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Background: Internal hernia after gastric bypass is common, occurring with an incidence approaching 10% in some series. Operative management of internal hernia after gastric bypass presents significant conceptual and technical challenges.Methods: This manuscript reviews management of internal hernia after gastric bypass with a focus on operative strategy. [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]

Introduction: Hypoxia regulates adipocyte metabolism. Hexosamine biosynthesis is implicated in murine 3T3L1 adipocyte differentiation and is a possible underlying mechanism for hypoxia’s effects on adipocyte metabolism. Methods: Lipid metabolism was studied in human visceral and subcutaneous adipocytes in in vitro hypoxic culture with adipophilic staining, glycerol release, and palmitate oxidation assays. Gene expression and hexosamine biosynthesis activation was studied with QRTPCR, immunofluorescence microscopy, and Western blotting. Results: Hypoxia inhibits lipogenesis and induces basal lipolysis in visceral and subcutaneous human adipocytes. Hypoxia induces fatty acid oxidation in visceral adipocytes but had no effect on fatty acid oxidation in subcutaneous adipocytes. Hypoxia inhibits hexosamine biosynthesis in adipocytes. Inhibition of hexosamine biosynthesis with azaserine attenuates lipogenesis and induces lipolysis in adipocytes in normoxic conditions, while promotion of hexosamine biosynthesis with glucosamine in hypoxic conditions slightly increases lipogenesis. Conclusions: Hypoxia’s net effect on human adipocyte lipid metabolism would be expected to impair adipocyte buffering capacity and contribute to systemic lipotoxicity. Our data suggest that hypoxia may mediate its effects on lipogenesis and lipolysis through inhibition of hexosamine biosynthesis. Hexosamine biosynthesis represents a target for manipulation of adipocyte metabolism. [ABSTRACT FROM AUTHOR]

Abstract: Background: Gastric bypass remains the mainstay of surgical therapy for obesity. Abdominal pain after gastric bypass is common and accounts for up to half of all postoperative complaints and emergency room visits. This article reviews the most important causes of abdominal pain specific to gastric bypass and discusses management considerations. Methods: The current surgical literature was reviewed using PubMed, with a focus on abdominal pain after gastric bypass and the known pathologies that underlie its pathogenesis. Results: The etiologies of abdominal pain after gastric bypass are diverse. A thorough understanding of their pathogenesis impacts favorably on clinical outcomes. Conclusions: The differential diagnosis for abdominal pain after gastric bypass is large and includes benign and life-threatening entities. Its diverse causes require a broad evaluation that should be directed by history and clinical presentation. In the absence of a clear diagnosis, the threshold for surgical exploration in patients with abdominal pain after gastric bypass should be low. [Copyright &y& Elsevier]

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]

The main results of the Clinical Outcomes Utilizing Revascularization and Aggressive DruG Evaluation (COURAGE) trial revealed no significant differences in the primary end point of all-cause mortality or nonfatal myocardial infarction [MI] or major secondary end points (composites of death/MI/stroke; hospitalization for acute coronary syndromes [ACSs]) during a median 4.6-year follow-up in 2,287 patients with stable coronary artery disease randomized to optimal medical therapy (OMT) with or without percutaneous coronary intervention (PCI). We sought to assess the impact of PCI when added to OMT on major prespecified tertiary cardiovascular outcomes (time to first event), namely cardiac death and composites of cardiac death/MI, cardiac death/MI/hospitalization for ACS, cardiac death/MI/stroke, MI/stroke, or cardiac death/MI/ACS/stroke, during study follow-up. There were no significant differences between treatment arms for the composite of cardiac death or MI (15% in PCI + OMT group vs 14.2% in OMT group, hazard ratio 1.07, 95% confidence interval 0.86 to 1.33, p = 0.62) or in any of the major prespecified composite cardiovascular events during long-term follow-up, even after excluding periprocedural MI as an outcome of interest. Overall, cause-specific cardiovascular outcomes paralleled closely the primary and secondary composite outcomes of the trial as a whole. In conclusion, compared with an initial management strategy of OMT alone, addition of PCI did not decrease the incidence of major cardiovascular outcomes including cardiac death or the composite of cardiac death/MI/ACS/stroke in patients with stable coronary artery disease. [Copyright &y& Elsevier]

Background: In patients with stable coronary artery disease, it remains unclear whether an initial management strategy of percutaneous coronary intervention (PCI) with intensive pharmacologic therapy and lifestyle intervention (optimal medical therapy) is superior to optimal medical therapy alone in reducing the risk of cardiovascular events. Methods: We conducted a randomized trial involving 2287 patients who had objective evidence of myocardial ischemia and significant coronary artery disease at 50 U.S. and Canadian centers. Between 1999 and 2004, we assigned 1149 patients to undergo PCI with optimal medical therapy (PCI group) and 1138 to receive optimal medical therapy alone (medical-therapy group). The primary outcome was death from any cause and nonfatal myocardial infarction during a follow-up period of 2.5 to 7.0 years (median, 4.6). Results: There were 211 primary events in the PCI group and 202 events in the medical-therapy group. The 4.6-year cumulative primary-event rates were 19.0% in the PCI group and 18.5% in the medical-therapy group (hazard ratio for the PCI group, 1.05; 95% confidence interval [CI], 0.87 to 1.27; P=0.62). There were no significant differences between the PCI group and the medical-therapy group in the composite of death, myocardial infarction, and stroke (20.0% vs. 19.5%; hazard ratio, 1.05; 95% CI, 0.87 to 1.27; P=0.62); hospitalization for acute coronary syndrome (12.4% vs. 11.8%; hazard ratio, 1.07; 95% CI, 0.84 to 1.37; P=0.56); or myocardial infarction (13.2% vs. 12.3%; hazard ratio, 1.13; 95% CI, 0.89 to 1.43; P=0.33). Conclusions: As an initial management strategy in patients with stable coronary artery disease, PCI did not reduce the risk of death, myocardial infarction, or other major cardiovascular events when added to optimal medical therapy. (ClinicalTrials.gov number, NCT00007657.) [ABSTRACT FROM AUTHOR]

