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Dysfunctional visceral adipose tissue (VAT) in obesity is associated with type 2 diabetes (DM) but underlying mechanisms remain unclear. Our objective in this discovery analysis was to identify genes and proteins regulated by DM to elucidate aberrant cellular metabolic and signaling mediators. We performed label-free proteomics and RNA-sequencing analysis of VAT from female bariatric surgery subjects with DM and without DM (NDM). We quantified 1965 protein groups, 23 proteins, and 372 genes that were differently abundant in DM vs. NDM VAT. Proteins downregulated in DM were related to fatty acid synthesis and mitochondrial function (fatty acid synthase, FASN; dihydrolipoyl dehydrogenase, mitochondrial, E3 component, DLD; succinate dehydrogenase-α, SDHA) while proteins upregulated in DM were associated with innate immunity and transcriptional regulation (vitronectin, VTN; endothelial protein C receptor, EPCR; signal transducer and activator of transcription 5B, STAT5B). Transcriptome indicated defects in innate inflammation, lipid metabolism, and extracellular matrix (ECM) function, and components of complement classical and alternative cascades. The VAT proteome and transcriptome shared 13 biological processes impacted by DM, related to complement activation, cell proliferation and migration, ECM organization, lipid metabolism, and gluconeogenesis. Our data revealed a marked effect of DM in downregulating FASN. We also demonstrate enrichment of complement factor B (CFB), coagulation factor XIII A chain (F13A1), thrombospondin 1 (THBS1), and integrins at mRNA and protein levels, albeit with lower q-values and lack of Western blot or PCR confirmation. Our findings suggest putative mechanisms of VAT dysfunction in DM. [ABSTRACT FROM AUTHOR]

The adipose tissue extracellular matrix (ECM) regulates adipocyte cellular metabolism and is altered in obesity and type 2 diabetes, but mechanisms underlying ECM-adipocyte metabolic crosstalk are poorly defined. Advanced glycation end-product (AGE) formation is increased in diabetes. AGE alter tissue function via direct effects on ECM and by binding scavenger receptors on multiple cell types and signaling through Rho GTPases. Our goal was to determine the role and underlying mechanisms of AGE in regulating human ECM-adipocyte metabolic crosstalk. Visceral adipocytes from diabetic and non-diabetic humans with obesity were studied in 2D and 3D-ECM culture systems. AGE is increased in adipose tissue from diabetic compared to non-diabetic subjects. Glycated collagen 1 and AGE-modified ECM regulate adipocyte glucose uptake and expression of AGE scavenger receptors and Rho signaling mediators, including the DIAPH1 gene, which encodes the human Diaphanous 1 protein (hDia1). Notably, inhibition of hDia1, but not scavenger receptors RAGE or CD36, attenuated AGE-ECM inhibition of adipocyte glucose uptake. These data demonstrate that AGE-modification of ECM contributes to adipocyte insulin resistance in human diabetes, and implicate hDia1 as a potential mediator of AGE-ECM-adipocyte metabolic crosstalk. [ABSTRACT FROM AUTHOR]

Background: Few in vivo models of esophageal reflux and fundoplication suitable for the study of the pathogenesis of Barrett's esophagus and esophageal cancer exist. We describe a modification of a rat model of duodenoesophageal reflux that incorporates Nissen fundoplication and uses it to study the role of fundoplication in ameliorating esophageal reflux.Methods: A previously described rat model of duodenoesophageal reflux was modified to include Nissen fundoplication. Reflux threshold (RT), defined as the gastric pressure required to cause gastroesophageal reflux during transgastric instillation of saline, was measured in 12 Sprague-Dawley rats at baseline, after cardiomyotomy with esophagogastroduodenal anastomosis (EGDA), after subsequent Nissen fundoplication, and, finally, after takedown of Nissen fundoplication (NF).Results: Cardiomyotomy with EGDA induced no significant change in RT compared with baseline (mean RT +/- SD: 4.0 +/- 1.9 mmHg and 6.0 +/- 2.5 mmHg, respectively, p = 0.741). Nissen fundoplication led to a 14-fold increase in RT (56.4 +/- 18.2 mmHg) compared with cardiomyotomy. RT pressure reverted to baseline levels after NF takedown (4.7 +/- 2.9 mmHg, p < 0.001). Antegrade esophageal flow was demonstrated without an increase in distal esophageal pressure after NF.Conclusions: Nissen fundoplication creates a one-way antireflux mechanism that eliminates gastroesophageal reflux in this rat model. This modification of an in vivo model of duodenoesophageal reflux represents a unique opportunity to investigate the effect of NF on cardiomyotomy-induced reflux and distal esophageal exposure to duodenogastric refluxate, and could be useful in the study of the role of NF in preventing progression to BE and ECA. [ABSTRACT FROM AUTHOR]

