Antirestenotic Effects of a Novel Polymer-Coated D-24851 Eluting Stent. Experimental Data in a Rabbit Iliac Artery Model

Experimental and clinical data suggest that stents eluting antiproliferative agents can be used for the prevention of in-stent restenosis. Here we investigate in vitro the antiproliferative and apoptotic effect of D-24851 and evaluate the safety and efficacy of D-24851-eluting polymer-coated stents in a rabbit restenosis model (n = 53). Uncoated stents (n = 6), poly (dl-lactide-co-glycolide) (PLGA)-coated stents (n = 7), and PLGA-coated stents loaded with 0.08 ± 0.0025 μM (31 ± 1 μg; low dose; n = 7), 0.55 ± 0.02 μM (216 ± 8 μg; high dose; n = 6), and 4.55 ± 0.1 μM (1774 ± 39 μg; extreme dose; n = 5) of D-24851 were randomly implanted in New Zealand rabbit right iliac arteries and the animals were sacrificed after 28 days for histomorphometric analysis. For the assessment of endothelial regrowth in 90 days, 12 rabbits were subjected to PLGA-coated (n = 3), low-dose (n = 3), high-dose (n = 3), and extreme-dose (n = 3) stent implantation. In vitro studies revealed that D-24851 exerts its growth inhibitory effects via inhibition of proliferation and induction of apoptosis without increasing the expression of heat shock protein-70, a cytoprotective and antiapoptotic protein. Treatment with low-dose D-24851 stents was associated with a significant reduction in neointimal area and percentage stenosis only compared with bare metal stents (38% [P = 0.029] and 35% [P = 0.003] reduction, respectively). Suboptimal healing, however, was observed in all groups of D-24851-loaded stents in 90 days in comparison with PLGA-coated stents. We conclude that low-dose D-24851-eluting polymer-coated stents significantly inhibit neointimal hyperplasia at 28 days through inhibition of proliferation and enhancement of apoptosis. In view of the suboptimal re-endothelialization, longer-term studies are needed in order to establish whether the inhibition of intimal growth is maintained.     

Improved outcomes using a systematic and evidence-based approach to the laparoscopic Roux-en-Y gastric bypass in a single academic institution

No standardized approach exists for laparoscopic Roux-en-Y gastric bypass (LRYGB). At a newly instituted bariatric surgery program, four experienced laparoscopic surgeons used the systematic and evidence-based approach consisting of multidisciplinary preoperative evaluation, screening, and education; standardized operative technique; inpatient clinical pathway; and close postoperative follow-up. The outcomes were subsequently analyzed to determine if this approach improved the morbidity and mortality. From January 2003 to June 2006, 835 consecutive LRYGBs were performed. The patient population was 85 per cent women with a mean body mass index (BMI) of 50.4 kg/m2 (range 33-96 kg/m2). The mean age was 44 (range 15-67). Sixty-two per cent of the patients had previous abdominal or pelvic operations. The conversion rate to open surgery was 0.2 per cent. The average length of hospital stay was 2.6 days (range 2-13 days). There were no anastomotic leaks or deaths. The 30-day readmission and re-operation rates were 3.2 per cent and 1.8 per cent, respectively. The incidence of anastomotic stricture, marginal ulcer, bleeding, pulmonary embolism, and internal hernia was 0.8 per cent, 3.5 per cent, 4.2 per cent, 0.1 per cent, and 0.4 per cent, respectively. A systematic and evidence-based approach to the LRYGB by experienced laparoscopic surgeons resulted in a lower incidence of complications when compared with the published results from other comparable institutions.     

Rupture of membranes in second trimester of pregnancy

The management of rupture of membranes at a nearly viability stage is still controversial. A case of a primigravida, who had rupture of membranes at 23 weeks of gestation, is reported. On conservative management, her pregnancy continued to 30 weeks and she delivered a normal fetus, who showed no abnormality till one year of follow-up.     

tPA-mediated generation of plasmin is catalyzed by the proteoglycan NG2

Paralysis resulting from spinal cord injury is devastating and persistent. One major reason for the inability of the body to heal this type of injury ensues from the local increase of glial cells leading to the formation of a glial scar, and the upregulation of chondroitin sulfate proteoglycans (CSPGs) at the site of injury through which axons are unable to regenerate. Experimental approaches to overcome this problem have accordingly focused on reducing the inhibitory properties of CSPGs, for example by using chondroitinase to remove the sugar chains and reduce the CSPGs to their core protein constituents, although this step alone does not provide dramatic benefits as a monotherapy. Using in vitro and in vivo approaches, we describe here a potentially synergistic therapeutic opportunity based on tissue plasminogen activator (tPA), an extracellular protease that converts plasminogen (plg) into the active protease plasmin. We show that tPA and plg both bind to the CSPG protein NG2, which functions as a scaffold to accelerate the tPA-driven conversion of plg to plasmin. The binding occurs via the tPA and plg kringle domains to domain 2 of the NG2 CSPG core protein, and is enhanced in some settings after chondroitinase-mediated removal of the NG2 proteoglycan side chains. Once generated, plasmin then degrades NG2, both in an in vitro setting using recombinant protein, and in vivo models of spinal cord injury. Our finding that the tPA and plg binding is in some instances more efficient after exposure of the NG2 proteoglycan to chondroitinase treatment suggests that a combined therapeutic approach employing both chondroitinase and the tPA/plasmin proteolytic system could be of significant benefit in promoting axonal regeneration through glial scars after spinal cord injury.     

