Benjamin E. Schneider

FNDC5 and irisin in humans: I. Predictors of circulating concentrations in serum and plasma and II. mRNA expression and circulating concentrations in response to weight loss and exercise

OBJECTIVE In mouse, PGC1-α overexpression in muscle stimulates an increase in expression of FNDC5, a membrane protein that is cleaved and secreted as a newly identified hormone, irisin. One prior study has shown that FNDC5 induces browning of subcutaneous fat in mice and mediates beneficial effects of exercise on metabolism, but a more recent study using gene expression arrays failed to detect a robust increase in FNDC5 mRNA in human muscles from exercising subjects. No prior study has reported on the physiological regulation and role of circulating irisin and FNDC5 in humans. MATERIALS/METHODS A. FNDC5 gene expression studies: We first examined tissue distribution of FNDC5 in humans. B. Cross-sectional studies: Predictors of FNDC5 mRNA expression levels were examined in muscle tissues from 18 healthy subjects with a wide range of BMI. Assays were optimized to measure circulating FNDC5 and irisin levels, and their associations with anthropometric and metabolic parameters were analyzed in two cross-sectional studies that examined 117 middle-aged healthy women and 14 obese subjects, respectively. C. Interventional studies: The effect of weight loss on FNDC5 mRNA and/or circulating irisin levels was examined in 14 obese subjects before and after bariatric surgery. The effect of acute and chronic exercise was then assessed in 15 young healthy adults who performed intermittent sprint running sessions over an 8 week period. RESULTS Tissue arrays demonstrated that in humans, the FNDC5 gene is predominantly expressed in muscle. Circulating irisin was detected in the serum or plasma of all subjects studied, whereas circulating FNDC5 was detected in only a distinct minority of the subjects. Cross-sectional studies revealed that circulating irisin levels were positively correlated with biceps circumference (used as a surrogate marker of muscle mass herein), BMI, glucose, ghrelin, and IGF-1. In contrast, irisin levels were negatively correlated with age, insulin, cholesterol, and adiponectin levels, indicating a possible compensatory role of irisin in metabolic regulation. Multivariate regression analysis revealed that biceps circumference was the strongest predictor of circulating irisin levels underlying the association between irisin and metabolic factors in humans at baseline. Both muscle FNDC5 mRNA levels and circulating irisin levels were significantly downregulated 6 months after bariatric surgery. Circulating irisin levels were significantly upregulated 30 min after acute exercise and were correlated mainly with ATP levels and secondarily with metabolites related to glycolysis and lipolysis in muscle. CONCLUSIONS Similar to mice, the FNDC5 gene is expressed in human muscle. Age and muscle mass are the primary predictors of circulating irisin, with young male athletes having several fold higher irisin levels than middle-aged obese women. Circulating irisin levels increase in response to acute exercise whereas muscle FNDC5 mRNA and circulating irisin levels decrease after surgically induced weight loss in parallel to decrease in body mass. Further studies are needed to study the regulation of irisin levels and its physiological effects in humans and to elucidate the mechanisms underlying these effects.

Is routine cholecystectomy required during laparoscopic gastric bypass

Background: Routine cholecystectomy is often performed at the time of gastric bypass for morbid obesity. The aim of our study was to determine the incidence of gallstone formation requiring cholecystectomy following a laparoscopic Roux-en-Y gastric bypass (LRYGBP). Methods: 289 LRYGBP were performed between November 1999 and May 2002. 60 patients (21%) who had prior cholecystectomy were excluded. If gallstones were identified by intra-operative ultrasound (IOUS), simultaneous cholecystectomy was performed. Patients without gallstones were prescribed ursodiol for 6 months and scheduled for follow-up with transabdominal ultrasound. Results: During LRYGBP, gallstones were detected in 40 patients using IOUS (14%) and simultaneous cholecystectomy was performed. Of 189 patients with no stones identified by IOUS, 151 patients (80%) had a postoperative ultrasound after 6 months. 39 patients developed gallstones (22%) and 12 developed sludge (8%), as demonstrated by ultrasound at the time of follow-up. 11 patients had gallstone-related symptoms and subsequently underwent cholecystectomy (7%). 106 patients (70%) were gallstone-free at the time of ultrasound follow-up. Ursodiol compliance was found to be significantly lower for patients developing stones than for gallstone-free patients (38.9% vs 58.3%, z =-2.00, P = 0.045). Conclusions: There is a low incidence of symptomatic gallstones requiring cholecystectomy after LRYGBP. Prophylactic ursodiol is protective. Routine IOUS and selective cholecystectomy with close patient follow-up is a rational approach in the era of laparoscopy.