Background: Stress gated myocardial perfusion single photon emission computed tomography (gSPECT) is increasingly used before and after intercurrent therapeutic intervention and is the basis for ongoing evaluation in the Department of Veterans Affairs clinical outcomes utilizing revascularization and aggressive drug evaluation (COURAGE) trial.Methods and Results: The COURAGE trial is a North American multicenter randomized clinical trial that enrolled 2287 patients to aggressive medical therapy vs percutaneous coronary intervention plus aggressive medical therapy. Three COURAGE nuclear substudies have been designed. The goals of substudy 0 are to examine the diagnostic accuracy of the extent and severity of inducible ischemia at baseline in COURAGE patients compared with patient symptoms and quantitative coronary angiography and to explore the relationship between inducible ischemia and the benefit from revascularization when added to medical therapy. Substudy 1 will correlate the extent and severity of provocative ischemia with the frequency, quality, and instability of recurrent symptoms in postcatheterization patients. Substudy 2 (n = 300) will examine the usefulness of sequential gSPECT monitoring 6 to 18 months after therapeutic intervention. Together, these nuclear substudies will evaluate the role of gSPECT to determine the effectiveness of aggressive risk-factor modifications, lifestyle interventions, and anti-ischemic medical therapies with or without revascularization in reducing patients' ischemic burdens.Conclusions: The unfolding of evidence on the application of gSPECT in trials such as COURAGE defines a new era for nuclear cardiology. We hope the evidence that emerges from the COURAGE trial will further establish the role of nuclear imaging in the evidence-based management of patients with stable coronary disease. [ABSTRACT FROM AUTHOR]

Background: Intermittent, reversible intraabdominal vagal blockade (VBLOC® Therapy) demonstrated clinically important weight loss in feasibility trials. EMPOWER, a randomized, double-blind, prospective, controlled trial was conducted in USA and Australia. Methods: Five hundred three subjects were enrolled at 15 centers. After informed consent, 294 subjects were implanted with the vagal blocking system and randomized to the treated ( n = 192) or control ( n = 102) group. Main outcome measures were percent excess weight loss (percent EWL) at 12 months and serious adverse events. Subjects controlled duration of therapy using an external power source; therapy involved a programmed algorithm of electrical energy delivered to the subdiaphragmatic vagal nerves to inhibit afferent/efferent vagal transmission. Devices in both groups performed regular, low-energy safety checks. Data are mean ± SEM. Results: Study subjects consisted of 90 % females, body mass index of 41 ± 1 kg/m, and age of 46 ± 1 years. Device-related complications occurred in 3 % of subjects. There was no mortality. 12-month percent EWL was 17 ± 2 % for the treated and 16 ± 2 % for the control group. Weight loss was related linearly to hours of device use; treated and controls with ≥12 h/day use achieved 30 ± 4 and 22 ± 8 % EWL, respectively. Conclusions: VBLOC® therapy to treat morbid obesity was safe, but weight loss was not greater in treated compared to controls; clinically important weight loss, however, was related to hours of device use. Post-study analysis suggested that the system electrical safety checks (low charge delivered via the system for electrical impedance, safety, and diagnostic checks) may have contributed to weight loss in the control group. [ABSTRACT FROM AUTHOR]

