Dean J. Mikami

Visceral Adipose Inflammation in Obesity Is Associated with Critical Alterations in Tregulatory Cell Numbers

Background The development of insulin resistance (IR) in mouse models of obesity and type 2 diabetes mellitus (DM) is characterized by progressive accumulation of inflammatory macrophages and subpopulations of T cells in the visceral adipose. Regulatory T cells (Tregs) may play a critical role in modulating tissue inflammation via their interactions with both adaptive and innate immune mechanisms. We hypothesized that an imbalance in Tregs is a critical determinant of adipose inflammation and investigated the role of Tregs in IR/obesity through coordinated studies in mice and humans. Methods and Findings Foxp3-green fluorescent protein (GFP) “knock-in” mice were randomized to a high-fat diet intervention for a duration of 12 weeks to induce DIO/IR. Morbidly obese humans without overt type 2 DM (n = 13) and lean controls (n = 7) were recruited prospectively for assessment of visceral adipose inflammation. DIO resulted in increased CD3+CD4+, and CD3+CD8+ cells in visceral adipose with a striking decrease in visceral adipose Tregs. Treg numbers in visceral adipose inversely correlated with CD11b+CD11c+ adipose tissue macrophages (ATMs). Splenic Treg numbers were increased with up-regulation of homing receptors CXCR3 and CCR7 and marker of activation CD44. In-vitro differentiation assays showed an inhibition of Treg differentiation in response to conditioned media from inflammatory macrophages. Human visceral adipose in morbid obesity was characterized by an increase in CD11c+ ATMs and a decrease in foxp3 expression. Conclusions Our experiments indicate that obesity in mice and humans results in adipose Treg depletion. These changes appear to occur via reduced local differentiation rather than impaired homing. Our findings implicate a role for Tregs as determinants of adipose inflammation.

Transgastric instrumentation and bacterial contamination of the peritoneal cavity

IntroductionNatural orifice transluminal endoscopic surgery (NOTES) is a rapidly evolving technique providing access to the peritoneum utilizing an endoscope via a natural orifice. One of the most significant requirements of this technique is the need to minimize the risk of clinically significant peritoneal contamination. We report the bacterial load and contamination of the peritoneal cavity in patients requiring a gastrotomy Roux-en-Y gastric bypass (LSRYGB).MethodsWe prospectively studied 50 patients undergoing a gastrotomy with creation of a gastrojejunostomy during LSRYGB. We recorded the patient’s proton-pump inhibitor (PPI) utilization preoperatively and sampled gastric contents without lavage. We also sampled peritoneal fluid prior to and after gastrotomy, noting the length of time the gastrotomy was open to the peritoneum. Each of the three samples was sent for bacterial colony counts, and culture with identification of species.ResultsFifty patients underwent LSRYGB with a mean operative time of 93 min. The gastrotomy was open to the peritoneal cavity for an average of 18 min. Seventeen of 50 patients were on PPIs preoperatively, resulting in a significant difference in postgastrostomy peritoneal bacterial counts. The average number of colony-forming units (CFU) of the gastric aspirate was 22,303 CFU/ml. Peritoneal aspirates obtained for examination prior to creation of a gastrotomy showed no CFUs in 44 of 50 patients. Peritoneal sampling after gastrotomy showed contamination of the abdomen with an average of 1102 CFU/ml. There was no correlation between the bacterial load in the stomach and peritoneal load after gastrotomy. No infectious complications or leaks developed. One complication of rhabdomyolysis in a patient with no peritoneal bacterial contamination developed.ConclusionsTransgastric instrumentation does contaminate the abdominal cavity but pathogens are clinically insignificant due to species or bacterial load. Patients on PPIs do have an increased bacterial load in the gastric aspirate, with no clinical significant infection.

