ObjectiveTo evaluate the efficacy of mesh fixation with fibrin sealant (FS) in laparoscopic preperitoneal inguinal hernia repair and to compare it with stapled fixation. Summary Background DataLaparoscopic hernia repair involves the fixation of the prosthetic mesh in the preperitoneal space with staples to avoid displacement leading to recurrence. The use of staples is associated with a small but significant number of complications, mainly nerve injury and hematomas. FS (Tisseel) is a biodegradable adhesive obtained by a combination of human-derived fibrinogen and thrombin, duplicating the last step of the coagulation cascade. It can be used as an alternative method of fixation. MethodsA prosthetic mesh was placed laparoscopically into the preperitoneal space in both groins in 25 female pigs and fixed with either FS or staples or left without fixation. The method of fixation was chosen by randomization. The pigs were killed after 12 days to assess early graft incorporation. The following outcome measures were evaluated: macroscopic findings, including graft alignment and motion, tensile strength between the grafts and surrounding tissues, and histologic findings (fibrous reaction and inflammatory response). ResultsThe procedures were completed laparoscopically in 49 sites. Eighteen grafts were fixed with FS and 16 with staples; 15 were not fixed. There was no significant difference in graft motion between the FS and stapled groups, but the nonfixed mesh had significantly more graft motion than in either of the fixed groups. There was no significant difference in median tensile strength between the FS and stapled groups. The tensile strength in the nonfixed group was significantly lower than the other two groups. FS triggered a significantly stronger fibrous reaction and inflammatory response than in the stapled and control groups. No infection related to method of fixation was observed in any group. ConclusionAn adequate mesh fixation in the extraperitoneal inguinal area can be accomplished using FS. This method is mechanically equivalent to the fixation achieved by staples and superior to nonfixed grafts. Biologic soft fixation with FS will prevent early graft migration and will avoid the complications associated with staple use.Laparoscopic hernia repair is an effective technique, offering more rapid recovery and less pain than with the traditional open approach; recurrence rates are equivalent to those of the traditional open approach.

OBJECTIVE-Intravenous insulin infusion rapidly increases plasma insulin, yet glucose disposal occurs at a much slower rate. This delay in insulin's action may be related to the protracted time for insulin to traverse the capillary endothelium. An increased delay may be associated with the development of insulin resistance. The purpose of the present study was to investigate whether bypassing the transendothelial insulin transport step and injecting insulin directly into the interstitial space would moderate the delay in glucose uptake observed with intravenous administration of the hormone. RESEARCH DESIGN AND METHODS-Intramuscular injec-tions of saline (n ϭ 3) or insulin (n ϭ 10) were administered directly into the vastus medialis of anesthetized dogs. Injections of 0.3, 0.5, 0.7, 1.0, and 3.0 units insulin were administered hourly during a basal insulin euglycemic glucose clamp (0.2mU ⅐ minRESULTS-Unlike the saline group, each incremental insulin injection caused interstitial (lymph) insulin to rise within 10 min, indicating rapid diffusion of the hormone within the interstitial matrix. Delay in insulin action was virtually eliminated, indicated by immediate dose-dependent increments in hindlimb glucose uptake. Additionally, bypassing insulin transport by direct injection into muscle revealed a fourfold greater sensitivity to insulin of in vivo muscle tissue than previously reported from intravenous insulin administration.CONCLUSIONS-Our results indicate that the transport of insulin to skeletal muscle is a rate-limiting step for insulin to activate glucose disposal. Based on these results, we speculate that defects in insulin transport across the endothelial layer of skeletal muscle will contribute to insulin resistance. Diabetes 57:828-835, 2008

