Activated Kupffer cells inhibit insulin sensitivity in obese mice.

Obesity promotes insulin resistance associated with liver inflammation, elevated glucose production, and type 2 diabetes. Although insulin resistance is attenuated in genetic mouse models that suppress systemic inflammation, it is not clear whether local resident macrophages in liver, denoted Kupffer cells (KCs), directly contribute to this syndrome. We addressed this question by selectively silencing the expression of the master regulator of inflammation, NF-κB, in KCs in obese mice. We used glucan-encapsulated small interfering RNA particles (GeRPs) that selectively silence gene expression in macrophages in vivo. Following intravenous injections, GeRPs containing siRNA against p65 of the NF-κB complex caused loss of NF-κB p65 expression in KCs without disrupting NF-κB in hepatocytes or macrophages in other tissues. Silencing of NF-κB expression in KCs in obese mice decreased cytokine secretion and improved insulin sensitivity and glucose tolerance without affecting hepatic lipid accumulation. Importantly, GeRPs had no detectable toxic effect. Thus, KCs are key contributors to hepatic insulin resistance in obesity and a potential therapeutic target for metabolic disease.

Optimizing laparoscopic task efficiency: the role of camera and monitor positions.

BACKGROUND: Alterations of video monitor and laparoscopic camera position may create perceptual distortion of the operative field, possibly leading to decreased laparoscopic efficiency. We aimed to determine the influence of monitor/camera position on the laparoscopic performance of surgeons of varying skill levels. METHODS: Twelve experienced and 12 novice participants performed a one-handed task with their dominant hand in a modified laparoscopic trainer. Initially, the camera was fixed directly in front of the participant (0 degrees) and the monitor location was varied between three positions, to the left of midline (120 degrees), directly across from the participant (180 degrees), and to the right of the midline (240 degrees). In the second experiment monitor position was constant straight across from the participant (180 degrees) while the camera position was adjusted between the center position (0 degrees), to the left of midline (60 degrees), and to the right of midline (300 degrees). Participants completed five trials in each monitor/camera setting. The significance of the effects of skill level and combinations of camera and monitor angle were evaluated by analysis of variance (ANOVA) for repeated measures using restricted maximum likelihood estimation. RESULTS: Experienced surgeons completed the task significantly faster at all monitor/camera positions. The best performance in both groups was observed when the monitor and camera were located at 180 degrees and 0 degrees, respectively. Monitor positioning to the right of midline (240 degrees) resulted in significantly worse performance compared to 180 degrees for both experienced and novice surgeons. Compared to 0 degrees (center), camera position to the left or the right resulted in significantly prolonged task times for both groups. Novice subjects also demonstrated a significantly lower ability to adjust to suboptimal camera/monitor positions. CONCLUSION: Experienced subjects demonstrated superior performance under all study conditions. Optimally, the camera should be directly in front and the monitor should be directly across from a surgeon. Alternatively, the monitor/camera could be placed opposite to the surgeon's non-dominant hand. The suboptimal camera/monitor conditions are especially difficult to overcome for inexperienced subjects. Monitor and camera positioning must be emphasized to ensure optimal laparoscopic performance.

Advantages of mini-laparoscopic vs conventional laparoscopic cholecystectomy: results of a prospective randomized trial.

HYPOTHESIS: The use of smaller instruments during laparoscopic cholecystectomy (LC) has been proposed to reduce postoperative pain and improve cosmesis. However, despite several recent trials, the effects of the use of miniaturized instruments for LC are not well established. We hypothesized that LC using miniports (M-LC) is safe and produces less incisional pain and better cosmetic results than LC performed conventionally (C-LC). DESIGN: A patient- and observer-blinded, randomized, prospective clinical trial. SETTING: A tertiary care, university-based hospital. PATIENTS: Seventy-nine patients scheduled for an elective LC who agreed to participate in this trial were randomized to undergo surgery using 1 of the 2 instrument sets. The criteria for exclusion were American Society of Anesthesiologists class III or IV, age older than 70 years, liver or coagulation disorders, previous major abdominal surgical procedures, and acute cholecystitis or acute choledocholithiasis. INTERVENTION: Laparoscopic cholecystectomy performed with either conventional or miniaturized instruments. MAIN OUTCOME MEASURES: Patients' age, sex, operative time, operative blood loss, intraoperative complications, early and late postoperative incisional pain, and cosmetic results. RESULTS: Thirty-three C-LCs and 34 M-LCs were performed and analyzed. There were 8 conversions (24%) to the standard technique in the M-LC group. No intraoperative or major postoperative complications occurred in either group. The average incisional pain score on the first postoperative day was significantly less in the M-LC group (3.9 vs 4.9; P = .04). No significant differences occurred in the mean scores for pain on postoperative days 3, 7, and 28. However, 90% of patients in the M-LC group and only 74% of patients in the C-LC group had no pain (visual analog scale score of 0) at 28 days postoperatively (P = .05). Cosmetic results were superior in the M-LC group according to both the study nurse's and the patients' assessments (38.9 vs 28.9; P<.001, and 38.8 vs 33.4; P = .001, respectively). CONCLUSIONS: Laparoscopic cholecystectomy can be safely performed using 10-mm umbilical, 5-mm epigastric, 2-mm subcostal, and 2-mm lateral ports. The use of mini-laparoscopic techniques resulted in decreased early postoperative incisional pain, avoided late incisional discomfort, and produced superior cosmetic results. Although improved instrument durability and better optics are needed for widespread use of miniport techniques, this approach can be routinely offered to many properly selected patients undergoing elective LC.

