Comparative efficacy of topical versus systemic teicoplanin in experimental model of wound infections

INTRODUCTION: Surgical site infections are the second most common cause of nosocomial infections and, typically, gram-positive pathogens are involved. MATERIALS AND METHODS: A mouse model was used to investigate the efficacy of different methods for the treatment of wound infections. A full thickness wound was established on the back subcutaneous tissue of adult male BALB/c mice. A small gauze was placed over each wound and then inoculated with 5 x 10(7) colony-forming units of Staphylococcus aureus. The study included a control group that did not receive any treatment and four contaminated groups treated, respectively, with: (1) drug-free Allevyn (Smith and Nephew Healthcare, Yorkshire, United Kingdom), (2) teicoplanin-soaked Allevyn, (3) drug-free Allevyn and daily intraperitoneal teicoplanin (7 mg/kg) and, finally, (4) teicoplanin-soaked Allevyn and daily intraperitoneal teicoplanin (7 mg/kg). Main outcome measures were quantitative bacterial culture, assessment of vascular endothelial growth factor (VEGF) plasma levels, histological examination with assessment of microvessel density, and of VEGF expression in tissue sections. RESULTS: Data analysis showed that strong inhibition of bacterial growth was achieved in any group treated with intraperitoneal teicoplanin. However, the highest inhibition of bacterial growth was obtained in the group that received teicoplanin-soaked Allevyn and intraperitoneal teicoplanin. Histological examination showed that each treatment modality was able to reduce the delay in wound repair. The most effective treatment appeared to be the local application of teicoplanin-soaked hydro gel foam. The tissue effects were associated with an increase in neovascularization and VEGF expression by endothelial cells and fibroblasts in the granulation tissue. Bacterial colonies also were reduced, especially when teicoplanin was given parenterally. CONCLUSIONS: Soaking a hydro cellular foam with an antistaphylococcal agents, such as teicoplanin, may be useful for the management of infected wounds.     

Prolonged islet allograft survival in diabetic mice upon macrophage depletion by clodronate-loaded erythrocytes

Early impairment of islet function and graft loss strongly limit the success of allogenic islet transplantation in insulin-dependent diabetes. Macrophages play a key role in this process thus the depletion of these cells may strongly affect islet survival. In this study, we have evaluated the effect of the depletion of macrophages in mouse allograft rejection using a new approach based on a single infusion of red blood cells loaded with the synthetic analogue of pyrophosphate clodronate. Graft survival was 19.4+/-0.89 and 20+/-2 days in the two control groups treated with physiological solution and unloaded erythrocytes, respectively; 25+/-1.9 days in the group treated with free-clodronate and 35+/-6 days in the erythrocytes-loaded group. Our results indicate clodronate selectively targeted to the macrophagic cells by a single administration of engineered erythrocytes can significantly prolong islet graft survival and open new therapeutic strategies in islet transplantation.     

Fluvastatin in the prevention of renal transplant vasculopathy: results of a prospective, randomized, double-blind, placebo-controlled trial

BACKGROUND: Statins prevent the progression of transplant vasculopathy in heart transplants, but its beneficial effect on the transplanted kidney is controversial. METHODS: The aim is to evaluate the utility of fluvastatin 80 mg/day to reduce the progression of 6-month renal transplant vasculopathy in a multicenter, prospective, randomized, placebo-controlled trial stratified according to donor age. All patients received cyclosporine, mycophenolate mofetil, and prednisone. The progression of transplant vasculopathy was evaluated in paired donor and 6-month protocol biopsies. The primary efficacy variable was the progression of mean arterial intimal volume fraction (deltaVvintima/artery) evaluated with histomorphometry. The minimum sample size to detect a 50% reduction in the progression of deltaVvintima/artery was 62 patients per group. The secondary efficacy variable included the incidence of transplant vasculopathy evaluated according to Banff criteria. RESULTS: A total of 89 patients were included, 74 completed the 6-month study and 57 have paired biopsies with sufficient tissue for histological evaluation. The deltaVvintima/artery was not different between treatment and placebo groups (6.9+/-8.2% vs. 6.9+/-7.4%, P=ns), whereas the incidence of transplant vasculopathy was lower in the fluvastatin group (7% vs. 33%; P=0.02). Because there was a discrepancy between the primary and secondary efficacy variables, post hoc analysis was performed to evaluate the reproducibility of both variables in a subset of 50 biopsies. The reproducibility of transplant vasculopathy was higher than the reproducibility of Vvintima/artery (kappa 0.86 vs. 0.33). CONCLUSIONS: In summary, there were no differences in deltaVvintima/artery between groups, but fluvastatin treatment was associated with a reduced incidence of transplant vasculopathy.     

A nomogram for staging of exclusive nonobturator lymph node metastases in men with localized prostate cancer

OBJECTIVES: Some patients with localized prostate cancer are at risk of nonobturator lymph node invasion (NOLNI) and may require an extended pelvic lymph node dissection (ePLND). We explored the rate of exclusive NOLNI and developed a nomogram to predict it. MATERIAL AND METHODS: We mapped all ePLND specimens according to their anatomic location (obturator, external iliac, internal iliac lymph nodes) and assessed the location-specific rate of LNI in 565 patients. A multivariate logistic regression-based nomogram predicting NOLNI was then internally validated with 200 bootstrap resamples. RESULTS: Overall, 11.1% (63 of 565) had LNI and 21 (3.7%) had exclusive NOLNI. The nomogram predicting exclusive NOLNI was 80.2% accurate. The nomogram's negative predictive value was 99%, when it predicted 0-10% probability of NOLNI. This approach could allow the omission of an ePLND in 350 of 565 (61.9%) patients and still correctly stage 85.8% of NOLNI cases. CONCLUSIONS: Our nomogram-based approach offers the possibility of identifying men who are at virtually zero risk of exclusive NOLNI. In these men, an ePLND may be safely avoided.     