Efficacy of Metreleptin in Obese Patients With Type 2 Diabetes: Cellular and Molecular Pathways Underlying Leptin Tolerance

OBJECTIVE Metreleptin has been efficacious in improving metabolic control in patients with lipodystrophy, but its efficacy has not been tested in obese patients with type 2 diabetes. RESEARCH DESIGN AND METHODS We studied the role of leptin in regulating the endocrine adaptation to long-term caloric deprivation and weight loss in obese diabetic subjects over 16 weeks in the context of a double-blinded, placebo–controlled, randomized trial. We then performed detailed interventional and mechanistic signaling studies in humans in vivo, ex vivo, and in vitro. RESULTS In obese patients with diabetes, metreleptin administration for 16 weeks did not alter body weight or circulating inflammatory markers but reduced HbA1c marginally (8.01 ± 0.93–7.96 ± 1.12, P = 0.03). Total leptin, leptin-binding protein, and antileptin antibody levels increased, limiting free leptin availability and resulting in circulating free leptin levels of ∼50 ng/mL. Consistent with clinical observations, all metreleptin signaling pathways studied in human adipose tissue and peripheral blood mononuclear cells were saturable at ∼50 ng/mL, with no major differences in timing or magnitude of leptin-activated STAT3 phosphorylation in tissues from male versus female or obese versus lean humans in vivo, ex vivo, or in vitro. We also observed for the first time that endoplasmic reticulum (ER) stress in human primary adipocytes inhibits leptin signaling. CONCLUSIONS In obese patients with diabetes, metreleptin administration did not alter body weight or circulating inflammatory markers but reduced HbA1c marginally. ER stress and the saturable nature of leptin signaling pathways play a key role in the development of leptin tolerance in obese patients with diabetes.

Laparoscopic skills training

Since the era of William Halsted, surgical education in the United States has followed a preceptor model whereby the student learned by watching the teacher. The student was allowed graded ‘‘hands-on’’ experience over time with variable degrees of supervision. Increasingly, many surgical educators have called into question the traditional dogma of ‘‘See one—Do one—Teach one.’’ With the recent movement to limit the resident work week to 80 hours, research has focused on determining whether technical skills are better taught outside the operating room. Basic laparoscopic skills and cognitive knowledge of laparoscopic surgery can be taught outside the operating room to medical students. Efforts today are aimed at training surgeons before they perform a new laparoscopic procedure, so complications can be minimized or avoided altogether. This review will provide a general overview of the experience with skills training to date and set the discussion for standardizing a surgical curriculum for general surgery residents.

Leptin and amylin act in an additive manner to activate overlapping signaling pathways in peripheral tissues; in vitro and ex vivo studies in humans

OBJECTIVE Amylin interacts with leptin to alter metabolism. We evaluated, for the first time, amylin- and/or leptin-activated signaling pathways in human peripheral tissues (hPTs). RESEARCH DESIGN AND METHODS Leptin and amylin signaling studies were performed in vitro in human primary adipocytes (hPAs) and human peripheral blood mononuclear cells (hPBMCs) and ex vivo in human adipose tissue (hAT) from male versus female subjects, obese versus lean subjects, and subjects with subcutaneous versus omental adipose tissue. RESULTS The long form of leptin receptor was expressed in human tissues and cells studied in ex vivo and in vitro, respectively. Leptin and amylin alone and in combination activate signal transducer and activator of transcription 3 (STAT3), AMP-activated protein kinase, Akt, and extracellular signal-regulated kinase signaling pathways in hAT ex vivo and hPAs and hPBMCs in vitro; all phosphorylation events were saturable at leptin and amylin concentrations of ∼50 and ∼20 ng/ml, respectively. The effects of leptin and amylin on STAT3 phosphorylation in hPAs and hPBMCs in vitro were totally abolished under endoplasmic reticulum stress and/or in the presence of a STAT3 inhibitor. Results similar to those in the in vitro studies were observed in hAT studied ex vivo. CONCLUSIONS Leptin and amylin activate overlapping intracellular signaling pathways in humans and have additive, but not synergistic, effects in signaling pathways studied in hPTs in vitro and ex vivo.

