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Obesity is associated with metabolic disorders such as insulin resistance and type 2 diabetes mellitus (T2DM), further increasing an already heightened cardiovascular risk. Here, amongst obese class III bariatric surgery patients, we have investigated the effect of T2DM in serum and in two, same patient, adipose tissue (AT) depots through proteomic profile expression analyses. Serum and AT samples from subcutaneous (SAT) and visceral (VAT) fat were collected during bariatric surgery. Bead-based targeted multiplex assay systems were used to simultaneously detect and quantify multiple targets in serum samples (targeted proteomics) and analyze changes in adipokine serum composition. AT samples were assessed through an untargeted proteomics approach. Through a systems biology analysis of the proteomic data, information on the affected biological pathways was acquired. In obese class III individuals, the presence of T2DM induced a significantly higher systemic release of ghrelin, GLP-1, glucagon, MMP3, BAFF, chitinase 3-like 1, TNF-R1 and TNF-R2, and a lower systemic release of IL-8. SAT and VAT proteomes belonging to the same patient showed significant differences in local protein content. While the proteins upregulated in VAT were indicative of metabolic dysregulation, SAT protein upregulation suggested adequate endocrine regulation. The presence of T2DM significantly affected VAT protein composition through the upregulation of dysregulating metabolic pathways, but SAT protein composition was not significantly modified. Our results show that T2DM induces metabolic dysregulation in obese individuals with changes in systemic marker levels and impairment of proteostasis in VAT but not in SAT. more...

Cellular responses to stress generally lead to the activation of the endoplasmic reticulum-associated protein degradation (ERAD) pathway. Several lines of study support that ERAD may be playing a proviral role during flaviviral infection. A key host factor in ERAD is the valosin-containing protein (VCP), an ATPase which ushers ubiquitin-tagged proteins to degradation by the proteasome. VCP exhibits different proviral activities, such as engaging in the biogenesis of viral replication organelles and facilitating flavivirus genome uncoating after the viral particle entry. To investigate the possible antiviral value of drugs targeting VCP, we tested two inhibitors: eeyarestatin I (EEY) and xanthohumol (XAN). Both compounds were highly effective in suppressing Zika virus (ZIKV) and Usutu virus (USUV) replication during infection in cell culture. Further analysis revealed an unexpected virucidal activity for EEY, but not for XAN. Preincubation of ZIKV or USUV with EEY before inoculation to cells resulted in significant decreases in infectivity in a dose- and time-dependent manner. Viral genomes in samples previously treated with EEY were more sensitive to propidium monoazide, an intercalating agent, with 10- to 100-fold decreases observed in viral RNA levels, supporting that EEY affects viral particle integrity. Altogether, these results support that EEY is a strong virucide against two unrelated flaviviruses, encouraging further studies to investigate its potential use as a broad-acting drug or the development of improved derivatives in the treatment of flaviviral infection. more...

Background: Obesity has increased over the last years and it is one of the most common cardiovascular risk factors. In addition obesity is associated with the development of other metabolic disorders such as insulin resistance and type-2 diabetes mellitus (T2DM). Here, we have investigated two adipose tissue depots (AT) proteome and secreted serum proteins in obese patients to understand fat tissue characteristics in metabolic syndrome and T2DM.Methods: We used an untargeted proteomic approach to compare white AT of subcutaneous (SAT) and visceral (VAT) depots in type 3 obese patients. In silico analysis and bioinformatics were applied to proteomic data to gain systems biology information. By bead-based targeted multiplex assay system, we simultaneously detected and quantified multiple targets in qualified complex samples and analyzed the changes produced in the adipokine serum composition due to obesity and T2DM.Results: Protein composition in SAT and VAT showed significant differences. There was upregulation of proteins related with the endocrine regulation system in SAT, whereas proteins upregulated in VAT were related to metabolic disorders. VAT protein composition was more sensitive to the presence of diabetes than SAT. A pro-inflammatory state, caused by the secretion of cytokines and related adypokines, was observed in the serum protein composition of both obese and diabetic patients.Conclusions: Our results show a synergic alteration in the metabolic and inflammatory state in both VAT and serum due to the presence of diabetes, whereas changes in SAT were related with endocrine regulation. more...