Body mass index-independent inflammation in omental adipose tissue associated with insulin resistance in morbid obesity.

BACKGROUND: Obesity is a strong risk factor for resistance to insulin-mediated glucose disposal, a precursor of type 2 diabetes and other disorders. However, not all obese individuals are insulin resistant. We sought to identify the molecular pathways that might cause obesity-associated insulin resistance in humans by studying the morbidly obese who were insulin sensitive versus insulin resistant, thereby eliminating obesity as a variable. METHODS: Combining gene expression profiling with computational approaches, we determined the global gene expression signatures of omental and subcutaneous adipose tissue samples obtained from similarly obese patients undergoing gastric bypass surgery. RESULTS: Gene sets related to chemokine activity and chemokine receptor binding were identified as most highly expressed in the omental tissue from insulin-resistant compared with insulin-sensitive subjects, independent of the body mass index. These upregulated genes included chemokines (C-C motif) ligand 2, 3, 4, and 18 and interleukin-8/(CC-X motif) ligand 8 and were not differentially expressed in the subcutaneous adipose tissues between the 2 groups of subjects. Insulin resistance, but not the body mass index, was associated with increased macrophage infiltration in the omental adipose tissue, as was adipocyte size, in these morbidly obese subjects. CONCLUSION: Our findings have demonstrated that inflammation of the omental adipose tissue is strongly associated with insulin resistance in human obesity even in subjects with similar body mass index values.

Reduced heart rate variability correlates with insulin resistance but not with measures of obesity in population undergoing laparoscopic Roux-en-Y gastric bypass.

BACKGROUND: Obesity is associated with a pathologic predominance of sympathetic over parasympathetic tone. With respect to the heart, this autonomic dysfunction presents as a decreased heart rate variability (HRV), which has been associated with increased cardiovascular morbidity. Gastric bypass (GB) reduces cardiovascular mortality, and, thus, could beneficially affect the HRV. We sought to identify the factors predictive of HRV in a severely obese population of undergoing GB at a university hospital in the United States. METHODS: The data of all patients presenting for GB were included in a prospective database. The homeostatic model of assessment (HOMA) was used to calculate the insulin resistance and glucose disposition index. A 24-hour Holter monitor was used to assess the HRV. Measurements were repeated at 2 weeks and 6 months postoperatively. The correlations between variables were determined using linear mixed models. RESULTS: We studied 30 patients undergoing GB. All exhibited some degree of reduced HRV that improved postoperatively. The HOMA-insulin resistance inversely correlated with the HRV, and the HOMA-glucose disposition index directly correlated with the parameters of HRV in our longitudinal models. Weight, body mass index, excess body weight, gender, and age did not correlate with HRV. Improvements in HRV correlated with reductions in the average heart rate, underscoring a postoperative increase in relative vagal tone. CONCLUSION: HRV in the severely obese is better predicted by the degree of insulin resistance, than by the degree of obesity, age, or gender. GB led to an improvement in HRV, the magnitude of which correlated with the change in insulin resistance and glucose disposition index, but not with weight loss.

Early results of conversion of laparoscopic adjustable gastric band to Roux-en-Y gastric bypass.

BACKGROUND: As the number of laparoscopic adjustable gastric bands (LAGBs) placed has increased, the number of patients requiring removal of the device has also increased. METHODS: The data from our institution, a U.S. university medical center, were reviewed to determine the feasibility, patient characteristics, and early results of converting patients from LAGB to laparoscopic Roux-en-Y gastric bypass. RESULTS: A total of 350 patients underwent LAGB placement at our institution from 2001 to 2008. Of these, 26 required conversion to laparoscopic Roux-en-Y gastric bypass for the following reasons: slippage, poor weight loss, LAGB intolerance, esophageal dilation, infection, and gastric ischemia. All conversions were completed laparoscopically. The average operating time and length of stay was 160 minutes and 3 days, respectively. Three complications developed. The average interval to conversion was 29 months. The average follow-up after conversion was 18 months. The average percentage of excess body weight loss at conversion was 23%. At 12 months after conversion, the patients had achieved an average percentage of excess body weight loss of 56% from their pre-LAGB weight. CONCLUSION: The increasing popularity of the LAGB has led to a considerable number of revisions of the device. Our early experience has shown that converting patients from LAGB to laparoscopic Roux-en-Y gastric bypass is feasible and safe and can offer patients substantial additional weight loss.