Nicholas Stylopoulos

Reprogramming of Intestinal Glucose Metabolism and Glycemic Control in Rats After Gastric Bypass

Glucose Control Goes Out on a Limb Roux-en-Y gastric bypass, a surgical procedure used to induce weight loss in morbidly obese patients, often leads to permanent remission of diabetes, even when patients regain weight. Studying a rat model, Saeidi et al. (p. 406; see Perspective by Berthoud) found that the surgically reconfigured intestinal segment (the Roux limb) underwent an adaptive response characterized by increased glucose uptake and utilization, apparently triggered by exposure to undigested nutrients. As a result of this change, the intestine provided a major tissue for whole-body glucose control. Whether the same adaptive response occurs in the human intestine remains to be examined. The intestine can adopt a role in glucose control after surgery, possibly explaining why the surgery cures diabetes. [Also see Perspective by Berthoud] The resolution of type 2 diabetes after Roux-en-Y gastric bypass (RYGB) attests to the important role of the gastrointestinal tract in glucose homeostasis. Previous studies in RYGB-treated rats have shown that the Roux limb displays hyperplasia and hypertrophy. Here, we report that the Roux limb of RYGB-treated rats exhibits reprogramming of intestinal glucose metabolism to meet its increased bioenergetic demands; glucose transporter-1 is up-regulated, basolateral glucose uptake is enhanced, aerobic glycolysis is augmented, and glucose is directed toward metabolic pathways that support tissue growth. We show that reprogramming of intestinal glucose metabolism is triggered by the exposure of the Roux limb to undigested nutrients. We demonstrate by positron emission tomography–computed tomography scanning and biodistribution analysis using 2-deoxy-2-[18F]fluoro-d-glucose that reprogramming of intestinal glucose metabolism renders the intestine a major tissue for glucose disposal, contributing to the improvement in glycemic control after RYGB.

Roux-en-Y Gastric Bypass Enhances Energy Expenditure and Extends Lifespan in Diet-induced Obese Rats

Gastrointestinal weight‐loss surgery (GIWLS) is currently the most effective treatment for severe obesity, with Roux en‐Y gastric bypass (RYGB) among the best of the available surgical options. Despite its widespread clinical use, the mechanisms by which RYGB induces its profound weight loss remain largely unknown. This procedure effects weight loss by altering the physiology of weight regulation and eating behavior rather than by simple mechanical restriction and/or malabsorption as previously thought. To study how RYGB affects the physiology of energy balance, we developed a rat model of this procedure. In this report, we demonstrate that RYGB in diet‐induced obese (DIO) rats induces a 25% weight loss, prolongs mean survival by 45%, and normalizes glucose homeostasis and lipid metabolism. RYGB induced a 19% increase in total and a 31% increase in resting energy expenditure (REE). These effects, along with a 17% decrease in food intake and a 4% decrease in nutrient absorption account for the normalization of body weight after this procedure. These effects indicate that surgery acts by altering the physiology of weight regulation and help to explain the effectiveness of RYGB in comparison to restrictive dieting and other forms of dietary and pharmacological therapies for obesity. The clinical effectiveness of RYGB and its physiological effects on body weight regulation and energy expenditure (EE) suggest that this operation provides a unique opportunity to explore the mechanisms of energy homeostasis and to identify novel therapies for obesity and related metabolic diseases.

The Benefit of Force Feedback in Surgery: Examination of Blunt Dissection

Force feedback is widely assumed to enhance performance in robotic surgery, but its benefits have not yet been systematically assessed. In this study we examine the effects of force feedback on a blunt dissection task. Twenty subjects used a telerobotic system to expose an artery in a synthetic model while viewing the operative site with a video laparoscope. Subjects were drawn from a range of surgical backgrounds, from inexperienced to attending surgeons. Performance was compared between three force feedback gains: 0 (no force feedback), 37, and 75. The absence of force feedback increased the average force magnitude applied to the tissue by at least 50, and increased the peak force magnitude by at least 100. The number of errors that damage tissue increased by over a factor of 3. The rate and precision of dissection were not significantly enhanced with force feedback. These results hold across all levels of previous surgical experience. We hypothesize that force feedback is helpful in this blunt dissection task because the artery is stiffer than the surrounding tissue. This mechanical contrast serves to constrain the subjects hand from commanding inappropriate motions that generate large forces.