BACKGROUND Alanine aminotransferase (ALT) is a marker of nonalcoholic fatty liver disease (NAFLD) and predicts type 2 diabetes mellitus (DM2) as well as coronary events independently of traditional risk factors and the features of the metabolic syndrome. The extent to which interventricular septum thickness (IVS) and left ventricular mass (LVM) are associated with ALT levels in cohorts of individuals with body weights ranging from overweight to morbid obesity and NAFLD remains still unknown. MATERIALS AND METHODS This was a cross-sectional pilot study involving 151 young White participants with liver ultrasound-proven NAFLD. Standard echocardiograms were used to define LVM, IVS, and left ventricle diastolic function [mitral inflow velocity pattern (E/A ratio) and mitral annulus velocity by tissue Doppler imaging (Em/Am ratio)]. Participants were classified according to ALT quartiles: p25, p50, p75, and p100. RESULTS The study included 36 men and 115 women with an age of 38.4 ± 0.7 years and BMI of 43.9 ± 0.6 kg/m2. p100 participants disclosed significantly higher homeostasis model assessment (P=0.003), DM2 (P=0.002), and hypertension (P=0.01) prevalence, whereas LVM, IVS, E/A, and Em/Am ratios were significantly higher in this group when compared with their p25 peers (P more...

It has been demonstrated that the adi- pose tissue, a highly functional metabolic tissue, is a reservoir of mesenchymal stem cells. The potential use of adipose-derived stem cells (ADSCs) from white adipose tissue (WAT) for organ repair and regenera- tion has been considered because of their obvious benefits in terms of accessibility and quantity of avail- able sample. However, the functional capability of ADSCs from subjects with different adiposity has not been investigated. It has been our hypothesis that ADSCs from adipose tissue of patients with metabolic syndrome and high adiposity may be functionally im- paired. We report that subcutaneous WAT stromal vascular fraction (SVF) from nonobese individuals had a significantly higher number of CD90 cells than SVF from obese patients. The isolated ADSCs from WAT of obese patients had reduced differentiation potential and were less proangiogenic. Therefore, ADSCs in adipose tissue of obese patients have lower capacity for spontaneous or therapeutic repair than ADSCs from nonobese metabolically normal individuals.—Onate, B., Vilahur, G., Ferrer-Lorente, R., Ybarra, J., Diez- Caballero, A., Ballesta-Lopez, C., Moscatiello, F., Her- rero, J., Badimon, L. The subcutaneous adipose tissue reservoir of functionally active stem cells is reduced in obese patients. FASEB J. 26, 000 - 000 (2012). www. fasebj.org more...

Laparoscopic Roux-en-Y gastric bypass (LRYGB) is the most frequent technique performed in bariatric surgery. Gastrojejunal anastomotic stricture is one of the most common postoperative complications. The aims of this study were to evaluate the efficacy and safety of endoscopic balloon dilation in the treatment of the gastrojejunal anastomotic strictures after LRYGB and to look for predicting factors that would indicate the need of repeated dilations. We included all patients with morbid obesity who underwent a LRYGB at our institution between January 2002 and July 2007. All patients who developed symptoms compatible with stricture of the gastrojejunostomy were referred to upper gastrointestinal endoscopy and underwent endoscopic balloon dilation. One hundred and five out of the 1,330 patients (7.8%) developed an anastomotic stricture. The mean time to diagnosis was 3 months after the surgery. The mean diameter of the stricture was 5 mm. Sixty out of the 105 patients required only one dilation (57%), 29 required two dilations (27,6%), 13 required three dilations, and 3 patients underwent a fourth dilation. Clinical success was achieved in 100% of the cases, with an average of 1.6 dilations. The statistical analysis showed that only the time from surgery to stricture formation (p = 0.007) and the diameter achieved at the first dilation (p = 0.015) had statistical significance as predictors of the need of one or more dilations. Endoscopic balloon dilation is a safe and effective method. Most of the patients are successfully managed with one or two dilations. The longer time from surgery to the appearance of symptoms ant the largest diameter achieved at the first dilation are the only predicting factors of success with only one dilation. more...