During insulin resistance, glucose homeostasis is maintained by an increase in plasma insulin via increased secretion and/or decreased first-pass hepatic insulin extraction. However, the relative importance of insulin secretion vs. clearance to compensate for insulin resistance in obesity has yet to be determined. This study utilizes the fat-fed dog model to examine longitudinal changes in insulin secretion and first-pass hepatic insulin extraction during development of obesity and insulin resistance. Six dogs were fed an isocaloric diet with an approximately 8% increase in fat calories for 12 wk and evaluated at weeks 0, 6, and 12 for changes in 1) insulin sensitivity by euglycemic-hyperinsulinemic clamp, 2) first-pass hepatic insulin extraction by direct assessment, and 3) glucose-stimulated insulin secretory response by hyperglycemic clamp. We found that 12 wk of a fat diet increased subcutaneous and visceral fat as assessed by MR imaging. Consistent with increased body fat, the dogs exhibited a approximately 30% decrease in insulin sensitivity and fasting hyperinsulinemia. Although insulin secretion was substantially increased at week 6, beta-cell sensitivity returned to prediet levels by week 12. However, peripheral hyperinsulinemia was maintained because of a significant decrease in first-pass hepatic insulin extraction, thus maintaining hyperinsulinemia, despite changes in insulin release. Our results indicate that when obesity and insulin resistance are induced by an isocaloric, increased-fat diet, an initial increase in insulin secretion by the beta-cells is followed by a decrease in first-pass hepatic insulin extraction. This may provide a secondary physiological mechanism to preserve pancreatic beta-cell function during insulin resistance.

Senescent squirrel monkey is a valuable model to study pathogenesis of cerebrovascular amyloid angiopathy (CAA). Cerebrovascular sequestration and bloodbrain barrier (BBB) permeability to 1251-amyloid~3(1 -40) synthetic peptide (sA/3 1_40) were studied in adult versus aged squirrel monkey 1 h after a single intravenous injection. In aged monkey, the half-time of elimination of sA/31_40, t~12, was prolonged by 0.6 h, the systemic clearance,~was reduced from 1.8 to 1.1 mI/mm/kg, and the mean residence time of intact peptide in the circulation was increased by 1 h (45%). In adult monkey, cerebrovascular sequestration of intact sA/31_40 was significant, and the BBB permeability was 18.6-fold higher than for inulin. In aged monkey, the sequestration of intact sA/3140 by cortical and leptomeningeal microvessels and the BBB permeability were increased by 5.9, 1.8-, and 2.1 -fold, respectively, in the presence of an unchanged barrier to inulin. In brain parenchyma of aged animals, 76.1% of circulating sA/31_40 remained intact versus 45.7% in adult. We conclude that multiple age-related systemic effects, i.e., reduced body elimination and systemic clearance of sA/3140, and reduced peripheral metabolism, may act in concert with BBB mechanisms, i.e., increased transendothelial transport and microvascular accumulation of blood-borne sAft~40, and reduced brain metabolism to enhance the development of CAA. Key Words: Alzheimer's amyloid /3-Cerebrovascular amybid angiopathy-Squirrel monkey-Cerebrovascular sequestration-Blood-brain barrier permeability-Aging.

Despite the well-described association between obesity and insulin resistance, the physiologic mechanisms that link these two states are poorly understood. The present study was performed to elucidate the role of visceral adipose tissue in whole-body glucose homeostasis. Dogs made abdominally obese with a moderately elevated fat diet had catheters placed into the superior mesenteric artery so that the visceral adipose bed could be insulinized discretely. Omental insulin infusion was extracted at ϳ27%, such that systemic insulin levels were lower than in control (portal vein) insulin infusions. Omental infusion did not lower systemic free fatty acid levels further than control infusion, likely because of the resistance of the omental adipose tissue to insulin suppression and the confounding lower systemic insulin levels. The arteriovenous difference technique showed that local infusion of insulin did suppress omental lipolysis, but only at extremely high insulin concentrations. The median effective dose for suppression of lipolysis was almost fourfold higher in the visceral adipose bed than for whole-body suppression of lipolysis. Thus, the omental adipose bed represents a highly insulin-resistant depot that drains directly into the portal vein. Increased free fatty acid flux to the liver may account for hepatic insulin resistance in the moderately obese state. Diabetes 51:755-761, 2002