Major improvements in medical therapy and percutaneous coronary intervention for coronary artery disease (CAD) have emerged during the previous 2 decades, but no randomized trial in patients with stable CAD has been powered to compare these 2 strategies for the hard clinical end points of death or myocardial infarction (MI), and previous studies have not evaluated the effect of coronary stents and intensive medical therapy on cardiac events during long-term follow-up. Between 1999 and 2004, 2,287 patients with documented myocardial ischemia and angiographically confirmed CAD were randomized to the Clinical Outcomes Utilizing Revascularization and Aggressive DruG Evaluation (COURAGE) trial, with a principal hypothesis that a strategy of percutaneous coronary intervention plus intensive, guideline-driven medical therapy would be superior to a strategy of intensive medical therapy alone. The primary end point was a composite of all-cause mortality or acute MI (time to first event) during a 2.5- to 7-year (median 5) follow-up. Baseline characteristics were a mean age of 62 ± 5 years, 85% men, and 86% Caucasian. Mean duration of angina before randomization was 26 months (average 10 episodes/week), and 29% of patients were smokers, 67% had hypertension, 38% had previous MI, 71% had dyslipidemia, 34% had diabetes, 27% had previous revascularization, and 69% had multivessel CAD. Approximately 55% of patients met established criteria for the metabolic syndrome. In conclusion, baseline characteristics of the COURAGE trial study population indicate a highly symptomatic group of patients with CAD who have a significant duration and frequency of antecedent angina pectoris and a high prevalence of cardiac risk factors. [Copyright &y& Elsevier]

Abstract: Background: The optimal common channel (CC) length for malabsorptive weight loss surgeries is unknown even though these surgeries were developed in the 1970s (biliopancreatic diversion [BPD]) and the 1990s (biliopancreatic diversion with a duodenal switch [BPD DS]). We hypothesized that the length of the CC correlates with a successful weight loss result. Methods: We evaluated 3 groups of patients based on the length of the CC whose duration of follow-up evaluation was at least 1 year. We reviewed all patients who had either an open BPD (5 patients) or a BPD DS (119 patients) from August 1998 to October 2003, for which D.B.M. was the participating surgeon. Results: Group I comprised 15 patients: their preoperative body mass index (BMI) was 53.9 kg/m2; 73.3% of patients had a BMI more than 50, and the CC length was 150 cm. Group II comprised 76 patients: their preoperative BMI was 54.25 kg/m2; 73.3% of patients had a BMI more than 50, and the CC length was 100 cm. Group III comprised 33 patients: their preoperative BMI was 60.1 kg/m2; 84% of patients had a BMI more than 50, and the CC length was 80 to 90 cm. The mean weight loss in group I was 45 kg (44% mean excess weight loss). The mean weight loss in groups II and III was 55.8 and 61.5 kg, respectively (a 57% and 54.8% mean excess weight loss, respectively) (all P &#60; .05 by analysis of variance). A weight loss of greater than 50% of excess body weight occurred in 40% of patients in group I versus 63% of patients in groups II and III combined (P &#60; .01 by χ2). Conclusions: The length of the CC contributes significantly to successful excess weight loss in BPD and BPD DS patients. In general, the length of the CC should not exceed 100 cm. [Copyright &y& Elsevier]

Background: Biliary reconstruction represents a relatively untested frontier in laparoscopy.Methods: Retrospective review of all patients who underwent laparoscopic biliary operations at Legacy Health System from 1998 to 2003.Results: Seven patients underwent laparoscopic biliary reconstruction. Indications included benign calculous disease in 4 patients, benign stricture on 1 patient, choledochal cyst in 1 patient, and malignant biliary obstruction in 1 patient. Operations performed included choledochoduodenostomy, hepaticojejunostomy, stricturoplasty, choledochal cyst excision with hepaticojejunostomy, and cholecystojejunostomy. Median operative time was 300 minutes. Median hospital stay was 4 days. One perioperative complication of a bowel obstruction required reoperation. Median follow-up was 15 months. One patient died of metastatic cancer 8 months after surgery. All other patients are symptom free with no signs of stricture or recurrent biliary obstruction.Conclusions: Laparoscopic biliary reconstruction represents a viable treatment option in carefully selected patients. [Copyright &y& Elsevier]

Discusses approaches in the diagnosis and management of unstable angina and non-stress-testing-segment elevation myocardial infarction. Patient identification and risk stratification; Improvement of balance between myocardial oxygen supply and demand; Benefits of aspirin and heparin; Platelet activation and thrombin generation after plaque disruption.

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. [ABSTRACT FROM AUTHOR]

Adverse cardiac events during noncardiac surgery are a major cause of morbidity and mortality. As the population ages, greater numbers of patients (including the elderly) are undergoing noncardiac surgical procedures; additional emphasis must therefore be placed on effective preoperative risk assessment. On a national level, the estimated annual expenditure for this process is already $3.7 billion. There is a need for both the specialist and primary care provider to execute a safe, methodical, and cost efficient screening plan. This process should identify both the patients at highest risk and also those at lowest risk. Subsequently, the emphasis should attempt to minimize the overall risk of perioperative complications. The cornerstone of risk assessment requires meticulous history taking, a thorough physical examination, and usually a chest radiograph and an ECG. Five subsequent (basic) steps for the evaluation of patients for noncardiac surgery are outlined here in assessment of clinical markers and the patient's functional capacity, risk of the surgical procedure, the need for noninvasive testing, and when appropriate, the indications for invasive testing. The AHA/ACC Practice Guidelines Committee has outlined a clinical algorithm which provides a stepwise approach to guide the clinician during the decision making process. The purpose of preoperative evaluation is not to “give medical clearance” per se, but rather to evaluate the patient's current medical status, detect stress-induced ischemia in a cost effective manner, and to make recommendations about patient management throughout the entire perioperative period. [ABSTRACT FROM AUTHOR]

