Assessment of celecoxib pharmacodynamics in pancreatic cancer

Cyclooxygenase-2 (COX-2) inhibitors are being developed as chemopreventive and anticancer agents. This study aimed to determine the biological effect of the COX-2 inhibitor celecoxib in pancreatic cancer as an early step to the further development of the agent in this disease. Eight patients scheduled for resection of an infiltrating adenocarcinoma of the pancreas were randomized to receive celecoxib at a dose of 400 mg twice daily or placebo for 5 to 15 days before the surgery. In addition, carcinomas from nine additional patients were xenografted in nude mice, expanded, and treated with vehicle or celecoxib for 28 days. Celecoxib markedly decreased the intra-tumor levels of prostaglandin E2 in patient carcinomas and in the heterotransplanted xenografts. However, this effect did not result in inhibition of cell proliferation or microvessel density (as assessed by Ki67 and CD31 staining). In addition, a panel of markers, including bcl-2, COX-1, COX-2, and VEGF, did not change with treatment in a significant manner. Furthermore, there was no evidence of antitumor effects in the xenografted carcinomas. In summary, celecoxib efficiently inhibited the synthesis of prostaglandin E2 both in pancreatic cancer surgical specimens and in xenografted carcinomas but did not exert evident antitumor, antiproliferative, or antiangiogenic effect as a single agent. The direct pancreatic cancer xenograft model proved to be a valuable tool for drug evaluation and biological studies and showed similar results to those observed in resected pancreatic cancer specimens.     

Metabolic syndrome in pediatric renal transplant recipients: Comparing early discontinuation of steroids vs. steroid group

Maduram A, John E, Hidalgo G, Bottke R, Fornell L, Oberholzer J, Benedetti E. Metabolic syndrome in pediatric renal transplant recipients: Comparing early discontinuation of steroids vs. steroid group. Pediatr Transplantation 2010:14:351–357. © 2009 John Wiley & Sons A/S. Abstract: Steroids have played a valuable role in transplantation as a treatment option. The purpose of this study is to assess the prevalence of MS in pediatric RT patients receiving SG or early SWG; SG discontinued five days after transplantation. We retrospectively reviewed 58 pediatric RT patients between 2000 and 2007. MS criterion was defined as the presence of any three of five criteria: (i) BMI >97th percentile, (ii) hypertension (SBP/DBP > 95th percentile or on medications); (iii) triglycerides > 95thpercentile, (iv) HDL cholesterol < 5th percentile, (v) fasting glucose > 100 mg/dL. Twenty‐five patients (43%) received SG and 33 patients (57%) received SWG. The prevalence of MS in SG was 68% compared to 15% in SWG. At six months and one yr after transplantation, mean serum glucose, total cholesterol, and triglycerides were significantly lower in the SWG. The prevalence of hypertension was significantly lower in the SWG, and patients in the SWG received significantly less lipid‐lowering and anti‐hypertensive medications than SG. Mean BMI percentile was significantly higher in SG one yr after transplantation but not after six months, although always significantly higher in patients with MS (p < 0.05). From this study, we conclude that for pediatric RT patients, cardiovascular risk factors are significantly lower in SG withdrawal groups.     

Structural and functional polarity of porcine hepatocyte cultured spheroids

Hepatocytes are epithelial cells that show a complex polarity in vivo. However, hepatocytes isolated and cultured in vitro normally lose both their differentiated properties and polarity. Culturing hepatocyte spheroids seems to be the accurate approach to maintain tissue level of organization. The structural and functionalpolarities of pig liver spheroids were analyzed in this work. Swine liver cells were isolated and cultured as spheroids. Their metabolic activity was proved through the metabolism of diazepam, ammonium and synthesis of albumin. Several structural features show the presence of polarity in the cells inside the spheroids. Reticular and collagen fibers, as well as Ck19(+) cells forming duct-like structures were found. _eta and _-catenins and pancadherins were positive in different regions of the spheroids, mainly in the outer cell layers, which have cuboidal epithelia features. The scanning electron microscopy showed a tightly compacted architecture, with smooth surface. The transmission electron microscopy analysis showed bile canaliculi with microvilli, tight junctions, zonula adherens and desmosome-like junctions. Well-maintained cellular organelles, as mitochondria, nucleus, nucleolus, peroxisomes, endoplasmic reticulum, were seen in the spheroids. A complex inner bile canaliculi network was shown by using a fluorescent bile acid analogue incorporated and excreted by the spheroids. Furthermore, excretion of a normal pattern of bile acids was demonstrated. The morphology and functionality of the spheroids may provide an appropriate model for applications where the maintenance of liver-specific functions is crucial, as a bioartificial liver device.     

Strongyloides stercoralis hyperinfection in systemic lupus erythematosus and the antiphospholipid syndrome

OBJECTIVE: The Strongyloides stercoralis hyperinfection syndrome (SHS) may develop in individuals with asymptomatic infection receiving immunosuppressive treatment. This report summarizes current knowledge regarding SHS in patients with systemic lupus erythematosus (SLE) and associated antiphospholipid syndrome (APS). METHODS: Two patients with active SLE and associated APS presenting with SHS are reported. Additional cases of strongyloidiasis in SLE were identified and reviewed. RESULTS: Patient 1: A 34-year-old woman with SLE and APS characterized by active glomerulonephritis, stroke, and several hospital-acquired infections presented with vomiting and diffuse abdominal pain. Intestinal vasculitis was suspected, and treatment with methylprednisolone and cyclophosphamide was given. Response was partial. A gastric biopsy revealed S. stercoralis larvae. She received ivermectin and eventually recovered. Patient 2: A 37-year-old man with active glomerulonephritis and APS with recurrent thrombosis presented with digital necrosis. Necrotizing vasculitis was suspected and treated with immunosupressants. He suddenly developed respiratory failure secondary to alveolar hemorrhage and bronchoalveolar lavage was performed. The patient developed Gram-negative septic shock and died. The postmortem result of bronchoalveolar lavage yielded Strongyloides larvae. Nine cases of strongyloidiasis and the SHS in SLE patients reported in the literature were identified and reviewed. Five of these patients died; none had associated APS. CONCLUSIONS: These cases suggest that the SHS can exacerbate SLE and APS, predisposing to Gram-negative sepsis and death. Immunocompromised patients need an early diagnosis and specific treatment of parasitic diseases and their complications. The SHS should be considered in the differential diagnosis of lupus complications in patients from endemic areas.