adipose tissue stromovascular cells.

AIMS: Hypoxia has been implicated as a cause of adipose tissue inflammation in obesity, although the inflammatory response of human adipose tissue to hypoxia is not well understood. The goal of this study was to define in vitro inflammatory responses of human adipose tissue to hypoxia and identify molecular mechanisms of hypoxia-induced inflammation. METHODS: The inflammatory milieu and responses of visceral (VAT) and subcutaneous (SAT) adipose tissue explants and purified stromovascular cells (SVFs) from obese and lean humans were studied in an in vitro hypoxic culture system using quantitative real-time PCR, ELISA, western blotting, immunofluorescence microscopy, flow cytometry and immunohistochemistry. RESULTS: Human adipose tissue in obesity demonstrates an increased leucocyte infiltrate that is greater in VAT than SAT and involves macrophages, T cells and natural killer (NK) cells. Hypoxic culture regulates inflammatory cytokine secretion and transcription of metabolic stress response genes in human adipose tissue SVF. Adipocyte diameter is increased and adipose tissue capillary density is decreased in obese participants. Inhibition of c-Jun terminal kinase (JNK) or p38 significantly attenuates hypoxia-induced SVF inflammatory responses. Hypoxia induces phosphorylation of p38 in adipose tissue. CONCLUSIONS: Human adipose tissue in obesity is characterised by a depot-specific inflammatory cell infiltrate that involves not only macrophages, but also T cells and NK cells. Hypoxia induces inflammatory cytokine secretion by human adipose tissue SVF, the primary source of which is adipose tissue macrophages. These data implicate p38 in the regulation of hypoxia-induced inflammation and suggest that alterations in adipocyte diameter and adipose tissue capillary density may be potential underlying causes of adipose tissue hypoxia.

Trends in the management of esophageal carcinoma based on provider volume: treatment practices of 618 esophageal surgeons.

Controversy exists regarding optimal treatment practices for esophageal cancer. Esophagectomy has received focus as one of the index procedures for both hospital and surgical quality despite a relative paucity of controlled trials to define best practices. A survey was created to determine the degree of heterogeneity in the treatment of esophageal cancer among a diverse group of surgeons and to use high-volume (HV) (>/=15 cases/year) and low-volume (LV) (<15 cases/year) designations to discern specific differences in the management of esophageal cancer from the surgeon's perspective. Based on society rosters, surgeons (n = 4000) in the USA and 15 countries were contacted via mail and queried regarding their treatment practices for esophageal cancer using a 50-item survey instrument addressing demographics, utilization of neoadjuvant chemoradiotherapy, and choice of surgical approach for esophageal resection and palliation. There were 618 esophageal surgeons among respondents (n = 1447), of which 77 (12.5%) were considered HV. The majority of HV surgeons (87%) practiced in an academic setting and had cardiothoracic training, while most LV surgeons were general surgeons in private practice (52.3%). Both HV and LV surgeons favored the hand-sewn cervical anastomosis and the stomach conduit. Minimally invasive esophagectomy is performed more frequently by HV surgeons when compared with LV surgeons (P = 0.045). Most HV surgeons use neoadjuvant therapy for patients with nodal involvement, while LV surgeons are more likely to leave the decision to the oncologist. With a few notable exceptions, substantial heterogeneity exists among surgeons' management strategies for esophageal cancer, particularly when grouped and analyzed by case volume. These results highlight the need for controlled trials to determine best practices in the treatment of this complex patient population.

Depot-specific differences in inflammatory mediators and a role for NK cells and IFN-gamma in inflammation in human adipose tissue.