Acute aortic regurgitation usually results from infective endocarditis, but is also caused by aortic dissection and trauma to the heart. Most of the left ventricular stroke volume is regurgitated back into the left ventricle; thus, the forward stroke volume to the body and the cardiac output may be severely compromised. An acute increase in left ventricular end-diastolic volume results in a marked increase in left ventricular end-diastolic pressure, and the mitral valve usually closes prematurely. Compensatory tachycardia is the rule and helps to shorten diastole; thus, the time available for aortic regurgitation to occur is reduced, and the cardiac output is often maintained.On physical examination, there is tachycardia; the peripheral arterial pulse shows a rapid rise, but the systolic pressure is normal; the diastolic pressure is normal or even reduced; and the pulse pressure is often normal. The electrocardiogram (ECG) may be normal except for sinus tachycardia and often for nonspecific ST-T changes. The chest roentgenogram usually shows signs of pulmonary venous hypertension or even pulmonary edema. Echocardiography may show vegetations on the aortic valve, prolapse of an aortic leaflet into the left ventricle, and premature mitral valve closure. Doppler echocardiography is useful in detecting the presence of aortic regurgitation.In cases of infective endocarditis, the appropriate antibiotic therapy must be given. Aortic regurgitation due to dissection of the aorta is usually an indication for surgery. In patients with severe aortic regurgitation, available medical therapy includes digitalis, diuretics, and vasodilators. When patients respond dramatically to the use of digitalis, diuretics, and arterial dilators, surgical therapy can be delayed until heart failure and infection are controlled and the patient is more stable. If the patient does not respond immediately and dramatically to therapy, then valve replacement should not be delayed, even if the infection is uncontrolled or the patient has had little antibiotic therapy. [ABSTRACT FROM PUBLISHER]

Cardiovascular disease is a major clinical problem in the elderly, with coronary heart disease the most frequent cause of death and with hypertension present in as many as 50% of these patients. The cardiovascular manifestations of aging must be differentiated from those due to disease. There are clinical manifestations and responses to therapy in the elderly that differ from those in younger patients. The extent of diagnostic and therapeutic procedures undertaken should be based on the patient's physiologic age, the presence and severity of concomitant diseases, mental status and cognitive ability, and the patient's expectations from medical care. Preventive approaches are also warranted. [ABSTRACT FROM AUTHOR]

The authors of the meta-analysis of a percutaneous coronary intervention (PCI)-based invasive strategy for improving prognosis for the treatment of angina conclude that a pooling of data from various studies can be sufficiently powered to evaluate the impact of PCI on long-term mortality. However, most randomized coronary artery patient trials have insufficient power to detect significant differences in hard end points. Randomized trials in patients with chronic stable angina enroll few patients who are over age 65 years, have depressed ventricular function, have clinical instability, or who have undergone previous coronary artery bypass grafting (CABG) or PCI. “Medical therapy” today no longer means the absence of PCI, but rather the presence of intensive, evidence-based pharmacologic intervention. The COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive druG Evaluation) trial randomized 2,287 patients to optimal medical therapy alone or optimal medical therapy plus PCI. Optimal medical therapy consisted of antiplatelet therapy, anti-ischemic therapy, and aggressive lipid and blood pressure control. Based on the strength of the evidence, the author of this commentary recommends more-aggressive medical therapy for patients with moderate-to-severe angina, and PCI or CABG for many patients in whom symptoms persist. Optimal medical therapy is a proven option for chronic stable angina. [Copyright &y& Elsevier]

Alterations of the extracellular matrix contribute to adipose tissue dysfunction in metabolic disease. We studied the role of matrix density in regulating human adipocyte phenotype in a tunable hydrogel culture system. Lipid accumulation was maximal in intermediate hydrogel density of 5 weight %, relative to 3% and 10%. Adipogenesis and lipid and oxidative metabolic gene pathways were enriched in adipocytes in 5% relative to 3% hydrogels, while fibrotic gene pathways were enriched in 3% hydrogels. These data demonstrate that the intermediate density matrix promotes a more adipogenic, less fibrotic adipocyte phenotype geared towards increased lipid and aerobic metabolism. These observations contribute to a growing literature describing the role of matrix density in regulating adipose tissue function. [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]

White adipose tissue (WAT) lipolysis releases free fatty acids as a key energy substance to support metabolism in fasting, cold exposure, and exercise. Atgl, in concert with Cgi‐58, catalyzes the first lipolytic reaction. The sympathetic nervous system (SNS) stimulates lipolysis via neurotransmitter norepinephrine that activates adipocyte β adrenergic receptors (Adrb1‐3). In obesity, adipose Adrb signaling and lipolysis are impaired, contributing to pathogenic WAT expansion; however, the underling mechanism remains poorly understood. Recent studies highlight importance of N6‐methyladenosine (m6A)‐based RNA modification in health and disease. METTL14 heterodimerizes with METTL3 to form an RNA methyltransferase complex that installs m6A in transcripts. Here, this work shows that adipose Mettl3 and Mettl14 are influenced by fasting, refeeding, and insulin, and are upregulated in high fat diet (HFD) induced obesity. Adipose Adrb2, Adrb3, Atgl, and Cgi‐58 transcript m6A contents are elevated in obesity. Mettl14 ablation decreases these transcripts' m6A contents and increases their translations and protein levels in adipocytes, thereby increasing Adrb signaling and lipolysis. Mice with adipocyte‐specific deletion of Mettl14 are resistant to HFD‐induced obesity, insulin resistance, glucose intolerance, and nonalcoholic fatty liver disease (NAFLD). These results unravel a METTL14/m6A/translation pathway governing Adrb signaling and lipolysis. METTL14/m6A‐based epitranscriptomic reprogramming impairs adipose Adrb signaling and lipolysis, promoting obesity, NAFLD, and metabolic disease. [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.

Obesity-associated type 2 diabetes (DM) leads to adipose tissue dysfunction. Lumican is a proteoglycan implicated in obesity, insulin resistance (IR), and adipocyte dysfunction. Using human visceral adipose tissue (VAT) from subjects with and without DM, we studied lumican effects on adipocyte function. Lumican was increased in VAT and adipocytes in DM. Lumican knockdown in adipocytes decreased lipolysis and improved adipogenesis and insulin sensitivity in VAT adipocytes in DM, while treatment with human recombinant lumican increased lipolysis and impaired insulin-sensitivity in an ERK-dependent manner. We demonstrate that lumican impairs adipocyte metabolism, partially via ERK signalling, and is a potential target for developing adipose tissue-targeted therapeutics in DM. [ABSTRACT FROM AUTHOR]

A response by William E. Boden, Robert A. O'Rourke, and Michael H. Crawford to a letter to the editor about their article "Management of NonWave Myocardial Infarction," which was published in the July 18, 1998 issue, is presented.