Medical therapy is the foundation upon which all treatment for patients with stable coronary artery disease (CAD) is based, regardless of whether revascularization is performed. Although professional societies recommend comprehensive lifestyle and pharmacologic interventions with specific risk factor targets, in practice this does not usually occur. The COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) trial tested multiple simultaneous lifestyle and pharmacologic interventions (referred to as 'optimal medical therapy' [OMT]) with or without percutaneous coronary intervention (PCI) in patients with stable CAD. Nurse case managers were trained to counsel patients according to protocols designed to achieve predefined lifestyle and risk factor goals. Medications were provided at no cost to patients. Adherence to lifestyle and medication prescription was very high and resulted in significant improvement in risk factor targets. COURAGE found no benefit from the addition of PCI to OMT in the primary outcome of death or myocardial infarction. OMT as delivered in COURAGE has been praised but it has also been criticized as not achievable in 'real world' clinical practice. The authors, all COURAGE investigators, believe that the delivery of OMT in COURAGE represents a viable model for secondary prevention that can be translated to real practice, but acknowledge that it is difficult to do so in our fee-for-service health care system. New models of team-based healthcare to achieve evidence-based treatment targets and improved clinical outcomes are needed. Successful translation of COURAGE OMT to everyday practice will require a health care system that rewards quality of care. [ABSTRACT FROM AUTHOR]

Obesity is a major health crisis, and diabetes is one of its most serious sequelae. Obesity is associated with a state of chronic systemic inflammation that is a primary etiologic factor in the development of insulin resistance and diabetes. This inflammatory state is based in adipose tissue and mediated in large part by tissue macrophages and their cytokine and adipokine products. Recent research has identified specific molecular mediators of the link between inflammation and insulin resistance in obesity. Study of these mediators and the specific mechanisms underlying inflammation and insulin resistance in obesity holds the promise for novel pharmacotherapy for obesity-related metabolic disease. [ABSTRACT FROM AUTHOR]

Administrative and financial pressures on surgical education have created a need for efficient training curricula. Predictors of innate technical ability, which would guide the optimization of such a curriculum, are not well described. The goal of this study was to identify student characteristics predictive of innate pretraining skill level and response to training during the course of a four-week laparoscopic skills development program. Laparoscopic skills in 35 first-year surgical residents were assessed with the McGill Inanimate System for Training and Evaluation of Laparoscopic Skills (MISTELS) before and after a four-week skills training program and after an interval of approximately 1 year. The correlation between trainee characteristics, including age, sex, designated surgical specialty, and laparoscopic skill level was assessed by using Pearson’s correlation and paired t-test studies. Intake MISTELS scores showed no significant correlation to age, sex, or designated field. Interns designated for the general surgery training program had significantly higher final scores than those entering other fields ( p = 0.02). There was a negative correlation between trainee age and both degree of improvement during training and final scores ( p = 0.02 and 0.05). A history of video game use correlated with significantly higher initial scores and better skills retention ( p = 0.03 and 0.04). A laparoscopic technical curriculum can achieve basic proficiency even when taught to a diverse group of trainees. Older residents beginning their surgical careers may be slower to develop technical skills. Choice of subspecialty seems to predict higher level of proficiency after completion of a skills training program among resident students. [ABSTRACT FROM AUTHOR]