BACKGROUND: Adipose tissue is a primary in vivo site of inflammation in obesity. Excess visceral adipose tissue (VAT), when compared to subcutaneous adipose tissue (SAT), imparts an increased risk of obesity-related comorbidities and mortality, and exhibits differences in inflammation. Defining depot-specific differences in inflammatory function may reveal underlying mechanisms of adipose-tissue-based inflammation. METHODS: Stromovascular cell fractions (SVFs) from VAT and SAT from obese humans undergoing bariatric surgery were studied in an in vitro culture system with transcriptional profiling, flow cytometric phenotyping, enzyme-linked immunosorbent assay and intracellular cytokine staining. RESULTS: Transcriptional profiling of SVF revealed differences in inflammatory transcript levels in VAT relative to SAT, including elevated interferon-gamma (IFN-gamma) transcript levels. VAT demonstrated a broad leukocytosis relative to SAT that included macrophages, T cells and natural killer (NK) cells. IFN-gamma induced a proinflammatory cytokine expression pattern in SVF and adipose tissue macrophages (ATM). NK cells, which constitutively expressed IFN-gamma, were present at higher frequency in VAT relative to SAT. Both T and NK cells from SVF expressed IFN-gamma on activation, which was associated with tumor necrosis factor-alpha expression in macrophages. CONCLUSION: These data suggest involvement of NK cells and IFN-gamma in regulating ATM phenotype and function in human obesity and a potential mechanism for the adverse physiologic effects of VAT.

Psychiatric illness delays diagnosis of esophageal cancer.

Evidence suggests that patients with psychiatric illnesses may be more likely to experience a delay in diagnosis of coexisting cancer. The association between psychiatric illness and timely diagnosis and survival in patients with esophageal cancer has not been studied. The specific aim of this retrospective cohort study was to determine the impact of coexisting psychiatric illness on time to diagnosis, disease stage and survival in patients with esophageal cancer. All patients with a diagnosis of esophageal cancer between 1989 and 2003 at the Portland Veteran's Administration hospital were identified by ICD-9 code. One hundred and sixty patients were identified: 52 patients had one or more DSM-IV diagnoses, and 108 patients had no DSM-IV diagnosis. Electronic charts were reviewed beginning from the first recorded encounter for all patients and clinical and demographic data were collected. The association between psychiatric illness and time to diagnosis of esophageal cancer and survival was studied using Cox proportional hazard models. Groups were similar in age, ethnicity, body mass index, and history of tobacco and alcohol use. Psychiatric illness was associated with delayed diagnosis (median time from alarm symptoms to diagnosis 90 days vs. 35 days in patients with and without psychiatric illness, respectively, P < 0.001) and the presence of advanced disease at the time of diagnosis (37% vs. 18% of patients with and without psychiatric illness, respectively, P= 0.009). In multivariate analysis, psychiatric illness and depression were independent predictors for delayed diagnosis (hazard ratios 0.605 and 0.622, respectively, hazard ratio < 1 indicating longer time to diagnosis). Dementia was an independent risk factor for worse survival (hazard ratio 2.984). Finally, psychiatric illness was associated with a decreased likelihood of receiving surgical therapy. Psychiatric illness is a risk factor for delayed diagnosis, a diagnosis of advanced cancer, and a lower likelihood of receiving surgical therapy in patients with esophageal cancer. Dementia is associated with worse survival in these patients. These findings emphasize the importance of prompt evaluation of foregut symptoms in patients with psychiatric illness.

Esophageal motility disorders after gastric banding.

The long-term effects of gastric banding on esophageal function are not well described. This report describes a 28-year-old woman who developed signs and symptoms of abnormal esophageal motility and lower esophageal sphincter hypotension after gastric banding for morbid obesity. The current literature addressing the effects of gastric banding on esophageal function in light of this case report is discussed.

Serum leptin levels, hepatic leptin receptor transcription, and clinical predictors of non-alcoholic steatohepatitis in obese bariatric surgery patients.