Background: Non–Q-wave myocardial infarction is usually managed according to an “invasive” strategy (i.e., one of routine coronary angiography followed by myocardial revascularization). Methods: We randomly assigned 920 patients to either “invasive” management (462 patients) or “conservative” management, defined as medical therapy and noninvasive testing, with subsequent invasive management if indicated by the development of spontaneous or inducible ischemia (458 patients), within 72 hours of the onset of a non–Q-wave infarction. Death or nonfatal infarction made up the combined primary end point. Results: During an average follow-up of 23 months, 152 events (80 deaths and 72 nonfatal infarctions) occurred in 138 patients who had been randomly assigned to the invasive strategy, and 139 events (59 deaths and 80 nonfatal infarctions) in 123 patients assigned to the conservative strategy (P=0.35). Patients assigned to the invasive strategy had worse clinical outcomes during the first year of follow-up. The number of patients with one of the components of the primary end point (death or nonfatal myocardial infarction) and the number who died were significantly higher in the invasive-strategy group at hospital discharge (36 vs. 15 patients, P=0.004, for the primary end point; 21 vs. 6, P=0.007, for death), at one month (48 vs. 26, P=0.012; 23 vs. 9, P=0.021), and at one year (111 vs. 85, P=0.05; 58 vs. 36, P=0.025). Overall mortality during follow-up did not differ significantly between patients assigned to the conservative-strategy group and those assigned to the invasive-strategy group (hazard ratio, 0.72; 95 percent confidence interval, 0.51 to 1.01). Conclusions: Most patients with non–Q-wave myocardial infarction do not benefit from routine, early invasive management consisting of coronary angiography and revascularization. A conservative, ischemia-guided initial approach is both safe and effective. (N Engl J Med 1998;338:1785-92.) [ABSTRACT FROM AUTHOR]

Background: The functional lumen imaging probe (FLIP) uses impedance planimetry to measure the geometry of a distensible organ. The purpose of this study was to evaluate FLIP as a method to determine structural changes at the gastroesophageal junction (GEJ) following transoral incisionless fundoplication (TIF) and compare these findings with the accepted methods of esophageal testing.Methods: Two different approaches (TIF1.0 and 2.0) using the EsophyX™ device were performed in six and five animals, respectively. Three dogs underwent a sham procedure. FLIP measurements were performed pre- and post-procedure and at 2-week follow-up. Upper endoscopy, manometry, and 48-h pH testing were also performed at each time point. FLIP was performed in ten patients before and 3 months after TIF.Results: Following TIF procedures, there was a significant decrease in cross-sectional area (CSA) of GEJ compared to baseline; however, the CSA of both groups returned to baseline at 2-week follow-up. The FLIP results were supported with pH testing and correlated highly with both measures of GEJ structural integrity (LES and cardia circumference). Following TIF in humans, there was a decrease in GEJ distensibility compared to baseline that persisted to the 3-month evaluation.Conclusion: FLIP is able to measure and display changes in tissue distensibility at the GEJ, and results correlate with established methods of testing. FLIP may represent a single testing modality by which to diagnose GERD and evaluate the outcome after antireflux surgery. [ABSTRACT FROM AUTHOR]

Objectives: This paper describes the medical therapy used in the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) trial and its effect on risk factors. Background: Most cardiovascular clinical trials test a single intervention. The COURAGE trial tested multiple lifestyle and pharmacologic interventions (optimal medical therapy) with or without percutaneous coronary intervention in patients with stable coronary disease. Methods: All patients, regardless of treatment assignment, received equivalent lifestyle and pharmacologic interventions for secondary prevention. Most medications were provided at no cost. Therapy was administered by nurse case managers according to protocols designed to achieve predefined lifestyle and risk factor goals. Results: The patients (n = 2,287) were followed for 4.6 years. There were no significant differences between treatment groups in proportion of patients achieving therapeutic goals. The proportion of smokers decreased from 23% to 19% (p = 0.025), those who reported <7% of calories from saturated fat increased from 46% to 80% (p < 0.001), and those who walked ≥150 min/week increased from 58% to 66% (p < 0.001). Body mass index increased from 28.8 ± 0.13 kg/m2 to 29.3 ± 0.23 kg/m2 (p < 0.001). Appropriate medication use increased from pre-randomization to 5 years as follows: antiplatelets 87% to 96%; beta-blockers 69% to 85%; renin-angiotensin-aldosterone system inhibitors 46% to 72%; and statins 64% to 93%. Systolic blood pressure decreased from a median of 131 ± 0.49 mm Hg to 123 ± 0.88 mm Hg. Low-density lipoprotein cholesterol decreased from a median of 101 ± 0.83 mg/dl to 72 ± 0.88 mg/dl. Conclusions: Secondary prevention was applied equally and intensively to both treatment groups in the COURAGE trial by nurse case managers with treatment protocols and resulted in significant improvement in risk factors. Optimal medical therapy in the COURAGE trial provides an effective model for secondary prevention among patients with chronic coronary disease. (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation; NCT00007657) [Copyright &y& Elsevier]

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]

Although expressed at very low levels in islets of NOD mice, GAD65 is a candidate islet autoantigen. Two transgenic lines of NOD/Lt mice expressing high levels of human GAD65 from a rat insulin promoter were generated. Transgenes were integrated on proximal chromosome 15 of the A line and on the Y chromosome of the Y line. Transgenic A-line mice were obligate hemizygotes, since homozygous expression resulted in developmental lethality. A twofold higher level of hGAD65 transcripts in A-line islets from young donors was associated with higher GAD protein and enzyme activity levels. Y-line males developed diabetes at a similar rate and incidence as standard NOD/Lt males. In contrast, A-line mice of both sexes exhibited a markedly lowered incidence of diabetes. Insulitis, present in both transgenic lines, developed more slowly in A-line mice and correlated with a reduction in the ratio of gamma-interferon to interleukin-10 transcripts. Splenic leukocytes from young A-line donors transferred diabetes into NOD-scid recipients at a retarded rate compared with those from nontransgenic donors. Further, nontransgenic NOD T-cells transferred diabetes more slowly in NOD-scid recipients that were congenic for A-line transgenes as compared with standard NOD-scid recipients. Primed T-cell responses and spontaneous humoral reactivity to GAD65 failed to distinguish transgenic from nontransgenic mice. Quantitative differences in expression level or insertional mutagenesis are possible mechanisms of protection in the A line. [ABSTRACT FROM AUTHOR]

