Javier A. Cienfuegos

The Decrease in Plasma Ghrelin Concentrations following Bariatric Surgery Depends on the Functional Integrity of the Fundus

Background: Gastric bypass surgery, which involves the production of a reduced stomach pouch,has been shown to markedly suppress circulating ghrelin concentrations. Since bypassing the ghrelin-producing cell population may be relevant to the disruption of fundic-derived factors participating in food intake signaling, the effect of weight loss induced by either adjustable gastric banding (AGB), Roux-en-Y gastric bypass (RYGBP) or biliopancreatic diversion (BPD) was studied. Methods: 16 matched obese patients [35.0 + 2.4 years; initial body weight 124.8 ± 5.7 kg; body mass index (BMI) 47.1 ± 2.2 kg/m2] in whom similar weight loss had been achieved by either AGB (n=7), RYGBP (n=6) or BPD (n=3) were studied. Blood was obtained for biochemical and hormonal analyses. Body composition was assessed by air-displacement-plethysmography. Results: Comparable weight loss (AGB: 26.1 ± 5.1 kg; RYGBP: 32.1 ± 5.0; BPD: 31.7 ± 6.1; P=NS) and decrease in percentage body fat (AGB: 10.0 ± 1.5%; RYGBP: 14.2 ± 2.8; BPD: 10.3 ± 1.0; P=NS) induced by bariatric surgery exerted significantly different (P=0.004) effects on plasma ghrelin concentrations, depending on the surgical procedure applied (AGB: 480 ± 78 pg/ml; RYGBP: 117 ± 34; BPD: 406 ± 86). Without significant differences in BMI, body fat, glucose, triglycerides, cholesterol, insulin and leptin levels, patients who had undergone the RYGBP exhibited statistically significant diminished circulating fasting plasma ghrelin concentrations compared with the other two bariatric techniques which conserve direct contact of the fundus with ingested food (P=0.003 vs AGB and P=0.020 vs BPD). Conclusion: Fasting circulating ghrelin concentrations in patients undergoing diverse bariatric operations depend on the degree of dysfunctionality of the fundus.

Gene expression profile of omental adipose tissue in human obesity

The aim of the present study was to gain insight into the pathophysiology of obesity by comparing the pattern of gene expression of omental adipose tissue of obese and lean volunteers using DNA microarrays. Omental adipose tissue biopsies were obtained by laparoscopic surgery from six male patients (44.2±6.3 yr). RNA was extracted and pooled for the obese (BMI: 37.3±2.5 kg/m2) and lean (BMI: 23.4±0.8 kg/m2) groups. From the total number of genes analyzed (1,152 well‐characterized human genes), 41% were expressed at sufficient levels in human adipose tissue for detection in the microarray experiments, finding that 89 genes were up‐ regulated while 64 were down‐regulated at least twofold in the omental adipose tissue obtained from obese patients. We found a general tendency to blunt lipolysis inducer genes and a global down‐regulation of genes encoding growth factors. Moreover, an up‐regulation in the expression of several mitogen‐activated protein kinases (MAPKs) was observed. The down‐regulation of genes involved in lipolysis activation may be involved in the etiopathogenesis of obesity. In addition, down‐regulation of growth factors and the up‐regulation of MAPKs may indicate an attempt to restrain adipocyte proliferation and differentiation. Furthermore, obesity is accompanied by an altered expression in omental adipose tissue of genes involved not only in energy homeostasis but also in quite diverse biological functions, such as immune response. The genomic approach underlines the importance of adipose tissue beyond energy metabolism.