Implication of BRCA2 -26G>A 5' untranslated region polymorphism in susceptibility to sporadic breast cancer and its modulation by p53 codon 72 Arg>Pro polymorphism

Introduction  

The absence of mutation or promoter hypermethylation in the BRCA2 gene in the majority of breast cancer cases has indicated alternative ways of its involvement, deregulated expression being one possibility. We show how a polymorphism in the 5' untranslated region (UTR) of BRCA2 can serve as one such factor. Based on the hypothesis that variants of genes involved in the same pathway can influence the risk provided for breast cancer, the status of p53 codon 72 polymorphism was also investigated and a possible interaction between the polymorphisms was examined.     

Extraosseous bone formation in the renal pelvis

PURPOSE: We evaluated the frequency and features of extraosseous bone formation in the kidneys of patients undergoing percutaneous nephrolithotomy. MATERIALS AND METHODS: Percutaneous nephrolithotomy was performed in 621 patients at our institution between 1997 and 2006. In 21 cases metaplastic bone arising from the urothelium was observed. Clinical, radiographic and histopathological features of this group were studied in detail. RESULTS: Patient age ranged from 7 to 40 years (median 11). Extraosseous bone formation was identified in 7 right (33%) and 14 left (67%) kidneys. In all cases extraosseous bone was identified at the angle of the pelvis and ureter, just proximal to the ureteropelvic junction. The typical radiographic appearance of a radiopaque eccentric halo surrounding an area of lesser radiological density connected with the urothelium was seen in 10 of 13 radiographs (77%). Histopathological evaluation showed well formed trabecular bone with surface osteoblastic activity, areas of intratrabecular adipose bone marrow and hematopoietic cells in 5 cases (24%); woven bone intimately related to trabecular bone with scattered hematopoietic cells in 14 (67%); and entirely woven bone with associated mineral deposits and prominent fibroblastic proliferation in 2 (10%). CONCLUSIONS: Although rarely reported in the literature, metaplastic bone formation in the renal pelvis was seen relatively frequently in our patient population. The pathogenesis of this phenomenon is not clearly understood. Recognition of extraosseous bone is important, since it has implications for management and prognosis. In-depth studies of this phenomenon are required to arrive at any conclusions regarding its etiology.     

Prediction of CYP-mediated silybin A-losartan pharmacokinetic interactions using physiological based pharmacokinetic modeling

Journal of Pharmacokinetics and Pharmacodynamics - The concomitant use of herbal products and synthetic drugs necessitates the assessment of their interaction potentials. The herbal...     

Six1 overexpression in ovarian carcinoma causes resistance to TRAIL-mediated apoptosis and is associated with poor survival

Tumorigenesis can arise from inappropriate activation of developmental genes in mature tissues. Here, we show that the developmental regulator Six1 is overexpressed in ovarian carcinoma cell lines (OCC) compared with normal ovarian surface epithelium. As observed in other cancers, Six1 overexpression in OCC leads to increased A-type cyclin expression and increased proliferation. In addition, Six1 overexpression renders OCC resistant to tumor necrosis factor-related apoptosis inducing ligand (TRAIL)-mediated apoptosis, and Six1 knockdown in the TRAIL-resistant SKOV3 ovarian carcinoma line dramatically sensitizes the cells to TRAIL. Because inactivation of the TRAIL response has been linked to metastasis, and because antibodies and recombinant ligand that activate the TRAIL pathway are currently in clinical trials against ovarian carcinoma, we screened normal ovarian and carcinoma specimens for Six1 mRNA. Six1 was overexpressed in 50% of the early-stage (stage I) and 63% of the late-stage (stages II, III, and IV) ovarian carcinomas examined, with late-stage carcinomas expressing approximately 3-fold higher Six1 mRNA levels on average compared with early-stage tumors. Importantly, in patients with late-stage disease, high Six1 expression was associated with significantly shortened survival (P = 0.0015). These data suggest that Six1 may contribute to ovarian epithelial carcinogenesis by simultaneously increasing proliferation and decreasing TRAIL-mediated apoptosis and imply that Six1 may be an important determinant of TRAIL therapy response that should be considered in patient selection for TRAIL-related clinical trials.