Spigelian hernia is an uncommon congenital or acquired defect in the transversus abdominis aponeurosis with non-specific symptoms posing a diagnostic challenge. There is a paucity of radiology literature on imaging findings of Spigelian hernia. The objective of this study is to explore the role of MDCT in evaluating Spigelian hernia along with clinical and surgical implications. In this IRB approved, HIPAA compliant retrospective observational analysis MDCT imaging findings of 43 Spigelian hernias were evaluated by two fellowship-trained radiologists. Imaging features evaluated were: presence of Spigelian hernia, laterality, relation to "hernia belt" (between 0 and 6 cm cranial to an imaginary axial line between both anterior superior iliac spines), the hernia neck and sac sizes, hernia content, and other coexistent hernias (umbilical, incisional, inguinal). Patient's demographics (age, gender, BMI, conditions with increased intra-abdominal pressure) were also recorded for any correlation. 60% (26/43) of Spigelian hernias were located below the hernia belt while 33% (14/43) within the hernia belt and 7% (3/43) above the hernia belt. The most common subtype of Spigelian hernia encountered was interparietal (84%). The mean hernia neck diameter was 3.4 cm, mean hernia sac volume was 329 cc. Hernia content included: fat (43/43) bowel (23/43), fluid (3/43). 3 patients had no clinical history provided, the remaining 37 patients' clinical presentation was asymptomatic in 73% (27/37), acute abdominal pain in 5% (2/37) and chronic abdominal pain in 22% (8/37). None of the hernia were incarcerated and none of the patients underwent emergent surgery. No significant correlation was noted between Spigelian hernia and causes of increased intra-abdominal pressure. 90% of our patients had other abdominal hernias. 30.9 was the mean BMI (20.8–69.1). Most of the Spigelian hernia occurred below the traditionally described hernia belt and the majority are of interparietal subtype that can be best diagnosed with MDCT in contrast to physical examination. • There is a paucity of radiology literature on imaging findings of Spigelian hernia • Only 50% of Spigelian hernias are diagnosed preoperatively by physical examination and have nonspecific clinical symptoms, with abdominal pain varying in type, severity, and location depending on the contents of a hernia and thus pose a diagnostic challenge clinically. • There are two major types of Spigelian hernia- interparietal and subcutaneous. The interparietal type does not penetrate the external oblique aponeurosis, and the subcutaneous type penetrates it. • The majority of Spigelian hernias occur in the hernia belt according to the surgical literature. Our findings show only 33% of the Spigelian hernias were located in the hernia belt. There was no significant statistical correlation between a Spigelian hernia and a list of causes that increase intra-abdominal pressure. • We found no statistically significant correlation between patient age, gender, body mass index (BMI) at the time of imaging, or history of acute or chronic hernia symptoms, and the presence of a Spigelian hernia. [ABSTRACT FROM AUTHOR]

Subcutaneous (SAT) and visceral (VAT) adipose tissues have distinct metabolic phenotypes. We hypothesized that the extracellular matrix (ECM) regulates depot-specific differences in adipocyte metabolic function inmurine obesity. VAT and SAT preadipocytes from lean or obese mice were subject to adipogenic differentiation in standard 2D culture on plastic tissue culture plates or in 3D culture in ECM, followed by metabolic profiling. Adipocytes from VAT relative to SATmanifested impaired insulin-stimulated glucose uptake and decreased adipogenic capacity. In 3D-ECM-adipocyte culture, ECM regulated adipocyte metabolism in a depot-specific manner, with SAT ECM rescuing defects in glucose uptake and adipogenic gene expression in VAT adipocytes, while VAT ECM impaired adipogenic gene expression in SAT adipocytes. These findings demonstrate that ECM-adipocyte crosstalk regulates depot-specific differences in adipocyte metabolic dysfunction in murine obesity. [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]

Sepsis is the leading cause of death in the intensive care unit with an overall mortality rate of 20%. Individuals who are obese and have type 2 diabetes have increased recurrent, chronic, nosocomial infections that worsen the long-term morbidity and mortality from sepsis. Additionally, animal models of sepsis have shown that obese, diabetic mice have lower survival rates compared with nondiabetic mice. Neutrophils are essential for eradication of bacteria, prevention of infectious complications, and sepsis survival. In diabetic states, there is a reduction in neutrophil chemotaxis, phagocytosis, and reactive oxygen species (ROS) generation; however, few studies have investigated the extent to which these deficits compromise infection eradication and mortality. Using a cecal ligation and puncture model of sepsis in lean and in diet-induced obese mice, we demonstrate that obese diabetic mice have decreased "emergency hematopoiesis" after an acute infection. Additionally, both neutrophils and monocytes in obese, diabetic mice have functional defects, with decreased phagocytic ability and a decreased capacity to generate ROS. Neutrophils isolated from obese diabetic mice have decreased transcripts of Axl and Mertk, which partially explains the phagocytic dysfunction. Furthermore, we found that exogenous GM-CSF administration improves sepsis survival through enhanced neutrophil and monocytes phagocytosis and ROS generation abilities in obese, diabetic mice with sepsis. [ABSTRACT FROM AUTHOR]

Predictors of weight loss responses are not well-defined. We hypothesized that adipose tissue phenotypic features related to remodeling would be associated with bariatric surgery weight loss responses. Visceral and subcutaneous adipose tissues collected from patients during bariatric surgery were studied with flow cytometry, immunohistochemistry, and QRTPCR, and results correlated with weight loss outcomes. Age, male sex, and a diagnosis of type 2 diabetes were associated with less weight loss. Adipocyte size was increased and preadipocyte frequency was decreased in visceral adipose tissue from diabetic subjects. Decreased adipose tissue preadipocyte frequency was associated with less weight loss in women but not men. These data suggest that phenotypic features of adipose tissue remodeling may predict responses to weight loss interventions. [ABSTRACT FROM PUBLISHER]