Fasting plasma Ghrelin concentrations 6 months after gastric bypass are not determined by weight loss or changes in insulinemia

Background: Ghrelin is a gastric peptide with potent orexigenic effects. Circulating ghrelin concentrations are increased in obese subjects, but increase after weight loss. However, in patients undergoing Roux-en-Y gastric bypass (RYGBP), a decrease in ghrelin levels has been reported. The effect of comparable weight loss induced by either adjustable gastric banding (AGB), RYGBP or conventional dietary treatment (Conv) on ghrelinemia was studied. Methods: 24 matched obese male patients in whom similar weight loss had been achieved by either AGB (n=8), RYGBP (n=8) or Conv (n=8) were studied before and 6 months after treatment start. The independence of ghrelin concentrations from body mass index (BMI) and weight loss was further analyzed in a group of patients with total gastrectomy (TtGx, n=6). Results: Comparable weight loss after 6 months exerted significantly different effects on plasma ghrelin concentrations, depending on the procedure applied (AGB: 424.6 ± 32.8 pg/ml; RYGBP: 131.4 ± 13.5; Conv: 457.3 ± 18.7; P<0.001). Without significant differences in body weight and BMI, patients who had undergone the RYGBP exhibited a statistically significant decrease in fasting ghrelin concentrations, while the other two procedures (AGB and Conv) showed a weight loss-induced increase in ghrelin levels. Despite significant differences in BMI between RYGBP and TtGx patients after 6 months (31.9 ± 2.2 vs 22.0 ± 0.7 kg/m2, respectively; P<0.05), both groups showed similar ghrelin concentrations. Conclusion: The reduction in circulating ghrelin concentrations in RYGBP patients after 6 months of surgery are not determined by an active weight loss or an improved insulin-sensitivity but rather depend on the surgically-induced bypass of the ghrelin-producing cell population of the fundus.

Role of the Extended Lymphadenectomy in Gastric Cancer Surgery: Experience in a Single Institution

Background: Although curative resection is the treatment of choice for gastric cancer, controversy exists about the adequate extent of lymph node dissection when resection is performed.Methods: We retrospectively assessed 85 patients who underwent a limited lymphadenectomy (D1) and 71 who had an extended lymph node dissection (D2) in a single institution between 1990 and 1998 (median follow-up, 37.3 months). Prognostic factors were assessed by Cox proportional hazard models adjusted for potential confounders.Results: We found no significant difference in the length of hospital stay (median, 12.1 and 13.1 days), overall morbidity (48.2% and 53.5%), or operative mortality (2.3% and 0%) between D1 and D2, respectively. Five-year survival in the D2 group was longer (50.6%) than in the D1 group (41.4%) for tumor stages (tumor-node-metastasis) >I. In multivariate analysis, tumor-node-metastasis stage (hazard ratio for stages >I vs. 0–I, 11.6), the ratio between invaded and removed lymph nodes, the presence of distant metastases, Laurén classification, and the extent of lymphadenectomy (hazard ratio for D1 vs. D2, 2.3; 95% confidence interval, 1.25–4.30) were the only significant prognostic factors.Conclusions: Our experience shows that extended (D2) lymph node dissection improves survival in patients with resected gastric cancer.

Involvement of leptin in the association between percentage of body fat and cardiovascular risk factors.