A Potential Role for Dendritic Cell/Macrophage-Expressing DPP4 in Obesity-Induced Visceral Inflammation

Dipeptidyl peptidase-4 (DDP4) inhibitors target the enzymatic degradation of incretin peptides and represent a major advance in the treatment of type 2 diabetes. DPP4 has a number of nonenzymatic functions that involve its interaction with adenosine deaminase (ADA) and other extracellular matrix proteins. Here, we assessed the nonenzymatic role of DPP4 in regulating dendritic cell (DC)/macrophage–mediated adipose inflammation in obesity. Both obese humans and rodents demonstrated increased levels of DPP4 expression in DC/macrophage cell populations from visceral adipose tissue (VAT). The DPP4 expression increased during monocyte differentiation to DC/macrophages and with lipopolysaccharide (LPS)-induced activation of DC/macrophages. The DPP4 colocalized with membrane-bound ADA on human DCs and enhanced the ability of the latter to stimulate T-cell proliferation. The DPP4 interaction with ADA in human DC/macrophages was competitively inhibited by the addition of exogenous soluble DPP4. Knockdown of DPP4 in human DCs, but not pharmacologic inhibition of their enzymatic function, significantly attenuated the ability to activate T cells without influencing its capacity to secrete proinflammatory cytokines. The nonenzymatic function of DPP4 on DC may play a role in potentiation of inflammation in obesity by interacting with ADA. These findings suggest a novel role for the paracrine regulation of inflammation in adipose tissue by DPP4.

Robotic and laparoscopic pancreaticoduodenectomy: A hybrid approach

Objectives: Minimally invasive surgery is beneficial for complex operations; robotics may improve performance in these procedures; however, robotic pancreaticoduodenectomy (PD) has been plagued by long operative times. We describe a small series (n = 5) of patients who underwent a hybrid PD for treatment of obstructive jaundice and pancreatic mass. Methods: After diagnostic laparoscopy, the gallbladder was retracted cephalad and the porta hepatis was dissected. The lesser sac was opened to expose the superior mesenteric vein below the pancreas. Once the vein was cleared, the bile duct, stomach, pancreas, and jejunum were transected. After the uncinate process was cleared, the specimen was removed. The da Vinci S Surgical Robotic System was docked to perform a mucosa-to-mucosa pancreaticojejunostomy and an end-to-side choledochojejunostomy. A stapled gastrojejunostomy and drain placement completed the operation. Results: Five patients underwent hybrid PD between May 2006 and June 2007. All patients had a history of pancreatitis and presented with obstructive jaundice and a pancreatic mass. The operations were completed with 5 ports. The mean operative time was 7 hours. The mean hospital stay was 9.6 days. At 6 months after the operation, all patients were disease-free. Conclusions: Complex procedures such as PD can be accomplished with minimally invasive surgical techniques using robotic instrumentation.

T-Cell Costimulation Protects Obesity-Induced Adipose Inflammation and Insulin Resistance

A key pathophysiologic role for activated T-cells in mediating adipose inflammation and insulin resistance (IR) has been recently postulated. However, mechanisms underlying their activation are poorly understood. In this study, we demonstrated a previously unrecognized homeostatic role for the costimulatory B7 molecules (CD80 and CD86) in preventing adipose inflammation. Instead of promoting inflammation, which was found in many other disease conditions, B7 costimulation reduced adipose inflammation by maintaining regulatory T-cell (Treg) numbers in adipose tissue. In both humans and mice, expression of CD80 and CD86 was negatively correlated with the degree of IR and adipose tissue macrophage infiltration. Decreased B7 expression in obesity appeared to directly impair Treg proliferation and function that lead to excessive proinflammatory macrophages and the development of IR. CD80/CD86 double knockout (B7 KO) mice had enhanced adipose macrophage inflammation and IR under both high-fat and normal diet conditions, accompanied by reduced Treg development and proliferation. Adoptive transfer of Tregs reversed IR and adipose inflammation in B7 KO mice. Our results suggest an essential role for B7 in maintaining Tregs and adipose homeostasis and may have important implications for therapies that target costimulation in type 2 diabetes.

A review of 130 humans enrolled in transgastric NOTES protocols at a single institution.