Dynamic changes of adipose tissue leukocytes, including adipose tissue macrophage (ATM) and adipose tissue dendritic cells (ATDCs), contribute to obesity-induced inflammation and metabolic disease. However, clear discrimination between ATDC and ATM in adipose tissue has limited progress in the field of immunometabolism. In this study, we use CD64 to distinguish ATM and ATDC, and investigated the temporal and functional changes in these myeloid populations during obesity. Flow cytometry and immunostaining demonstrated that the definition of ATM as F4/80+CD11b+ cells overlaps with other leukocytes and that CD45+CD64+ is specific for ATM. The expression of core dendritic cell genes was enriched in CD11c+CD64- cells (ATDC), whereas core macrophage genes were enriched in CD45+CD64+ cells (ATM). CD11c+CD64- ATDCs expressed MHC class II and costimulatory receptors, and had similar capacity to stimulate CD4+ T cell proliferation as ATMs. ATDCs were predominantly CD11b+ conventional dendritic cells and made up the bulk of CD11c+ cells in adipose tissue with moderate high-fat diet exposure. Mixed chimeric experiments with Ccr2-/- mice demonstrated that high-fat diet-induced ATM accumulation from monocytes was dependent on CCR2, whereas ATDC accumulation was less CCR2 dependent. ATDC accumulation during obesity was attenuated in Ccr7-/- mice and was associated with decreased adipose tissue inflammation and insulin resistance. CD45+CD64+ ATM and CD45+CD64-CD11c+ ATDCs were identified in human obese adipose tissue and ATDCs were increased in s.c. adipose tissue compared with omental adipose tissue. These results support a revised strategy for unambiguous delineation of ATM and ATDC, and suggest that ATDCs are independent contributors to adipose tissue inflammation during obesity. [ABSTRACT FROM AUTHOR]

Importance: Although conventional bariatric surgery results in weight loss, it does so with potential short-term and long-term morbidity.Objective: To evaluate the effectiveness and safety of intermittent, reversible vagal nerve blockade therapy for obesity treatment.Design, Setting, and Participants: A randomized, double-blind, sham-controlled clinical trial involving 239 participants who had a body mass index of 40 to 45 or 35 to 40 and 1 or more obesity-related condition was conducted at 10 sites in the United States and Australia between May and December 2011. The 12-month blinded portion of the 5-year study was completed in January 2013.Interventions: One hundred sixty-two patients received an active vagal nerve block device and 77 received a sham device. All participants received weight management education.Main Outcomes and Measures: The coprimary efficacy objectives were to determine whether the vagal nerve block was superior in mean percentage excess weight loss to sham by a 10-point margin with at least 55% of patients in the vagal block group achieving a 20% loss and 45% achieving a 25% loss. The primary safety objective was to determine whether the rate of serious adverse events related to device, procedure, or therapy in the vagal block group was less than 15%.Results: In the intent-to-treat analysis, the vagal nerve block group had a mean 24.4% excess weight loss (9.2% of their initial body weight loss) vs 15.9% excess weight loss (6.0% initial body weight loss) in the sham group. The mean difference in the percentage of the excess weight loss between groups was 8.5 percentage points (95% CI, 3.1-13.9), which did not meet the 10-point target (P = .71), although weight loss was statistically greater in the vagal nerve block group (P = .002 for treatment difference in a post hoc analysis). At 12 months, 52% of patients in the vagal nerve block group achieved 20% or more excess weight loss and 38% achieved 25% or more excess weight loss vs 32% in the sham group who achieved 20% or more loss and 23% who achieved 25% or more loss. The device, procedure, or therapy-related serious adverse event rate in the vagal nerve block group was 3.7% (95% CI, 1.4%-7.9%), significantly lower than the 15% goal. The adverse events more frequent in the vagal nerve block group were heartburn or dyspepsia and abdominal pain attributed to therapy; all were reported as mild or moderate in severity.Conclusion and Relevance: Among patients with morbid obesity, the use of vagal nerve block therapy compared with a sham control device did not meet either of the prespecified coprimary efficacy objectives, although weight loss in the vagal block group was statistically greater than in the sham device group. The treatment was well tolerated, having met the primary safety objective.Trial Registration: clinicaltrials.gov Identifier: NCT01327976. [ABSTRACT FROM AUTHOR]

IMPORTANCE Although conventional bariatric surgery results in weight loss, it does so with potential short-term and long-term morbidity. OBJECTIVE To evaluate the effectiveness and safety of intermittent, reversible vagal nerve blockade therapy for obesity treatment. DESIGN, SETTING, AND PARTICIPANTS A randomized, double-blind, sham-controlled clinical trial involving 239 participants who had a body mass index of 40 to 45 or 35 to 40 and 1 or more obesity-related condition was conducted at 10 sites in the United States and Australia between May and December 2011. The 12-month blinded portion of the 5-year study was completed in January 2013. INTERVENTIONS One hundred sixty-two patients received an active vagal nerve block device and 77 received a sham device. All participants received weight management education. MAIN OUTCOMES ANDMEASURES The coprimary efficacy objectives were to determine whether the vagal nerve block was superior in mean percentage excess weight loss to sham by a 10-pointmargin with at least 55%of patients in the vagal block group achieving a 20% loss and 45%achieving a 25%loss. The primary safety objective was to determine whether the rate of serious adverse events related to device, procedure, or therapy in the vagal block group was less than 15%. RESULTS In the intent-to-treat analysis, the vagal nerve block group had a mean 24.4% excess weight loss (9.2%of their initial body weight loss) vs 15.9%excess weight loss (6.0% initial body weight loss) in the sham group. The mean difference in the percentage of the excess weight loss between groups was 8.5 percentage points (95%CI, 3.1-13.9), which did not meet the 10-point target (P = .71), although weight loss was statistically greater in the vagal nerve block group (P = .002 for treatment difference in a post hoc analysis). At 12 months, 52%of patients in the vagal nerve block group achieved 20%ormore excess weight loss and 38%achieved 25%ormore excess weight loss vs 32%in the sham group who achieved 20%ormore loss and 23%who achieved 25%ormore loss. The device, procedure, or therapy--related serious adverse event rate in the vagal nerve block group was 3.7%(95% CI, 1.4%-7.9%), significantly lower than the 15%goal. The adverse events more frequent in the vagal nerve block group were heartburn or dyspepsia and abdominal pain attributed to therapy; all were reported as mild or moderate in severity. CONCLUSION AND RELEVANCE Among patients with morbid obesity, the use of vagal nerve block therapy compared with a sham control device did not meet either of the prespecified coprimary efficacy objectives, although weight loss in the vagal block group was statistically greater than in the sham device group. The treatment was well tolerated, having met the primary safety objective. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01327976 [ABSTRACT FROM AUTHOR]