It is well known that obesity is a risk factor for severe cardiovascular complications, such as coronary heart disease, heart failure, stroke, venous thromboembolic disease, and atrial fibrillation. Left ventricle (LV) and left atrium (LA) enlargement is a characteristic feature of these patients with the consequent cardiovascular risk. Factors other than hemodynamic may influence LA remodeling. The aim of the study is to evaluate the relationship between adiponectin and LA size in uncomplicated obese patients. Seventy-four asymptomatic obese patients and an age- and sex-matched control group (N = 70) were recruited. A detailed clinical, echocardiographic, and analytical study was performed. Insulin resistance was assessed using the homeostasis model assessment for insulin resistance (HOMA-IR) method. Insulin sensitivity was assessed measuring serum total adiponectin concentrations. Adiponectin levels were lower in the obese group (P < 0.001) and particularly so in those obese participants with enlarged LA (32%; P < 0.0005). LA sizes were higher in the obese group (P < 0.0005). Adiponectin displayed significant correlations with body mass index, glucose, insulin, high-density lipoprotein cholesterol, and triglyceride concentrations as well as HOMA-IR (P < 0.001 for all). Adiponectin displayed significant correlations with LV mass and LA size, diastolic and systolic cardiac volumes and diameters, and cardiac output (P < 0.001 for all). Adiponectin correlations with LA size (r = -0.429; P < 0.001) persisted after adjustment for HOMA-IR, age, sex, and LV mass. A novel inverse relationship between adiponectin and LA size independent of age, sex, insulin resistance, and LV mass appears in our series. Adiponectin could be a link between adipose tissue and the heart, having an influence on cardiac remodeling. more...

Anastomotic leaks after bariatric surgery carry high morbidity and mortality. We aimed to describe our experience of the diagnosis and management of gastrointestinal anastomotic leaks in patients undergoing laparoscopic gastric bypass in a single institution.Of 1,200 patients who underwent laparoscopic Roux-en-Y gastric bypass with manual gastrojejunal anastomosis for morbid obesity from January 2002 to January 2007, we retrospectively analyzed 59 patients with anastomotic leak. The location of the leak, day of diagnosis, diagnostic methods, clinical manifestations, treatment modalities, associated complications, and length of hospital stay were analyzed.Leaks were located as follows: 67.8% in the gastrojejunostomy, 10.2% in the gastric pouch, 3.4% in the excluded stomach, 5.1% in the jejunojejunal anastomosis, 3.4% in the gastrojejunostomy plus pouch, 3.4% in the pouch plus excluded stomach, and 6.8% in undetermined sites. Routine upper gastrointestinal series revealed contrast extravasation in nine patients (15.3%). Leaks were asymptomatic at diagnosis in 29 patients (49.2%). Surgical reintervention was carried out in 23 patients, and conservative treatment was provided in the remaining 36. Transfer to the intensive care unit was required in 11 patients, with five deaths (0.4%).In our experience, most anastomotic leaks can be managed with conservative measures alone. In many patients, abdominal drains are effective in the management of leaks, obviating the need for reintervention. Nasoenteral nutrition was effective in the non-operative management of gastrojejunal leaks in patients without signs of systemic toxicity. more...

Objective: To assess the relationship between insulin resistance (IR) and left ventricular diastolic dysfunction (LVDD) in asymptomatic patients with morbid obesity (MO). Methods: The study cohort consisted of 231 patients (165 women and 66 men) with MO (mean body mass index [BMI] of 46.0 kg/m2) and a control group of 93 ageand sex-matched apparently healthy control subjects (56 women and 37 men; mean BMI of 24.1 kg/m2). Tissue Doppler imaging echocardiography was used to provide measurements of ejection fraction, LVDD (peak early tissue Doppler velocity/peak late tissue Doppler velocity or Em/Am ratio), left ventricular mass (LVM), and left ventricular hypertrophy (LVH). Adiponectin levels, the homeostasis model assessment index, and the ratio of triglycerides to high-density lipoprotein cholesterol (TG/HDL) were used as surrogate markers of IR. Results: The ejection fraction was normal and similar in the patient and control groups. LVDD (Em/Am ratio more...

Background: Laparoscopic Roux-en-Y gastric bypass (LRYGBP) is a commonly performed bariatric surgical procedure for the treatment of morbid obesity (MO). Obesity-related co-morbidities reduce the quality and expectancy of life. We assessed gastrointestinal quality of life in patients following LRYGBP. Methods: The Gastrointestinal Quality of Life Index (GIQLI test) was used in this study. A higher score correlates with better quality of life. The GIQLI test was administered to 3 non-selected groups: 100 morbidly obese patients (MO group), 100 patients who had undergone LRYGBP (LRYGBP group); and a control group of 100 individuals (CO group). The CO group was composed of healthy individuals with a BMI more...