BackgroundThe methodology of Natural Orifice Translumenal Endoscopic Surgery (NOTES) has been validated in both human and animal models. Herein is a discussion of our experience gained from the initial 130 patients enrolled in transgastric pre-NOTES and NOTES protocols at our institution.MethodsA retrospective review of our research database was performed for all patients enrolled in NOTES protocols. The infectious risk of a gastrotomy with and without a NOTES procedure was assessed in 100 patients. Eighty patients completed a true NOTES protocol looking at staging, access, and insufflation with select patients evaluating the potential for bacterial contamination of the abdominal compartment.ResultsA total of 130 patients have completed pre-NOTES and NOTES protocols at our institution. We observed no clinically significant contamination of the abdomen secondary to transgastric procedures in 100 patients. Diagnostic transgastric endoscopic peritoneoscopy (DTEP) was completed in 20 patients with pancreatic head masses and found to have a 95% concordance with laparoscopic exploration for assessment of peritoneal metastases. Blind endoscopic gastrotomy and DTEP were evaluated in 40 patients who underwent laparoscopic Roux-en-Y gastric bypass procedures (LSRYGB) and were found to be safe, reliable, and without a clinically significant risk of contamination. Endoscopic peritoneal insufflation was successfully established and correlated with standard laparoscopic insufflation in 20 patients.ConclusionsTransgastric NOTES is a safe alternative approach to accessing the peritoneal cavity in humans. The risk of bacterial contamination secondary to peroral and transgastric access is clinically insignificant. A device for the facile closure of the gastric defect is the sole factor limiting institution of this methodology as a standalone technique.

Heating and humidifying of carbon dioxide during pneumoperitoneum is not indicated: A prospective randomized trial

BackgroundCarbon dioxide (CO2) pneumoperitoneum usually is created by a compressed gas source. This exposes the patient to cool dry gas delivered at room temperature (21°C) with 0% relative humidity. Various delivery methods are available for humidifying and heating CO2 gas. This study was designed to determine the effects of heating and humidifying gas for the intraabdominal environment.MethodsFor this study, 44 patients undergoing laparoscopic Roux-en-Y gastric bypass were randomly assigned to one of four arms in a prospective, randomized, single-blinded fashion: raw CO2 (group 1), heated CO2 (group 2), humidified CO2 (group 3), and heated and humidified CO2 (group 4). A commercially available CO2 heater–humidifier was used. Core temperatures, intraabdominal humidity, perioperative data, and postoperative outcomes were monitored. Peritoneal biopsies were taken in each group at the beginning and end of the case. Biopsies were subjected staining protocols designed to identify structural damage and macrophage activity. Postoperative narcotic use, pain scale scores, recovery room time, and length of hospital stay were recorded. One-way analysis of variance (ANOVA) and the nonparametric Kruskal–Wallis test were used to compare the groups.ResultsDemographics, volume of CO2 used, intraabdominal humidity, bladder temperatures, lens fogging, and operative times were not significantly different between the groups. Core temperatures were stable, and intraabdominal humidity measurements approached 100% for all the patients over the entire procedure. Total narcotic dosage and pain scale scores were not statistically different. Recovery room times and length of hospital stay were similar in all the groups. Only one biopsy in the heated–humidified group showed an increase in macrophage activity.ConclusionsThe intraabdominal environment in terms of temperature and humidity was similar in all the groups. There was no significant difference in the intraoperative body temperatures or the postoperative variable measured. No histologic changes were identified. Heating or humidifying of CO2 is not justified for patients undergoing laparoscopic bariatric surgery.