Objectives: Our purpose was to clarify the clinical utility of identifying metabolic syndrome (MetS) in patients with coronary artery disease (CAD). Background: It is uncertain whether MetS influences prognosis in patients with CAD and whether the risk associated with MetS exceeds the risk associated with the sum of its individual components. Methods: In a post hoc analysis, we compared the incidence of death or myocardial infarction (MI) in stable CAD patients in the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) trial according to the presence (+) or absence (−) of MetS and diabetes: Group A, −MetS/−diabetes; Group B, +MetS/−diabetes; Group C, −MetS/+diabetes; and Group D, +MetS/+diabetes. We explored which MetS components best predicted adverse outcomes and whether MetS had independent prognostic significance beyond its individual components. Results: Of 2,248 patients, 61% had MetS and 34% diabetes. Risk for death or MI increased from Group A (14%) to Group D (25%, p < 0.001). Hypertension (hazard ratio [HR]: 1.30; 95% confidence interval [CI]: 0.98 to 1.71; p = 0.07), low high-density lipoprotein cholesterol (HR: 1.26; 95% CI: 1.03 to 1.55; p = 0.03), and elevated glucose (HR: 1.17; 95% CI: 0.96 to 1.47; p = 0.11) most strongly predicted death or MI. MetS was associated with an increased risk of death or MI (unadjusted HR: 1.41; 95% CI: 1.15 to 1.73; p = 0.001). However, after adjusting for its individual components, MetS was no longer significantly associated with outcome (HR: 1.15; 95% CI: 0.79 to 1.68; p = 0.46). Allocation to initial percutaneous coronary intervention did not affect the incidence of death or MI within any group. Conclusions: Among stable CAD patients in the COURAGE trial, the presence of MetS identified increased risk for death or MI, but MetS did not have independent prognostic significance after adjusting for its constituent components. The addition of early percutaneous coronary intervention to optimal medical therapy did not significantly reduce the risk of death or MI regardless of MetS or diabetes status. (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation [COURAGE]; NCT00007657) [Copyright &y& Elsevier]

Chronic kidney disease (CKD) is a risk factor for poor outcomes in patients with coronary artery disease (CAD), but it is unknown whether CKD influences the efficacy of alternative CAD treatment strategies. Thus, we compared outcomes in stable CAD patients with and without CKD randomized to percutaneous coronary intervention (PCI) and optimal medical therapy (OMT) or OMT alone in a post hoc analysis of the 2,287 patient COURAGE study. At baseline, 320 patients (14%) had CKD defined as a glomerular filtration rate of <60 mL/min/1.73 m2, as estimated by the abbreviated 4-variable Modification of Diet in Renal Disease equation. The patients with CKD were older (68 ± 9 vs 61 ± 10 years; p <0.001) and more often had diabetes mellitus (42% vs 33%; p = 0.002), hypertension (81% vs 65%; p <0.03), heart failure (13% vs 3.4%; p <001), and three-vessel CAD (37% vs 29%, p = 0.01). After adjustment for these differences, CKD remained an independent predictor of death or nonfatal myocardial infarction (hazard ratio 1.48, 95% confidence interval 1.15 to 1.90). PCI had no effect on these outcomes. Furthermore, at 36 months, a similar percentage of patients with CKD treated with OMT (70%) and PCI plus OMT (76%) were angina free compared to patients without CKD. In conclusion, CKD is an important determinant of clinical outcomes in patients with stable CAD, regardless of the treatment strategy. Although PCI did not reduce the risk of death or myocardial infarction when added to OMT for patients with CKD, it also was not associated with worse outcomes in this high-risk group. [Copyright &y& Elsevier]

Introduction: Limitations of endoscopic therapies for Barrett's esophagus and superficial cancer include a compromised histological assessment, the need for surveillance, subsequent procedures, and stricture formation. Circumferential en bloc resection of the mucosa-submucosa complex followed by deployment of a biologic scaffold onto the remaining muscularis propria may address these concerns. The objective of this study was to determine technical feasibility of transoral resection of the esophageal lining.Materials and Methods: Transoral endoscopic inner layer esophagectomy was performed in ten swine. Endpoints included procedure duration, hemorrhage, number of perforations, and adequacy of resection length and depth.Results: Procedures were successfully completed in all animals without perioperative mortality. Procedure times averaged 179 min (range 125-320). No perforations were found, and a mean of 1.7 (0-4) interventions for hemorrhage was required. Complete longitudinal resection was achieved in nine of ten animals. Resection depth included all mucosal layers in 100% of tissue sections, the submucosal layers, SM1 in 100%, and SM2 in 96%. A portion of SM3 was adherent to the muscularis propria in 70%.Conclusion: Transoral endoscopic resection of the inner esophageal layers was feasible and reproducible. This technique may facilitate a single-step definitive treatment and staging tool for early neoplastic lesions, obviating the need for esophagectomy. [ABSTRACT FROM AUTHOR]