Cardiac remodeling after substantial weight loss: a prospective cardiac magnetic resonance study after bariatric surgery

BACKGROUND Obesity is a risk factor for left ventricular (LV) hypertrophy and excess cardiovascular disease and mortality. Substantial weight loss is associated with a decrease in cardiovascular mortality. Using volumetric cardiovascular magnetic resonance (CMR) imaging, we studied changes in cardiac anatomy and systolic function in women undergoing substantial weight loss in a university hospital. METHODS A total of 17 women (body mass index [BMI] 44.1 +/- 4.2 kg/m(2); age 44 +/- 11 yr) scheduled for bariatric surgery underwent volumetric CMR imaging before and 3 and 17 months after surgery. RESULTS The body weight declined by 37.2 +/- 10.5 kg (32%) with a decrease in BMI to 29.9 +/- 4.7 kg/m(2) (32%, P < .004) during 17 months of observation. The LV mass decreased from 120 +/- 23 g to 82 +/- 11 g (32%, P < .004), with a linear relationship between the decrease in BMI and decrease in LV mass (P = .008) for the duration of the observation period. After adjustment for systolic and/or diastolic blood pressure, the relationship remained significant (P < .001). The right ventricular (RV) mass declined from 31.7 +/- 6.7 g preoperatively to 26.6 +/- 4.5 g at 3 months (16%, P < .001) but without additional changes at 17 months. No change was found in the LV or RV end-diastolic volume or ejection fraction. CONCLUSION In morbidly obese women, substantial weight loss was associated with a reduction of LV and RV mass. The decrease in LV mass was linearly related to the reduction in BMI, independent of changes in blood pressure, and might partially explain the reduction in cardiovascular mortality associated with substantial weight loss. The BMI was a predictor of LV mass in this population.

Intraoperative ultrasonography during planned liver resections: why are we still performing it?

BackgroundIntraoperative ultrasonography (US) is used in many centers before oncologic liver resections to detect additional tumors and to evaluate the relationship of tumors to major vascular structures. As preoperative imaging improves, it is expected that the diagnostic yield from intraoperative US will diminish. In this study we attempt to determine if fewer unrecognized tumors were being detected and whether intraoperative US is having less impact on surgical decision making.MethodsWe compared 50 consecutive cases (mean age = 57.2 ± 10 years; 27 men) who underwent laparotomy for a planned resection of primary liver malignancies or metastases between September 2003 and July 2005 with 50 consecutive cases (mean age = 56.9 ± 14 years; 25 men) between January 1999 and September 2003. Dedicated intraoperative liver US was performed or supervised by a gastrointestinal radiologist using a 5.0-MHz linear- or curvilinear-array transducer during each procedure.ResultsThe rate of detecting unrecognized tumors has not changed significantly (14% vs. 20%, p = 0.70). The use of US to establish the relationship between tumor and the vasculature has not changed (48% vs. 60%, p = 0.23). The percentage of cases where the US findings were responsible for altering surgical management was 20% for both groups. The resection rate was 72% for both groups. The negative resection margin rate has also not changed significantly (86% vs. 69%, p = 0.09).ConclusionsDespite the advances in cross-sectional imaging, the frequency of unrecognized tumors found during intraoperative liver US and its use for surgical guidance has not changed significantly. Currently routine intraoperative US alters the management of approximately one fifth of our patients undergoing attempted liver resection for primary malignancies or metastases.

Contraceptive Counseling for Women Who Undergo Bariatric Surgery

BACKGROUND Women are counseled to avoid becoming pregnant for 12-24 months after bariatric surgery. The aim of this study was to assess contraceptive counseling and use in women who undergo bariatric surgery. METHODS A self-administered survey was completed by women aged 18-45 years at a postoperative clinic visit >2 months after bariatric surgery at an urban teaching hospital. RESULTS Of the 69 respondents, 94.2% knew to avoid pregnancy for at least 12 months after surgery. However, 16.3% did not use any contraception 2-12 months after surgery. The most common contraceptive methods used were condoms (30.6%) and oral contraceptives (16.3%). Longer-acting reversible contraceptives were used less frequently; for example, only 4% of women used intrauterine devices. Only 21.2% of respondents were referred to an obstetrician/gynecologist for contraceptive counseling. CONCLUSIONS Many women who undergo bariatric surgery are not using very effective contraceptive methods or any contraception. There is a clear opportunity to improve counseling and increase use of more effective contraception in this population.

Laparoscopic totally extraperitoneal versus Lichtenstein herniorrhaphy: cost comparison at teaching hospitals.

Laparoscopic hernia repair is safe and effective and may result in less postoperative pain and faster recuperation compared with traditional open hernia repairs. Controversy exists as to the increased cost associated with laparoscopic repairs. The purpose of this study was to quantify and compare the cost of the totally extraperitoneal (TEP) laparoscopic repair and the tension-free Lichtenstein repair at teaching hospitals. The records of consecutive TEP (n = 28) and Lichtenstein (n = 28) repairs performed at Parkland Memorial Hospital and Zale-Lipshy University Hospital were reviewed. A detailed cost analysis was performed. Total patient charge (

Patient selection optimization following combined abdominal procedures: analysis of 4925 patients undergoing panniculectomy/abdominoplasty with or without concurrent hernia repair.

5,509 vs.