BACKGROUND: Non-alcoholic steatohepatitis (NASH) is a major cause of liver disease in morbidly obese patients. Clinical predictors of NASH remain elusive, as do molecular mechanisms of pathogenesis. METHODS: A series of 35 morbidly obese patients undergoing bariatric surgery had a liver biopsy performed for standard histologic analysis. In addition, RNA was obtained from liver tissue and analyzed for leptin receptor gene expression. Regression analysis was used to correlate clinical variables, including serum leptin levels and hepatic leptin receptor gene expression, with the presence of histologically confirmed NASH. RESULTS: Of the 35 subjects enrolled, 29% had steatosis only, 60% had NASH, and 11% had normal liver histology. Among the clinical variables studied, only diabetes mellitus was an independent predictor of NASH. There was a trend toward lower levels of mRNA encoding the long form of the leptin receptor in hepatic tissue from patients with NASH compared to those with steatosis only. CONCLUSIONS: Diabetes mellitus is associated with an increased risk of NASH in obese patients. Downregulation of hepatic leptin receptor may play a role in the pathogenesis of NASH.

Alterations in peripheral blood lymphocyte cytokine expression in obesity.

Obesity is characterized by alterations in immune and inflammatory function. In order to evaluate the potential role of cytokine expression by peripheral blood mononuclear cells (PBMC) in obesity-associated inflammation, we studied serum protein levels and mRNA levels in PBMC of interleukin (IL)-6, IL-1beta, tumour necrosis factor (TNF)-alpha and IL-1Ra in nine lean and 10 obese subjects. Serum IL-1beta was undetectable, IL-1Ra serum levels were elevated, serum levels of TNF-alpha were decreased and serum levels of IL-6 were similar in obese subjects compared to lean subjects, while transcript levels of IL-6, IL-1beta and TNF-alpha, but not IL-1Ra, were decreased in PBMC from obese subjects. PBMC from obese subjects did, however, up-regulate cytokine expression in response to leptin. Thus, obesity-associated changes in IL-1Ra serum levels and IL-6 mRNA levels were not correlated with changes in cognate mRNA and serum levels, respectively, while TNF-alpha serum levels and PBMC mRNA levels were both decreased in obese patients. While immune alterations in obesity are manifest in peripheral blood lymphocytes, the general lack of correlation between altered serum levels and altered PBMC gene expression suggests that PBMC may not be the source of aberrant serum cytokine levels in obesity.

Transthoracic hepatic radiofrequency ablation.

BACKGROUND: Radiofrequency ablation (RFA) is an alternative for the treatment of unresectable hepatic tumors. Tumors beneath the diaphragmatic dome may be difficult to access by laparoscopy. In these cases, a transthoracic transdiaphragmatic approach for delivering RFA can be used. METHODS: Three patients with hepatic metastatic disease were treated using a transthoracic transdiaphragmatic approach to deliver RFA therapy for tumors in liver segments 7 and 8. The patients underwent thoracoscopy. The tumors were identified using transdiaphragmatic ultrasound, and transthoracic transdiaphragmatic RFA (TTRFA) was performed. RESULTS: In three patients, TTRFA was successfully used to ablate five lesions. There were no perioperative complications, blood loss was minimal,and postoperative hospital stays ranged from 2 to 8 days. There were no recurrences during a follow-up period of 4 to 20 months. CONCLUSIONS: TTRFA is a viable alternative for hepatic tumors located beneath the dome of the diaphragm that are difficult to access by laparoscopy.

Laparoscopic radiofrequency ablation and hepatic artery infusion pump placement in the evolving treatment of colorectal hepatic metastases.