Background The adipose tissue is an endocrine regulator and a risk factor for atherosclerosis and cardiovascular disease when by excessive accumulation induces obesity. Although the adipose tissue is also a reservoir for stem cells (ASC) their function and “stemcellness” has been questioned. Our aim was to investigate the mechanisms by which obesity affects subcutaneous white adipose tissue (WAT) stem cells. Results Transcriptomics, in silico analysis, real-time polymerase chain reaction (PCR) and western blots were performed on isolated stem cells from subcutaneous abdominal WAT of morbidly obese patients (ASCmo) and of non-obese individuals (ASCn). ASCmo and ASCn gene expression clustered separately from each other. ASCmo showed downregulation of “stemness” genes and upregulation of adipogenic and inflammatory genes with respect to ASCn. Moreover, the application of bioinformatics and Ingenuity Pathway Analysis (IPA) showed that the transcription factor Smad3 was tentatively affected in obese ASCmo. Validation of this target confirmed a significantly reduced Smad3 nuclear translocation in the isolated ASCmo. Conclusions The transcriptomic profile of the stem cells reservoir in obese subcutaneous WAT is highly modified with significant changes in genes regulating stemcellness, lineage commitment and inflammation. In addition to body mass index, cardiovascular risk factor clustering further affect the ASC transcriptomic profile inducing loss of multipotency and, hence, capacity for tissue repair. In summary, the stem cells in the subcutaneous WAT niche of obese patients are already committed to adipocyte differentiation and show an upregulated inflammatory gene expression associated to their loss of stemcellness., Acknowledgments This work was supported by Grants SAF 2010/16549, Retic-RIC (RD12/0042/0027) and Retic-TERCEL RD/06/0010/0017 from Instituto Salud Carlos III, Madrid, Spain; and Fundación Jesús Serra, Barcelona, Spain. L. B. is the Cardiovascular Research Chair, UAB, Barcelona, Spain. B. O. is the recipient of a Predoctoral Fellowship from Instituto Salud Carlos III, Madrid, Spain. G. V. is a recipient of a contract from the Innovation and Science Spanish Ministry (RyC-2009-5495), MICINN, Spain. The authors thank Marta Sánchez for her technical support more...

Background Laparoscopy has played an illdefined role as a diagnostic tool for the staging of gastric and other intra-abdominal malignancies for a long time. The widespread use of the laparoscopic approach for the treatment of some benign abdominal diseases, such as biliary lithiasis and gastroesophageal reflux disease, has encouraged the authors toward its use in the treatment of malignant gastric neoplasms, both for palliation and for curative surgery. Methods A five-puncture technique for laparoscopic distal subtotal gastrectomy, omentectomy, division of the left gastric artery at its origin, and D1 lymph node dissection has been developed by the authors, and is fully depicted and discussed. Reconstruction of digestive continuity is achieved through a posterior transmesocolic side-to-side stapled gastrojejunostomy, facilitated by an original method of suspension of the gastric stump to the anterior abdominal wall. Results In a preliminary series of 10 cases, this technique was demonstrated to be safe, showing no mortality, and having morbidity rates comparable to those of open surgery. Conclusion The operation is effective, with a mean number of resected nodes comparable to that usually achieved in open surgery, and no cases of conversion to laparotomy. more...

The most commonly encountered dyslipidemia in obese individuals is characterized by a cluster of interrelated plasma lipid and lipoprotein abnormalities including hypertriglyceridemia, low HDL cholesterol values, and increased small, dense LDL cholesterol particles. The aim of this study was to assess the changes in lipid profiles at baseline (pre-operatively) and at follow-up (6, 12, and 18 months) after a laparoscopic Roux-en-Y gastric bypass (LRYGBP). A retrospective observational study was performed involving all patients who consecutively underwent a LRYGBP between January 1, 2007 and December 31, 2009. Fasting lipids sub-fractions (total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides) were measured and HOMA-IR calculated pre-operatively and at follow-up post-LRYGBP. Pearson's correlation coefficients were used to assess the relationship between excess weight loss (EWL) and lipid sub-fractions. ANOVA was used to assess the differences between each lipid sub-fraction at various time-points. One hundred twenty eight (N = 128) medical charts were reviewed, and those containing data on lipid fractions at the three follow-up time-points were analyzed. One hundred fourteen patients (N = 114), 84 of whom were women (73.7%), were finally included in the study. Total cholesterol, LDL cholesterol, triglycerides, and HOMA-IR were significantly reduced after LRYGBP (P < 0.0005 for all). Inversely, HDL cholesterol disclosed a significant rise (P < 0.0005). Noteworthy significant associations between lipid subfractions and EWL were detected overall (P < 0.0005 for all). A gender effect was found since female patients displayed a milder association than male patients (P < 0.0005). LRYGBP-induced weight loss improves the lipid profile while reducing insulin resistance, with male patients showing a better profile than female patients. more...