We explored the safety and quality-of-life consequences of treating patients with stable coronary disease and high-risk features initially with optimal medical therapy (OMT) alone compared to OMT plus percutaneous coronary intervention. This was a post hoc analysis of Clinical Outcomes Utilizing Revascularization and Aggressive DruG Evaluation (COURAGE) trial patients. We defined high risk as the onset of Canadian Cardiovascular Society class III angina within 2 months or stabilized acute coronary syndrome within 2 weeks of enrollment. The primary end point was death or myocardial infarction after 4.6 years. Of the 2,287 patients enrolled in the COURAGE trial, 264 (12%) were high risk and had a relative risk of 1.56 for death or myocardial infarction (p = 0.0008) compared to those with non–high-risk features. A total of 35 primary events occurred in the OMT group and 32 in the percutaneous coronary intervention plus OMT group (hazard ratio 1.11, 95% confidence interval 0.69 to 1.79; p = 0.68). No significant difference was found in the prevalence of angina between the 2 groups at 1 year. During the first year of follow-up, 30% of the OMT patients crossed over to the revascularization group. In conclusion, an initial strategy of OMT alone for high-risk patients in the COURAGE trial did not result in increased death or myocardial infarction at 4.6 years or worse angina at 1 year, but it was associated with a high rate of crossover to revascularization. [Copyright &y& Elsevier]

Objectives: Our aim was to access clinical effectiveness of percutaneous coronary intervention (PCI) when added to optimal medical therapy (OMT) in older patients with stable coronary artery disease (CAD). Background: While older patients with CAD are at increased risk for cardiac events compared with younger patients, it is unclear whether PCI may mitigate this risk more effectively than OMT alone or, alternatively, may be associated with more complications. Methods: We conducted a pre-specified analysis of outcomes in stable CAD patients stratified by age and randomized to PCI + OMT or OMT alone in the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive druG Evaluation) trial. Results: A total of 1,381 patients (60%) were <65 years of age (mean 56 ± 6 years) and 904 patients (40%) were ≥65 years of age (mean 72 ± 5 years). Achieved treatment targets for blood pressure, low-density lipoprotein cholesterol, adherence to diet and exercise, and angina-free status did not differ by age or treatment assignment. Among older patients, there was a 2- to 3-fold higher death rate, but similar rates of myocardial infarction, stroke, and major cardiac events compared with younger patients. The addition of PCI to OMT did not improve or worsen clinical outcomes in patients ≥65 years of age during a median 4.6 year follow-up. Conclusions: These data support adherence to American College of Cardiology/American Heart Association clinical practice guidelines that advocate OMT as an appropriate initial management strategy, regardless of age. (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation [COURAGE]; NCT00007657 ) [Copyright &y& Elsevier]

Background: Anastomotic leak related to ischemia is a source of significant morbidity and mortality in gastrointestinal surgery. The aim of this study was to apply growth factor gene transfection for the purpose of up-regulating angiogenesis, increasing anastomotic strength, and ultimately preventing dehiscence.Methods: An opossum esophagogastrostomy model was employed. The human vascular endothelial growth factor (VEGF(165)) gene was incorporated into a recombinant plasmid. The VEGF plasmid vector was then complexed with a cationic synthetic carrier, polyethyleneimine. Control animals received plasmid devoid of VEGF(165) (n = 6). The experimental group received VEGF(165) plasmid (n = 5). After esophagogastrectomy and gastric tubularization, plasmid was injected into the submucosa of the neoesophagus at the anastomotic site. Conduit arteriography was performed before and 10 days after injection. Euthanasia occurred on post-injection day 10 and the anastomosis was removed en bloc. A second group of animals treated with VEGF(165) were euthanized 30 and 37 days post injection. Blood flow was measured with laser-Doppler prior to euthanasia. Ex vivo anastomotic bursting pressure was performed. Tissue samples were procured for RNA extraction and von Willebrand Factor staining. Microvessel counts were obtained by two blinded observers. Tissue VEGF transcript levels were measured with reverse transcriptase polymerase chain reaction (RT-PCR).Results: There was one anastomotic leak in the control group. Experimental animals demonstrated significantly increased bursting pressure (104.25 +/- 6.2 vs 86.73 +/- 9.4 mmHg, p = 0.021) and neovascularization (33.87 +/- 9.6 vs 20.33 +/- 8.1 vessels/hpf, p = 0.032) compared to controls. In addition, there was a strongly positive correlation between the number of microvessels and bursting pressure (r = 0.808, p = 0.015, Pearson's). On angiographic examination, treated animals demonstrated more neovascularization compared to controls. RT-PCR demonstrated up to a 5.6-fold increase in VEGF mRNA in treated compared to controls.Discussion: This description of gene therapy in gastrointestinal surgery using VEGF(165) transfection demonstrates increased angiogenesis with subsequently improved anastomotic healing in a clinically relevant model. [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]

Background: It has not been clearly established whether percutaneous coronary intervention (PCI) can provide an incremental benefit in quality of life over that provided by optimal medical therapy among patients with chronic coronary artery disease. Methods: We randomly assigned 2287 patients with stable coronary disease to PCI plus optimal medical therapy or to optimal medical therapy alone. We assessed angina-specific health status (with the use of the Seattle Angina Questionnaire) and overall physical and mental function (with the use of the RAND 36-item health survey [RAND-36]). Results: At baseline, 22% of the patients were free of angina. At 3 months, 53% of the patients in the PCI group and 42% in the medical-therapy group were angina-free (P<0.001). Baseline mean (±SD) Seattle Angina Questionnaire scores (which range from 0 to 100, with higher scores indicating better health status) were 66±25 for physical limitations, 54±32 for angina stability, 69±26 for angina frequency, 87±16 for treatment satisfaction, and 51±25 for quality of life. By 3 months, these scores had increased in the PCI group, as compared with the medical-therapy group, to 76±24 versus 72±23 for physical limitation (P=0.004), 77±28 versus 73±27 for angina stability (P=0.002), 85±22 versus 80±23 for angina frequency (P<0.001), 92±12 versus 90±14 for treatment satisfaction (P<0.001), and 73±22 versus 68±23 for quality of life (P<0.001). In general, patients had an incremental benefit from PCI for 6 to 24 months; patients with more severe angina had a greater benefit from PCI. Similar incremental benefits from PCI were seen in some but not all RAND-36 domains. By 36 months, there was no significant difference in health status between the treatment groups. Conclusions: Among patients with stable angina, both those treated with PCI and those treated with optimal medical therapy alone had marked improvements in health status during follow-up. The PCI group had small, but significant, incremental benefits that disappeared by 36 months. (ClinicalTrials.gov number, NCT00007657.) N Engl J Med 2008;359:677-87. [ABSTRACT FROM AUTHOR]