Metrics for Laparoscopic Skills Trainers: The Weakest Link!

Metrics are widely employed in virtual environments and provide a yardstick for performance measurement. The current method of defining metrics for medical simulation remains more an art than a science. Herein, we report a practical scientific approach to defining metrics, specifically aimed at computer-assisted laparoscopic skills training. We also propose a standardized global scoring system usable across different laparoscopic trainers and tasks. The metrics were defined in an explicit way based on the relevant skills that a laparoscopic surgeon should master. We used a five degree of freedom device and a software platform capable of 1) tracking the motion of two laparoscopic instruments 2) real time information processing and feedback provision. A validation study was performed. The results show that our metrics and scoring system represent a technically sound approach that can be easily incorporated in a computerized trainer for any task, enabling a standardized performance assessment method.

GLP-1 receptor signaling is not required for reduced body weight after RYGB in rodents

Exaggerated GLP-1 and PYY secretion is thought to be a major mechanism in the reduced food intake and body weight after Roux-en-Y gastric bypass surgery. Here, we use complementary pharmacological and genetic loss-of-function approaches to test the role of increased signaling by these gut hormones in high-fat diet-induced obese rodents. Chronic brain infusion of a supramaximal dose of the selective GLP-1 receptor antagonist exendin-9-39 into the lateral cerebral ventricle significantly increased food intake and body weight in both RYGB and sham-operated rats, suggesting that, while contributing to the physiological control of food intake and body weight, central GLP-1 receptor signaling tone is not the critical mechanism uniquely responsible for the body weight-lowering effects of RYGB. Central infusion of the selective Y2R-antagonist BIIE0246 had no effect in either group, suggesting that it is not critical for the effects of RYGB on body weight under the conditions tested. In a recently established mouse model of RYGB that closely mimics surgery and weight loss dynamics in humans, obese GLP-1R-deficient mice lost the same amount of body weight and fat mass and maintained similarly lower body weight compared with wild-type mice. Together, the results surprisingly provide no support for important individual roles of either gut hormone in the specific mechanisms by which RYGB rats settle at a lower body weight. It is likely that the beneficial effects of bariatric surgeries are expressed through complex mechanisms that require combination approaches for their identification.

Melanocortin-4 Receptor Signaling Is Required for Weight Loss after Gastric Bypass Surgery

CONTEXT Roux-en-Y gastric bypass (RYGB) is one of the most effective long-term therapies for the treatment of severe obesity. Recent evidence indicates that RYGB effects weight loss through multiple physiological mechanisms, including changes in energy expenditure, food intake, food preference, and reward pathways. OBJECTIVE Because central melanocortin signaling plays an important role in the regulation of energy homeostasis, we investigated whether genetic disruption of the melanocortin-4 receptor (MC4R) in rodents and humans affects weight loss after RYGB. METHODS AND RESULTS Here we report that MC4R(-/-) mice lost substantially less weight after surgery than wild-type animals, indicating that MC4R signaling is necessary for the weight loss effects of RYGB in this model. Mice heterozygous for MC4R remain fully responsive to gastric bypass. To determine whether mutations affect surgically induced weight loss in humans, we sequenced the MC4R gene in 972 patients undergoing RYGB. Patients heterozygous for MC4R mutations exhibited the same magnitude and distribution of postoperative weight loss as patients without such mutations, suggesting that although two normal copies of the MC4R gene are necessary for normal weight regulation, a single normal copy of the MC4R gene is sufficient to mediate the weight loss effects of RYGB. CONCLUSIONS MC4R is the first gene identified that is required for the sustained effects of bariatric surgery. The need for MC4R signaling for the weight loss effects of RYGB in mice underscores the physiological mechanisms of action of this procedure and demonstrates that RYGB both influences and is dependent on the normal pathways that regulate energy balance.

The history of hiatal hernia surgery: from Bowditch to laparoscopy.