OBJECTIVES Recent epidemiologic studies have shown that obesity is associated with elevated blood concentrations of prothrombotic-proinflammatory factors and markers of endothelial dysfunction such as fibrinogen, C-reactive protein (CRP), von Willebrand factor (vWF), and homocysteine. We have assessed whether these markers are associated with percentage of body fat (BF), insulin sensitivity as well as with leptin concentrations. DESIGN AND METHODS Twenty-five men aged 49.6 +/- 12.7 yr (mean +/- SD) underwent whole-body air displacement plethysmography (Bod-Pod(R)) for estimating BF. Blood analyses for leptin and several other metabolic and cardiovascular markers were carried out. RESULTS Obese subjects had higher levels as compared to controls of BF (37.5 +/- 5.1 vs. 26.0 +/- 6.6, p < 0.01), fibrinogen (3.30 +/- 0.43 vs. 2.67 +/- 0.11, p < 0.01), vWF (136.4 +/- 50.4% vs. 81.6 +/- 12.6%, p < 0.05), and leptin (17.6 +/- 8.7 vs. 6.2 +/- 3.3, p < 0.01), lower concentrations of HDL-cholesterol (1.09 +/- 0.20 vs. 1.51 +/- 0.10, p < 0.001) and lower QUICKI (1/[log(Ins(0)) + log(Glu(0))]) (0.31 +/- 0.03 vs. 0.34 +/- 0.02, p < 0.05). No significant changes were observed in CRP (5.7 +/- 3.4 vs. 3.8 +/- 1.6, p = 0.327) and homocysteine (9.4 +/- 4.2 vs. 8.3 +/- 0.9, p = 0.749). A positive correlation was observed between BF and fibrinogen (r = 0.67, p = 0.0003). Plasma leptin concentrations were correlated with fibrinogen (r = 0.71, p = 0.0001) and CRP (r = 0.43, p = 0.044). After adjustment for BF leptin emerged as a significant predictor of fibrinogen (beta = 0.47, p = 0.023; R(2) = 0.59, p < 0.001). QUICKI was positively correlated with HDL-cholesterol (r = 0.59, p = 0.010) and negatively with fibrinogen (r = -0.53, p = 0.025), CRP (r = -0.52, p = 0.028) and vWF (r = -0.56, p = 0.013). CONCLUSIONS Increased BF and impaired insulin sensitivity are associated with increased concentrations of cardiovascular risk factors. Leptin seems to be involved in this elevation and emerges as a predictor of circulating fibrinogen concentrations.

Expression of caveolin‐1 in human adipose tissue is upregulated in obesity and obesity‐associated type 2 diabetes mellitus and related to inflammation

Objective  Caveolin‐1 (CAV‐1) plays important roles in many aspects of cellular biology, including vesicular transport, cholesterol homeostasis and signal transduction. The aim of the present study was to explore gene expression levels of CAV‐1 in human adipose tissue in obesity and obesity‐associated type 2 diabetes mellitus (T2DM) and to analyse its potential implication in the inflammatory state associated with obesity.

Association of increased Visfatin/PBEF/NAMPT circulating concentrations and gene expression levels in peripheral blood cells with lipid metabolism and fatty liver in human morbid obesity

BACKGROUND AND AIMS Nicotinamide phosphoribosyltransferase (NAMPT) is an adipokine with physiological effects on the control of glucose homeostasis as well as potentially involved in inflammation. The association of circulating NAMPT concentrations with obesity has not been clearly established. The aim of the present work was to evaluate the effect of obesity on circulating concentrations and gene expression levels of NAMPT in human peripheral blood cells (PBCs) as well as its involvement in inflammation, glucose and lipid metabolism. METHODS AND RESULTS Forty-four serum samples obtained from 14 lean and 30 obese volunteers were used to analyse the circulating concentrations of NAMPT. In addition, PBC, omental adipose tissue (OM) and liver biopsy samples obtained from a subgroup of subjects were used to determine transcript levels of NAMPT by Real-time PCR. Glucose and lipid profile as well as several inflammatory factors and hepatic enzymes were analysed. NAMPT circulating concentrations (P<0.01) and gene expression levels in PBC (P<0.05) were significantly increased in obese patients as compared to lean subjects. Total-cholesterol (P=0.016), HDL-cholesterol (P=0.036) and triglycerides (P=0.050) were significant and independent determinants of circulating concentrations of NAMPT (P<0.01). Moreover, a positive correlation (P<0.01) was found with the hepatic enzymes alanine aminotransferase, aspartate aminotransferase, and γ-glutamyltransferase after BMI adjustment. CONCLUSION Our work shows that NAMPT circulating concentrations and mRNA expression levels in PBC are increased in obese patients and that plasma NAMPT levels are related to inflammation, lipid metabolism and hepatic enzymes suggesting a potential involvement in fatty liver disease and in the obesity-associated inflammatory state.