OBJECTIVES: A major limitation to screening and surveillance of Barrett's esophagus is the complexity, expense, and risk associated with sedation for upper endoscopy. This study examines the feasibility, accuracy, and patient acceptability of office-based unsedated endoscopy as an alternative. METHODS: Of 274 eligible adults scheduled for endoscopic screening for gastroesophageal reflux symptoms or surveillance of Barrett's esophagus at a tertiary care center, 121 underwent unsedated small-caliber endoscopy and conventional endoscopy in a randomized crossover study. The two procedures were compared with regard to histological detection of Barrett's esophagus and dysplasia and biopsy size. Patients answered questionnaires assessing the tolerability of the procedures. RESULTS: The prevalence of Barrett's esophagus was 26% using conventional endoscopy and 30% using unsedated endoscopy ( P= 0.503). The level of agreement between the two approaches was “moderate” (κ= 0.591). Each modality detected four cases of low-grade dysplasia with concordance on one case. The tissue samples collected with unsedated endoscopy were smaller than with conventional endoscopy ( P < 0.001). The majority of subjects rated their experience with both procedures as being well tolerated with minimal or no difficulty. When asked which procedure they would prefer in the future, 71% (81/114) chose unsedated small-caliber endoscopy. CONCLUSIONS: Office-based unsedated small-caliber endoscopy is technically feasible, well tolerated, and accurate in screening for Barrett's esophagus, despite yielding a smaller biopsy specimen. This approach bears the potential to eliminate the infrastructure and cost required for intravenous sedation in this application. [ABSTRACT FROM AUTHOR]

Roux-en-Y gastric bypass (RYGBP) is a mainstay of bariatric surgical therapy. Gastro-gastric fistula (GGF) is an infrequent but potentially serious complication of gastric bypass, and diagnosis may be difficult. We report two patients who underwent RYGBP complicated by development of GGF who nevertheless achieved excellent, durable weight loss. The pathogenesis, diagnosis, prevention and management of GGF after RYGBP is reviewed. GGF may not result in poor weight loss after RYGBP and is not an absolute indication for surgical revision. [ABSTRACT FROM AUTHOR]

Background: Obesity affects the regulation of immune and inflammatory responses. This study characterizes differences in peripheral blood lymphocyte phenotype in obese humans. Methods: Frequencies of lymphocyte subsets among peripheral blood mononuclear cells were compared between 10 obese (BMI ≥35) and 10 lean subjects, as determined by antibodies directed against cluster differentiation (CD) markers. Results: Obese patients demonstrated an increased frequency of CD3+CD4+ T-cells (mean difference 12%, P=0.004), a decreased frequency of CD3+CD8+ T-cells (mean difference 9.4%, P=0.016) and an increased frequency of CD3+CD8+CD95+ T-cells (mean difference 13.3%, P=0.032). No other differences among T-cell or monocyte subsets were noted. Conclusions: Obesity is associated with alterations in frequencies of peripheral CD4+ and CD8+ T-cells and aberrations in the expression of CD95 among CD8+ T-cells. These data suggest both CD4+ and CD8+ T-cell compartments, as well as the regulation of CD95 expression on CD8+ T-cells, as targets for further study into obesity's effects on the immune system. [ABSTRACT FROM AUTHOR]

The accuracy and sensitivity of myocardial imaging using intravenous Rb-81 in delineating the extent and subsequent changes in regional myocardial perfusion abnormalities were examined serially in 12 patients one to 510 days after an acute myocardial infarction. Definite regions of decreased Rb-81 uptake were noted in 10 patients with transmural infarction. There was excellent correlation between the site of perfusion abnormalities, the electrocardiographic infarct location and the region of segmental wall motion disorders. Follow-up studies revealed in 8 of 11 patients a decrease in the extent of the perfusion defect, which was associated with an improvement in the extent and/or severity of regional wall motion disorders. Conversely, wall motion abnormalities did not change in the remaining three patients in whom perfusion abnormalities persisted unchanged. We conclude that intravenous myocardial imaging permits visualization of myocardial perfusion abnormalities early after acute myocardial infarction. Serial imaging allows detection of changes in the extent of perfusion abnormalities, and, thus, might provide useful information with respect to the patient's prognosis and the effects of therapeutic interventions. [ABSTRACT FROM AUTHOR]