Antitumor activity, X-ray crystal structure, and DNA binding properties of thiocoraline A, a natural bisintercalating thiodepsipeptide

The marine natural product thiocoraline A displayed approximately equal cytotoxic activity at nanomolar concentrations in a panel of 12 human cancer cell lines. X-ray diffraction analyses of orthorhombic crystals of this DNA-binding drug revealed arrays of docked pairs of staple-shaped molecules in which one pendent hydroxyquinoline chromophore from each cysteine-rich molecule appears intercalated between the two chromophores of a facing molecule. This arrangement is in contrast to the proposed mode of binding to DNA that shows the two drug chromophores clamping two stacked base pairs, in agreement with the nearest-neighbor exclusion principle. Proof of DNA sequence recognition was obtained from both classical DNase I footprinting experiments and determination of the melting temperatures of several custom-designed fluorescently labeled oligonucleotides. A rationale for the DNA-binding behavior was gained when models of thiocoraline clamping a central step embedded in several octanucleotides were built and studied by means of unrestrained molecular dynamics simulations in aqueous solution.     

New fluorescent 2-phenylindolglyoxylamide derivatives as probes targeting the peripheral-type benzodiazepine receptor: design, synthesis, and biological evaluation

Fluorescent ligands for the peripheral-type benzodiazepine receptor (PBR) featuring the 7-nitrobenz-2-oxa-1,3-diazol-4-yl moiety were synthesized, based on N,N-dialkyl-2-phenylindol-3-ylglyoxylamides, a potent, selective class of PBR ligands previously described by us. All the new ligands are moderately to highly potent at the PBR, with a complete selectivity over the central benzodiazepine receptor. Results from fluorescence microscopy showed that these probes specifically labeled the PBR at the mitochondrial level in C6 glioma cells.     

5-amino-2-phenyl[1,2,3]triazolo[1,2-a][1,2,4]benzotriazin-1-one: a versatile scaffold to obtain potent and selective A3 adenosine receptor antagonists

Binding assays on human A1, A2A, and A3 adenosine receptors (ARs) and functional studies on A2B ARs revealed that various 2-phenyl[1,2,3]triazolo[1,2-a][1,2,4]benzotriazin-1,5(6H)-diones VIII, previously reported as ligands at the central benzodiazepine receptor (BzR), possess nanomolar affinity at the A3 AR. Replacement of the amide of VIII with an amidine moiety gave the 5-amino-2-phenyl[1,2,3]triazolo[1,2-a][1,2,4]benzotriazin-1-ones IX, which maintain a nanomolar potency at the A3 AR with selectivity over the BzR. Insertion of a p-methoxybenzoyl at the 5-amino moiety enhanced A3 AR affinity and selectivity over the A1, A2A, and A2B ARs. The best result of our lead optimization efforts is 9-chloro-5-(4-methoxybenzoyl)amino-2-phenyl[1,2,3]triazolo[1,2-a][1,2,4]benzotriazin-1-one (23), which displayed a Ki of 1.6 nM at the A3 AR and no significant affinity at the other ARs or the BzR. Docking simulations on selected ligands into a model of the A3 AR allowed us to rationalize the structure-activity relationships of phenyltriazolobenzotriazindiones VIII and aminophenyltriazolobenzotriazinones IX at the molecular level.     

Simple enucleation for the treatment of renal angiomyolipoma

OBJECTIVES: To report on the role of simple enucleation for treating renal angiomyolipoma (AML) in a series of patients treated in our department. PATIENTS AND METHODS: We retrospectively reviewed the data of all 37 patients with a histopathological diagnosis of renal AML who had either radical nephrectomy (three) or nephron-sparing surgery by simple enucleation (34) between January 1986 and December 2005. Indications for intervention included either symptomatic AML or a tumour of >4 cm, regardless to the presence of symptoms or renal masses suspicious of malignancy. The patients' status was evaluated last in October 2006. RESULTS: The mean (sd, median, range) pathological tumour size was 5.2 (3.4, 4.8, 1.5-15) cm; five patients (15%) were affected by tuberous sclerosis. Simple enucleation was successful in all patients but in three (9%) a sharp dissection a few millimetres from the tumour was used during critical steps of the procedure where it seemed difficult to define the right plane of enucleation. Warm ischaemia was used in 79% of patients, with a mean ischaemic time of 11.2 min. Two patients (6%) required renal hypothermia. A simple parenchymal compression was used in five cases (15%). The mean (range) intraoperative blood loss was 170 (70-650) mL. None of the patients had postoperative bleeding requiring re-intervention but one (3%) required two units of blood after surgery. There were no major complications, e.g. prolonged acute tubular necrosis/chronic renal insufficiency and urinary leakage/urinoma, but two patients had urosepsis not associated with perirenal fluid collection and that required targeted antibiotic therapy. At a mean (median, range) follow-up of 56 (50.5, 10-120) months none of the patients had local tumour recurrence. Two patients had a small AML elsewhere in the operated kidney, detected 18 and 36 months after surgery, with a kidney recurrence rate of 6%. CONCLUSIONS: Our data confirm the optimum results of simple enucleation for renal AMLs; this technique provides excellent long-term local control and no patient had urinary leakage/fistula afterward.     

Reconstruction of the right atrium with pulmonary artery homograft after resection of right atrial lipomatosis

We present a case of large right atrial mass due to lipomatous hypertrophy of the interatrial septum and left lower lobe adenocarcinoma. Combined resections of the right atrial mass with reconstruction of the superior atriocaval junction and right atrial free wall defects with pulmonary artery homograft and wedge excision of the lung tumor were performed through median sternotomy.