Totally laparoscopic Roux-en-Y duct-to-mucosa pancreaticojejunostomy after middle pancreatectomy: a consecutive nine-case series at a single institution.

Objective:To present the results of a series of laparoscopic middle pancreatectomies with roux-en-Y duct-to-mucosa pancreaticojejunostomy. Summary of Background Data:Middle pancreatectomy makes it possible to preserve pancreatic parenchyma in the resection of lesions that traditionally have been treated by distal splenopancreatectomy or cephalic duodenopancreatectomy. The laparoscopic approach could minimize the invasiveness of the procedure and enhance the benefits of middle pancreatectomy. Methods:From March 2005 to October 2007, 9 consecutive patients with benign or low malignant potential lesions in the pancreatic neck or body underwent surgery. Laparoscopic middle pancreatectomy with a roux-en-Y duct-to-mucosa pancreaticojejunostomy was planned on all of them. In the first 2 patients, the pancreas was transected by endostapler; in the last 7, the staple line was reinforced with absorbable polymer membrane. Results:The intervention was concluded laparoscopically in every case except 1 (laparoscopic-assisted) in which pancreaticojejunostomy was performed by means of minilaparotomy. Mortality was 0% and perioperative morbidity was 33%, (fistula of the cephalic stump in the first 2 patients (22%)). The pancreaticojejunostomy fistula rate was 0%. The median postoperative hospital stay was 5 days (range, 3–41). In the last 7 patients, in which pancreas was transected with staple line reinforcement material there were no stump fistulas; morbidity decreased to 14% and the median hospital stay was 4 days (range, 3–30). Conclusions:Laparoscopic middle pancreatectomy is feasible and safe. Duct-to-mucosa pancreaticojejunostomy can be performed safely using this approach. The method of pancreatic transection seems to be decisive in the incidence of cephalic stump fistulas.

Prognosis of hepatocellular carcinoma in relation to treatment: A multivariate analysis of 178 patients from a single European institution

BACKGROUND Because the prognosis of patients with hepatocellular carcinoma is not fully understood, particularly regarding therapy, we have evaluated it in a series of patients with a homogeneous diagnostic and therapeutic work-up. METHODS From 1985 to 1996, 42 variables were recorded prospectively in 178 constructive patients who had a diagnosis of hepatocellular carcinoma. Treatment consisted of liver transplantation ( n = 22), partial hepatectomy (n = 11), arterial, chemoembolization ( n = 52), systemic or regional chemotherapy (n = 51), and other therapies (n = 5); 37 patients received no specific therapy. Statistical analysis was performed according to a Cox model. RESULTS There were no differences between the survival of patients receiving chemotherapy, other therapies, or no treatment (control group n = 93). survival rates a 1,3, and 5 years were 81%, 74%, and 74% for liver transplantation, 72%, 58%, and 58% for hepatectomy, 55%, 26%, and 13% for chemoembolization, and 13%, 3%, and 0% for the control group. Cirrhosis, systemic syndrome, bilobar involvement, Childs stage C disease, and treatment were independent predictors of survival. CONCLUSIONS This series shows that certain easily accessible parameters may help establish individual prognosis and stratify patients in clinical trials and indicates that chemoembolization, partial resection, and liver transplantation can prolong life expectancy of patients with hepatocellular carcinoma.

The obestatin receptor (GPR39) is expressed in human adipose tissue and is down-regulated in obesity-associated type 2 diabetes mellitus.

Objective  The G protein‐coupled receptor 39 (GPR39) has recently been identified as the receptor for obestatin, a peptidic hormone involved in energy homeostasis. However, the expression levels of this receptor in human adipose tissue in obesity and obesity‐associated type 2 diabetes mellitus (T2DM) remain unknown. Therefore, we evaluated the actual presence of GPR39 mRNA in human adipose tissue and whether GPR39 expression levels are altered in obesity and obesity‐associated T2DM.