Faculty Bibliography

OBJECTIVES/OBJECTIVE:The objective of this study was to evaluate the efficacy of nonwoven bioabsorbable nanofibrous membranes of poly(lactideco-glycolide) for prevention of postsurgery-induced abdominal adhesions. SUMMARY BACKGROUND DATA/BACKGROUND:Recent reports indicated that current materials used for adhesion prevention have only limited success. Studies on other bioabsorbable materials using a new fabrication technique demonstrated the promising potential of generating an improved and inexpensive product that is suitable for a variety of surgical applications. METHODS:All rats underwent a midline celiotomy. The cecum was identified and scored using an abrasive pad until serosal bleeding was noted on the anterior surface. A 1 x 1 cm of abdominal wall muscle was excised directly over the cecal wound. The celiotomy was then closed in 2 layers immediately (control) after a barrier was laid in between the cecum and the abdominal wall. All rats underwent a second celiotomy after 28 days to evaluate the extent of abdominal adhesions qualitatively and quantitatively. RESULTS:Cecal adhesions were reduced from 78% in the control group to 50% in the group using biodegradable poly(lactide-co-glycolide) (PLGA) nonwoven nanofibrous membranes (n = 10, P = 0.2) and to 22% in the group using membranes containing PLGA and poly(ethylene glycol)/poly(D,L-lactide) (PEG-PLA) blends (n = 9, P = 0.03). Electrospinning method also enabled us to load an antibiotic drug Cefoxitin sodium (Mefoxin; Merck Inc., West Point, PA) with high efficacy. The electrospun PLGA/PEG-PLA membranes impregnated with 5 wt% cefoxitin sodium, which amounts to approximately 10% of the systemic daily dose typically taken after surgery in humans, completely prevented cecal adhesions (0%) in rats. CONCLUSIONS:Electrospun nonwoven bioabsorbable nanofibrous membranes of poly(lactide-co-glycolide) were effective to reduce adhesions at the site of injury using an objective rat model. The membrane acted as a physical barrier but with drug-delivery capability. The combined advantages of composition adjustment, drug-loading capability, and easy placement handling (relatively hydrophobic) make these membranes potentially successful candidates for further clinical evaluations.

OBJECTIVES/OBJECTIVE:The phosphorylation states and the inferred activation of specific members of the mitogen-activated protein kinase (MAPK) pathways (p42/44, p38, and SAPK/JNK) were quantitated in the livers of rats by Western blot analysis during the progression of sepsis. In addition, the authors examined the effects of insulin and mifepristone (RU-486) administration on these signal transduction pathways during sepsis. METHODS:Sepsis was brought about by the cecal ligation and puncture (CLP) method. The control group underwent sham operation. One experimental group was injected with insulin (0.5 U/kg, IV); prior to the CLP or sham procedure, the second group was injected with RU-486, a glucocorticoid antagonist (mifepristone, 20 mg/kg, IP), and the third group was injected with saline (control). RESULTS:The activities of SAPK/JNK were unaltered throughout the course of sepsis, while those of p42/44 MAPK increased four-fold after 24 hours of sepsis. The activation of p38 MAPK was also increased after 0.5 and 1.5 hours of sepsis, but returned to normal during late sepsis (24 hours). Rats that had received RU-486 before CLP showed no change in p42/44 MAPK compared with the untreated group, but the drug appeared to suppress the activation after 24 hours post-CLP. SAPK/JNK activation, on the other hand, was slightly enhanced by RU-486 pretreatment after 1.5 and 24 hours of CLP compared with the untreated CLP and the treated sham-operated rats. Insulin, given preoperatively, had no effect on the activation of SAPK/JNK, although p42/44 MAPK pathways were activated by the hormone at 0.5 hours and 1.5 hours post-CLP only, but not in the sham-operated controls or at 24 hours post-CLP. The p38 MAPK activation seen after 0.5 and 1.5 hours of CLP was suppressed by RU-486. Insulin pretreatment appears to suppress the phosphorylation of p38 in both the CLP and sham-operated groups. CONCLUSIONS:The data suggest that sepsis induces two phases of MAPK activation, an early phase in which p38 is active, followed by a second, more pronounced phase of p42/44 MAPK activation that occurs only late in sepsis. Hormonal administration results suggest that RU-486 suppresses the activation of p38 seen in early sepsis, and the activation of p42/44 MAPK seen in late sepsis.

The insulin-sensitizing drugs thiazolidinediones (TZDs), such as rosiglitazone, improve insulin sensitivity and also promote adipocyte differentiation in vitro. The authors hypothesized that TZDs might be beneficial to patients with HIV disease to improve insulin sensitivity and the distribution of body fat by increasing peripheral fat. The ability of rosiglitazone (8 mg/d) to improve insulin sensitivity (from hyperinsulinemic-euglycemic clamp) and to improve body fat distribution (determined from computed tomography measurements of visceral adipose tissue [VAT] and subcutaneous adipose tissue [SAT]) was determined in 8 HIV-positive patients. Before treatment, the insulin sensitivity of the patients was reduced to approximately 34% of that in control subjects. The rate of glucose disposal during a hyperinsulinemic-euglycemic clamp (Rd) was 3.8 +/-.4 (SEM) mg glucose/kg lean body mass/min compared with 11.08 +/- 1.1 (p<.001) in healthy age- and body mass index (BMI)-matched control subjects. After rosiglitazone treatment of 6 to 12 weeks, Rd increased to 5.99 +/-.9 (p=.02), an improvement of 59 +/- 22%. SAT increased by 23 +/- 10% (p=.05), and, surprisingly, VAT was decreased by 21 +/- 8% (p=.04) with a trend for increased SAT/VAT that failed to reach statistical significance. There were no significant changes in blood counts, viral loads, or CD4 counts with rosiglitazone treatment. The study demonstrates that rosiglitazone therapy improves insulin resistance and body fat distribution in some patients with HIV disease.