Obesity-related type 2 diabetes (DM) is a major public health concern. Adipose tissue metabolic dysfunction, including fibrosis, plays a central role in DM pathogenesis. Obesity is associated with changes in adipose tissue extracellular matrix (ECM), but the impact of these changes on adipose tissue mechanics and their role in metabolic disease is poorly defined. This study utilized atomic force microscopy (AFM) to quantify difference in elasticity between human DM and non-diabetic (NDM) visceral adipose tissue. The mean elastic modulus of DM adipose tissue was twice that of NDM adipose tissue (11.50 kPa vs. 4.48 kPa) to a 95% confidence level, with significant variability in elasticity of DM compared to NDM adipose tissue. Histologic and chemical measures of fibrosis revealed increased hydroxyproline content in DM adipose tissue, but no difference in Sirius Red staining between DM and NDM tissues. These findings support the hypothesis that fibrosis, evidenced by increased elastic modulus, is enhanced in DM adipose tissue, and suggest that measures of tissue mechanics may better resolve disease-specific differences in adipose tissue fibrosis compared with histologic measures. These data demonstrate the power of AFM nanoindentation to probe tissue mechanics, and delineate the impact of metabolic disease on the mechanical properties of adipose tissue. [ABSTRACT FROM AUTHOR]

BACKGROUND Controversy surrounds optimum treatment during the subacute phase after myocardial infarction (MI) in stable patients presenting with occlusion of the infarct-related artery. Percutaneous coronary intervention (PCI) is a favored procedure in these circumstances, but its efficacy has not been established. OBJECTIVE To determine whether PCI 3-28 days after MI, plus optimum medical therapy, improves long-term arterial patency and left ventricular (LV) size and function at 1 year when compared with medical therapy alone. DESIGN The Total Occlusion Study of Canada (TOSCA)-2 trial was an ancillary study of the international, randomized Occluded Artery Trial (OAT), and included patients already enrolled in OAT from 33 of 217 participating centers. Enrollment into the ancillary study took place between May 2000 and July 2005. All patients underwent cardiac catheterization 3-28 days after a documented MI, and had either proximal coronary occlusion of the artery supplying at least 25% of the left ventricle, or LV ejection fraction (LVEF) of less than 50%. Exclusion criteria included clinical instability, severe inducible ischemia, or left-main or three-vessel disease. INTERVENTION Patients were randomly assigned to receive PCI with optimum medical therapy (PCI+M; including aspirin, angiotensin-converting-enzyme inhibitors, β-blockers, lipid-lowering therapy, and anticoagulants), or medical therapy alone. PCI using one or more coronary stents was performed within 24 h of randomization. All patients undergoing PCI also received thienopyridine therapy before and 2-4 weeks after the procedure, with a recommendation for medication to be continued up to 1 year. Follow-up angiography took place 12±3 months after randomization. OUTCOME MEASURES There were two primary end points: IRA patency and change in LVEF. Changes in LV end-systolic and end-diastolic volume index were also assessed as secondary end points. RESULTS The TOSCA-2 trial enrolled 381 patients (PCI+M n=195; medical therapy n=186), representing 67% of the OAT study population. Crossover from the medical therapy group to the PCI+M group was 17.5%. Late arterial patency was observed in significantly more patients who underwent PCI+M than in those who received medical therapy alone (83% versus 25%, respectively; P<0.0001). Although both treatments resulted in an improvement in LVEF at 1-year follow-up, there was no significant difference between the groups (mean change in LVEF 4.2±8.9% versus 3.5±8.2%, respectively; P=0.47). Neither was there a significant difference between PCI+M and medical therapy in the two secondary end points of LV endsystolic volume index (P=0.10) and LV end-diastolic volume index (P = 0.07). CONCLUSION PCI and stenting of an occluded IRA 3-28 days following MI, plus optimum medical therapy, significantly improves long-term arterial patency, but not LVEF, when compared with medical therapy alone. [ABSTRACT FROM AUTHOR]

The article focuses on the inappropriateness of technology as a substitute for cognitive and preventive cardiology. It says that the time and ability of cardiologists to fully understand the patient clinically and emotionally could be adversely affected by the availability of technology. It states that reliance on costly technology is not beneficial to patients who depend on already variable system of health care delivery.