BACKGROUND: Laparoscopic radiofrequency ablation (LRFA) and laparoscopic hepatic artery infusion pump (LHAIP) placement are new treatment options for patients with colorectal liver metastases. This study investigates the selection criteria, safety, efficacy, and preliminary outcomes of patients treated with LRFA and LHAIP placement. METHODS: Fourty five patients with colorectal metastases confined to the liver, 37 of whom had failed systemic chemotherapy, were treated with LRFA and/or LHAIP between September 1996 and December 2001. Treatment selection was individualized, based on each patient's general health, liver function, and tumor size, number, location, and distribution. RESULTS: Twenty patients (44%) had LRFA alone, 10 (22%) had LHAIP placement alone, and 15 (33%) patients had combined LRFA and LHAIP therapy. The LRFA group had a significantly shorter mean operative time and blood loss (p <0.05), but hospital stays were similar when compared to patients receiving LRFA + LHAIP or LHAIP alone. Tumor characteristics were worse in both LHAIP groups, with a higher incidence of tumors >or=4 cm, major vascular involvement, diffuse tumor pattern, bilobar distribution, and involvement of more than three segments. During a mean follow-up period of 11.5 +/- 7.8 months (range, 1-38), the actuarial survival was 70%, 67%, and 50% for LRFA, LRFA + LHAIP, and LHAIP, respectively. LHAIP only patients had the shortest estimated mean survival time of the three groups by Kaplan-Meier survival curves (p = 0.001). CONCLUSION: LRFA and/or LHAIP placement are safe and feasible treatment options for the treatment of colorectal hepatic metastases. The choice of treatment for patients should be based primarily on tumor characteristics. Long-term studies, which will elucidate the role of these evolving treatments, are now under way.

A non-cleavable mutant of Fas ligand does not prevent neutrophilic destruction of islet transplants.

BACKGROUND: Fas ligand (FasL) mediates apoptosis of susceptible Fas-expressing lymphocytes, and may contribute to the maintenance of peripheral tolerance. In transplantation models, however, artificial expression of FasL on cellular as well as islet transplants results in accelerated rejection by neutrophils. The mechanism of the neutrophilic response to FasL expression is unknown. FasL, like other members of the tumor necrosis factor family, is cleaved to a soluble form by metalloproteases. We tested the hypothesis that soluble FasL (sFasL) was responsible for neutrophil migration by creating a non-cleavable mutant of FasL. METHODS: Three mutants of FasL with serial deletions in the putative proteolytic cleavage site of human FasL were made using inverse polymerase chain reaction. The relative fractions of sFasL and membrane-bound FasL were assessed by Western blot and immunoprecipitation, as well as by cytotoxicity assay using Fas-expressing target cells. The fully non-cleavable mutant was transduced into murine islets as well as myoblasts and tumor cell lines, and tested in a murine transplantation model. RESULTS: Serial deletions in the putative metalloprotease site of FasL resulted in a fully non-cleavable mutant of FasL (ncFasL). Expression of ncFasL in tumor lines induced higher levels of apoptosis in Fas bearing targets than wild-type FasL. Transplantation of ncFasL-expressing islets under the kidney capsule of allogenic mice resulted in accelerated rejection identical to that seen with wild-type Fas ligand-expressing islets. Myoblasts and tumor cell lines expressing ncFasL also induced neutrophil infiltration. CONCLUSIONS: Membrane-bound Fas ligand is fully capable of inducing a neutrophilic response to transplants, suggesting an activation by Fas ligand of neutrophil chemotactic factors.

A dendritic cell line genetically modified to express CTLA4-IG as a means to prolong islet allograft survival.

BACKGROUND: Dendritic cells are potent antigen-presenting cells that bind allogeneic T cells. They are thus candidates for targeting immunoregulatory molecules to the alloreactive T cell compartment and suppressing the alloimmune response. METHOD: A dendritic cell line derived from the BALB/c mouse (H2d) was genetically modified to express the immunoregulatory molecule CTLA4-Ig. The ability of these dendritic cell transfectants to downregulate the alloimmune response was tested in an islet transplant model. Allogeneic C57Bl/6 (H2b) mice were rendered diabetic with streptozocin, and they received BALB/c islet (H2d) transplants. Mice were administered 25 million untransfected or CTLA4-Ig-transfected D2SC/1 cells i.v. on the day of islet transplantation and 6 days later[fnc]. RESULT: Mice treated with CTLA4-Ig-transfected D2SC/1 cells demonstrated prolonged allograft survival (mean = 20 days, median = 17 days, SD = 9.39) compared with mice treated with untransfected D2SC/1 cells (mean = 12 days, median = 11 days, SD=2.74) or untreated control mice (mean = 11 days, median = 11 days SD = 1.41). Third party allograft survival was not prolonged in mice receiving similar treatment. CONCLUSIONS: These results demonstrate that a genetically modified dendritic cell line can suppress the alloimmune response and prolong islet allograft survival in an allospecific manner. The findings also suggest that genetically modified dendritic cells may be useful in targeting alloreactive T cells and prolonging allograft survival.