Endoluminal revision of gastric bypass for weight regain—a systematic review

BACKGROUND Weight recidivism after Roux-en-Y gastric bypass (RYGB) is a challenging problem for patients and bariatric surgeons alike. Traditional operative strategies to combat weight regain are technically challenging and associated with a high morbidity rate. Endoluminal interventions are thus an attractive alternative that may offer a good combination of results coupled with lower periprocedure risk that might one day provide a solution to this increasingly prevalent problem. The purpose of this article is to systematically review the available literature on endoluminal procedures used to address weight regain after RYGB, with specific attention to the safety profile, efficacy, cost, and current availability. This review focuses only on endoluminal procedures that are performed for weight regain after RYGB, as opposed to primary endoluminal obesity procedures. METHODS This study was a retrospective review. RESULTS Several methods of endoluminal intervention for weight regain are reviewed, ranging from injection of inert substances to suturing and clipping devices. The literature review shows the procedures on the whole to be well tolerated with limited efficacy. The majority of the literature is limited to small case series. Most of the reviewed devices are no longer commercially available. CONCLUSIONS Endoluminal therapy represents an intriguing strategy for weight regain after RYGB. However, the current and future technologies must be rigorously studied and improved such that they offer durable, repeatable, cost-effective solutions.

Gastrotomy closure using bioabsorbable plugs in a canine model.

The repair of gastric perforation commonly involves simple suture closure using an open or laparoscopic approach. An endolumenal approach using prosthetic materials may be beneficial. The role of bioprosthetics in this instance has not been thoroughly investigated, thus the authors evaluated the feasibility of gastric perforation repair using a bioabsorbable device and quantified gross and histological changes at the injury site. Twelve canines were anesthetized and underwent open gastrotomy. A 1-cm-diameter perforation was created in the anterior wall of the stomach and plugged with a bioabsorbable device. Intralumenal pH was recorded. Canines were sacrificed at one, four, six, eight, and 12 weeks. The stomach was explanted followed by gross and histological examination. The injury site was examined. The relative ability of the device to seal the perforation was recorded, as were postoperative changes. Tissue samples were analyzed for gross and microscopic tissue growth and compared to normal gastric tissue in the same animal as an internal control. A scoring system of −2 to +2 was used to measure injury site healing (−2= leak, −1= no leak and minimal ingrowth, 0= physiologic healing, +1= mild hypertrophic tissue, +2= severe hypertrophic tissue). In all canines, the bioprosthesis successfully sealed the perforation without leak under ex vivo insufflation. At one week, the device maintained its integrity but there was no tissue ingrowth. Histological healing score was −1. At 4–12 weeks, gross examination revealed a healed injury site in all animals. The lumenal portion of the plug was completely absorbed. The gross and histological healing score ranged from −1 to +1. The application of a bioabsorbable device results in durable closure of gastric perforation with physiologic healing of the injury site. This method of gastrotomy closure may aid in the evolution of advanced endoscopic approaches to perforation closure of hollow viscera.

Initial Experience with the Four-Arm Computer-Enhanced Telesurgery Device in Foregut Surgery

BACKGROUND The da Vinci robotic system (Intuitive Surgical, Sunnyvale, CA) has been used effectively and with good results. Previously, the surgeon could manipulate three arms on the robot: one camera port and two working ports. This configuration required a second surgeon for most general surgical procedures. Recently, the robotic device has been modified to include a fourth arm, adding another computer-assisted instrument that the surgeon can manipulate. In this report, we describe our experience with the da Vinci robot with a fourth arm modification for the performance of selected surgical procedures. MATERIALS AND METHODS A total of six patients were prospectively enrolled and underwent surgery using the modified da Vinci robot. Their average age was 56 years. Five patients underwent Nissen fundoplication, and one patient underwent Heller myotomy. Operative time, defined as the time from skin incision to completed skin closure, as well as robotic time, defined as the time during which the robot was being used, were recorded. Intra-operative and perioperative complications were also recorded. RESULTS Average operative and robotic times for Nissen fundoplication were 134 and 80 minutes, respectively. Operative and robotic times for the Heller myotomy were 118 and 70 minutes. All patients tolerated the procedure well and experienced no perioperative complications. CONCLUSIONS The da Vinci robot with the addition of the fourth arm results in a efficient and safe operation and allows the surgeon to perform additional maneuvers without the use of a surgical assistant.