Introduction and objective pancreatic endocrine tumors (PET) are difficult to diagnose. Their accurate localization using imaging techniques is intended to provide a definite cure. The goal of this retrospective study was to review a PET series from a private institution. Patients and methods the medical records of 19 patients with PETs were reviewed, including 4 cases of MEN-1, for a period of 17 years (1994-2010). A database was set up with ten parameters: age, sex, symptoms, imaging techniques, size and location in the pancreas, metastasis, surgery, complications, adjuvant therapies, definite diagnosis, and survival or death. Results a total of 19 cases were analyzed. Mean age at presentation was 51 years (range: 26-67 y) (14 males, 5 females), and tumor size was 5 to 80 mm (X: 20 mm). Metastatic disease was present in 37% (7/19). Most underwent the following imaging techniques: ultrasounds, computed tomography (CT) an magnetic resonance imaging (MRI). Fine needle aspiration punction (FNA) was performed for the primary tumor in 4 cases. Non-functioning: 7 cases (37%), insulinoma: 2 cases [1 with possible multiple endocrine neoplasia (MEN)], Zollinger-Ellison syndrome (ZES) from gastrinoma: 5 (3 with MEN-1), glucagonoma: 2 cases, 2 somatostatinomas; carcinoid: 1 case with carcinoide-like syndrome. Most patients were operated upon: 14/19 (73%). Four (4/14:28%) has postoperative complications following pancreatectomy: pancreatitis, pseudocyst, and abdominal collections. Some patients received chemotherapy (4), somatostatin (3) and interferon (2) before or after surgery. Median follow-up was 48 months. Actuarial survival during the study was 73.6% (14/19). Conclusions age was similar to that described in the literature. Males were predominant. Most cases were non-functioning (37%). Most patients underwent surgery (73%) with little morbidity (28%) and an actuarial survival of 73.6% at the time of the study. more...

Gemma Vilahur, PhD Cardiovascular Research Center (CSIC-ICCC), Institut Catala de Ciencies Cardiovasculars (ICCC), CIBEROBNPathophysiology of Obesity and Nutrition, Hospital Sta. Creu i St. Pau, Av. Sant AntoniM. Claret 167, 08025 Barcelona, Spain Prof. Lina Badimon Cardiovascular Research Center (CSIC-ICCC), Institut Catala de Ciencies Cardiovasculars, CIBEROBN-Pathophysiology of Obesity and Nutrition (PI), Hospital de la Santa Creu i Sant Pau, Av. Sant Antoni M. Claret 167, 08025 Barcelona, Spain more...

Introduction and objective: pancreatic endocrine tumors (PET) are difficult to diagnose. Their accurate localization using imaging techniques is intended to provide a definite cure. The goal of this retrospective study was to review a PET series from a private institution. Patients and methods: the medical records of 19 patients with PETs were reviewed, including 4 cases of MEN-1, for a period of 17 years (1994-2010). A database was set up with ten parameters: age, sex, symptoms, imaging techniques, size and location in the pancreas, metastasis, surgery, complications, adjuvant therapies, definite diagnosis, and survival or death. Results: a total of 19 cases were analyzed. Mean age at presentation was 51 years (range: 26-67 y) (14 males, 5 females), and tumor size was 5 to 80 mm (X: 20 mm). Metastatic disease was present in 37% (7/19). Most underwent the following imaging techniques: ultrasounds, computed tomography (CT) and magnetic resonance imaging (MRI). Fine needle aspiration punction (FNA) was performed for the primary tumor in 4 cases. Non-functioning: 7 cases (37%), insulinoma: 2 cases [1 with possible multiple endocrine neoplasia (MEN)], Zollinger-Ellison syndrome (ZES) from gastrinoma: 5 (3 with MEN-1), glucagonoma: 2 cases, 2 somatostatinomas; carcinoid: 1 case with carcinoide-like syndrome. Most patients were operated upon: 14/19 (73%). Four (4/14: 28%) has postoperative complications following pancreatectomy: pancreatitis, pseudocyst, and abdominal collections. Some patients received chemotherapy (4), somatostatin (3) and interferon (2) before or after surgery. Median follow-up was 48 months. Actuarial survival during the study was 73.6% (14/19). Conclusions: age was similar to that described in the literature. Males were predominant. Most cases were non-functioning (37%). Most patients underwent surgery (73%) with little morbidity (28%) and an actuarial survival of 73.6% at the time of the study. more...