Objective:This review addresses the historical evolution of hiatal hernia (HH) repair and reports in a chronological fashion the major milestones in HH surgery before the laparoscopic era. Methods:The medical literature and the collections of the History of Medicine Division of the National Library of Medicine were searched. Secondary references from all sources were studied. The senior authors experience and personal communications are also reported. Results:The first report of HH was published in 1853 by Bowditch. Rokitansky in 1855 demonstrated that esophagitis was due to gastroesophageal reflux, and Hirsch in 1900 diagnosed an HH using x-rays. Eppinger diagnosed an HH in a live patient, and Friedenwald and Feldman related the symptoms to the presence of an HH. In 1926, Akerlund proposed the term hiatus hernia and classified HH into the 3 types that we use today. The first elective surgical repair was reported in 1919 by Soresi. The physiologic link between HH and gastroesophageal reflux was made at the second half of the 20th century by Allison and Barrett. In the midst of a physiologic revolution, Nissen and Belsey developed their famous operations. In 1957, Collis published his innovative operation. Thal described his technique in 1965, and in 1967, Hill published his procedure. Many modifications of these procedures were published by Pearson and Henderson, Orringer and Sloan, Rossetti, Dor, and Toupet. Donahue and Demeester significantly improved Nissens operation, and they were the first to truly understand its physiologic mechanism. Conclusion:Hiatal hernia surgery has evolved from anatomic repair to physiological restoration.

An Endoluminal Sleeve Induces Substantial Weight Loss and Normalizes Glucose Homeostasis in Rats with Diet‐Induced Obesity

To investigate the contributions of two surgical gut manipulations—exclusion of the proximal intestine from alimentary flow and exposure of the jejunum to partially digested nutrients—to body weight regulation and metabolism, we have developed a rat model of an investigational device, the endoluminal sleeve (ELS). The ELS is a 10 cm, nutrient‐impermeable, flexible tube designed for endoluminal implantation. ELS devices were surgically implanted in the duodenal bulb of rats with diet‐induced obesity. Body weight, food intake, stool caloric content, and glucose homeostasis were subsequently evaluated. ELS‐implanted rats demonstrated a 20% reduction of body weight compared to sham‐operated (SO) controls. ELS‐treated animals consumed an average of 27% fewer kcal/day than SO, and there was no evidence of malabsorption. ELS treatment improved fasting glycemia and glucose tolerance after oral and intraperitoneal (IP) administration. ELS treatment enhanced insulin sensitivity, as demonstrated by decreased fasting and glucose‐stimulated insulin levels and confirmed by calculation of homeostasis model assessment of insulin resistance (IR). These data suggest that selective bypass of the proximal intestine by ELS, with enhanced delivery of partially digested nutrients to the jejunum, mimics many of the effects of Roux‐en‐Y gastric bypass (RYGB) on body weight and glucose metabolism. Thus, ELS implantation may be an effective treatment for obesity and diabetes. Since the ELS device is amenable to endoscopic placement, it may offer a valuable alternative to more invasive surgical approaches in selected patients with obesity and its metabolic complications.

Robotics and ergonomics

Industrial robotics have proven the benefit of using an untiring machine to perform precise repetitive tasks in uncomfortable or dangerous for humans environments. Highly skilled surgeons are trained to operate and adapt to difficult conditions. They are even capable of developing intelligent mechanisms to exploit a variety of tactile, visual, and other cues. The robotic systems, however, can enhance the surgeons capability to perform a wide variety of tasks. They cannot replace the surgeons problem-solving ability. Instead, they will redefine his role. They will significantly enhance the surgeons skills and dexterity by providing their complementary capabilities and an ergonomically efficient and more user-friendly working environment.

A cost-utility analysis of treatment options for inguinal hernia in 1,513,008 adult patients

Background: The controversial issue of the cost-effectiveness of laparoscopic inguinal hernia repair is examined, employing a decision analytic method. Materials and methods: The NSAS, NHDS (National Center for Health Statistics), HCUP-NIS (Agency for Healthcare Research and Quality) databases and 51 randomized controlled trials were analyzed. The study group constituted of a total of 1,513,008 hernia repairs. Projection of the clinical, economic, and quality-of-life outcomes expected from the different treatment options was done by using a Markov Monte Carlo decision model. Two logistic regression models were used to predict the probability of hospital admission after an ambulatory procedure and the probability of death after inguinal hernia repair. Four treatment strategies were modeled: (1) laparoscopic repair (LR), (2) open mesh (OM), (3) open non-mesh (ONM), and (4) expectant management. Costs were expressed in US dollars and effectiveness in quality-adjusted life years (QALYs). The main outcome measures were the average and the incremental cost-effectiveness (ICER) ratios. Results: Compared to the expectant management, the incremental cost per QALY gained was