Flow cytometry crossmatching as a predictor of acute rejection in sensitized recipients of cadaveric renal transplants.

Flow cytometry crossmatching (FCXM) was developed as a more sensitive assay than the standard complement-dependent cytotoxicity crossmatch (CDCXM) for the detection of anti-donor antibodies, that mediate hyperacute rejection and graft loss in the early post-transplant period in renal transplant recipients. The role of FCXM in predicting long-term clinical outcome in renal allograft recipients is unclear. This study examines the role of FCXM in predicting long-term clinical outcome in highly sensitized recipients of cadaveric renal transplants. All patients (n = 100) with peak panel reactive antibody (PRA) levels > 30%, who received cadaveric renal transplants between 1/1/'90 and 12/31/'95 at our institution, were divided into FCXM + and FCXM - groups. The incidence of acute rejection was determined for each group during the first yr after transplant. Graft survival rates at 1, 2, and 3 yr, and creatinine levels were also compared between groups. FCXM + patients experienced a higher incidence of acute rejection during the first yr after transplant (69 vs. 45%), and a higher percentage of FCXM + patients had more than one episode of acute rejection during the first yr after transplant (34 vs. 8%) when compared to FCXM - patients. There was no statistically significant difference in 1-, 2-, or 3-yr graft survival between FCXM + and FCXM - patients (76 vs. 83, 62 vs. 80, 62 vs. 72%, respectively). These results suggest that sensitized FCXM + cadaveric renal transplant recipients have a higher incidence of acute rejection episodes in the first yr after transplant. Given the association of multiple rejection episodes with poor long-term allograft survival, FCXM may be a useful predictor of long-term clinical outcome in this sub-group of renal transplant recipients.

Pancreas divisum and stenosis of the major and minor papillae in an 8-year-old girl: treatment by dual sphincteroplasty.

Pancreas divisum is the most common congenital anomaly of the pancreas. Its relationship to the development of pancreatitis is controversial. The authors report on an 8-year-old girl who presented with recurrent bouts of acute pancreatitis and multiple failed attempts at endoscopic retrograde cholangiopancreatography (ERCP) who was referred for surgical exploration. She was found to have marked stenoses of both major and minor papillae and an intraoperative pancreaticogram consistent with pancreas divisum. She underwent sphincteroplasty of both major and minor papillae and remains symptom-free after 22 months. It is believed that in a patient with pancreatitis and pancreas divisum, or in a patient with pancreatitis and multiple failed attempts at ERCP, transduodenal exploration and intraoperative pancreaticogram are appropriate next steps in management. If pancreas divisum in association with minor papilla stenosis is found, sphincteroplasty is appropriate therapy. If major papilla stenosis is also present, we recommend sphincteroplasty of both the major and minor papillae.

A potential transcriptional activation element in the p53 protein.

The human p53 gene codes for a 393 amino acid nuclear phosphoprotein. p53 is most commonly described as a tumor suppressor, or anti-oncogene, although its role in vivo remains unclear. We report that GAL4-p53 fusion protein can activate transcription of a CAT reporter gene downstream of a GAL4-DNA binding site. We tested both the amino terminal 160 amino acids and the carboxyl terminal 233 amino acids of the p53 protein and found that the transcriptional activating (TA) region was restricted to the amino terminal fragment. These results imply that p53 may be a transcriptional activating factor (TAF); furthermore, these data lend support to the hypothesis of p53 as a positive regulator of transcription which might mediate its tumor suppressor role by inducing expression of a set of genes with a negative effect on cellular growth.