The influence of indomethacin co-administration on ofloxacin levels in plasma and cerebrospinal fluid in rats

The possible increase of ofloxacin levels in serum and cerebrospinal fluid (CSF) by concomitant indomethacin administration was investigated in 120 healthy adult rats. The animals were administered intramuscular doses of ofloxacin 30 mg/kg alone (Group A, n = 60) or with indomethacin 2 mg/kg (Group B, n = 60). Blood and CSF samples were obtained from both groups at 30, 45, 60 and 90 min post-administration. Concentrations of ofloxacin were estimated using a microbiological assay. Co-administration of indomethacin did not affect plasma levels of ofloxacin significantly; however, higher levels were found in all CSF samples after co-administration with indomethacin, particularly after 90 min with 0.59 microg/ml versus zero median values when only ofloxacin was administered (P = 0.05). No central nervous system adverse effects were observed clinically. No correlation between levels of ofloxacin in plasma and CSF could be established either in rats administered only ofloxacin or in rats administered both drugs. The presented pharmacokinetic findings revealed that co-administration of ofloxacin and indomethacin may result in protracted quinolone levels in the CSF. However, the absence of significant correlation between concentrations of ofloxacin in plasma and CSF upon co-administration of indomethacin, as well as of central nervous system adverse effects, make the probability of an epileptogenic interaction between them unlikely. These results merit further clinical evaluation.     

Ex vivo synergy of arachidonate-enriched serum with ceftazidime and amikacin on multidrug-resistant Pseudomonas aeruginosa

Three multidrug-resistant strains of Pseudomonas aeruginosa were incubated ex vivo with sera sampled after a 10 min intravenous infusion of 25 mg/kg of arachidonic acid (AA) in 10 rabbits in the presence of ceftazidime and amikacin. Lipid peroxidation was assessed during bacterial growth. A statistically significant decrease in bacterial cells was found by the interaction of antimicrobials and serum sampled in the middle of infusion and 15 and 30 min after infusion of AA and was accompanied by elevated levels of malonodialdehyde. This effect of AA is probably attributed to lipid peroxidation and raises the possibility of its application in experimental infections.     

Low psychopathology scores in the prognosis of breast cancer. A preliminary report

BACKGROUND: Research findings regarding the influence of psychopathology on cancer progression are not yet clear. This preliminary report investigates the severity of psychopathology assessed before biopsy in patients with invasive breast carcinoma (IBC) and its association with two follow-up outcomes: disease-free (to first recurrence) and survival periods. METHOD: The psychiatric assessment of 80 patients under 70 years old was established by means of an interview before biopsy. The DSM-IV criteria were used to establish the past and current psychiatric diagnoses. The Present State Examination (PSE)-Index of Definition (ID)-computer program (CATEGO) was used to define total PSE score, clusters of psychiatric symptoms (psychiatric syndromes) and current clinical severity (ID). The independent influence of biological prognostic factors and psychiatric variables on first recurrence or survival period was tested using Cox's proportional hazards regression model. RESULTS: After biopsy, 38 IBC patients were followed up for 3 to 8-1/3 years. During this period, 8 patients died from IBC and 7 were alive with metastatic disease. Cox's proportional hazards regression analyses showed that tumor diameter and low ID were independent significant predictors of early recurrence, whereas tumor diameter, negative estrogen receptors and low ID were independent significant predictors of survival. CONCLUSIONS: A low prebiopsy psychopathology score in IBC is a predictor of early recurrence and short survival.     

Apoptotic susceptibility of cancer cells selected for camptothecin resistance: gene expression profiling,functional analysis,and molecular interaction mapping

To study the molecular mechanisms by which drug resistance develops, we compared DU145 humanprostate cancer cells with a subline selected for resistance to camptothecin.Differences in gene expression level were assessed by hybridizing the two cell types against each other using quadruplicate "Oncochip" cDNA microarrays that included 1648 cancer-related genes. Expression levels differing by a factor of >1.5 were detected for 181 of the genes. These differences were judged statistically reliable on the basis of a stratum-adjusted Kruskal-Wallis test, after taking into account a dye-dependent variable. The 181 expression-altered genes included a larger than expected number of the "apoptosis-related" genes (P = 0.04). To assess whether this observation reflected a generalized resistance of RCO.1 to apoptosis, we exposed the cells to a range of stresses (cisplatin, staurosporine, UV, ionizing radiation, and serum starvation) and found greatly reduced apoptotic responses for RC0.1 (relative to DU145) using flow cytometric Annexin V and terminal deoxynucleotidyl transferase-mediated nick end labeling assays. We next examined the apoptosis-related genes in the context of a molecular interaction map and found expression differences in the direction "expected" on the basis of the apoptosis-resistance of RC0.1 for BAD, caspase-6, and genes that signal via the Akt pathway. Exposure of the cells to wortmannin, an inhibitor of the Akt effector phosphatidylinositol 3-kinase, provided functional support for involvement of the Akt pathway. However, closer examination of the molecular interaction map revealed a paradox: many of the expression differences observed for apoptosis-related genes were in the direction "contrary" to that expected given the resistance of RC0.1. The map indicated that most of these unexpected expression differences were associated with genes involved in the nuclear factor kappa B and transforming growth factor beta pathways. Overall, the patterns that emerged suggested a two-step model for the selection process that led to resistance in RC0.1 cells. The first hypothesized step would involve a decrease in apoptotic susceptibility through changes in the apoptosis-control machinery associated with the Bcl-2 and caspase gene families, and also in antiapoptotic pathways operating through Akt/PKB. The second step would involve changes in multifunctional upstream genes (including some genes in the nuclear factor kappa B and transforming growth factor beta pathways) that can facilitate apoptosis but that would also tend to contribute to cell proliferation in the presence of drug. Thus, we propose that a downstream blockade of apoptosis was "permissive" for the selection of upstream pathway changes that would otherwise have induced apoptosis. This model is analogous to one suggested previously for the relationship between oncogene function and apoptosis in carcinogenesis.     

Immunolocalization of transitional cell carcinoma of the bladder with intravesically administered technetium-99m labelled HMFG1 monoclonal antibody

The aim of this study was the immunolocalization of transitional cell carcinoma of the bladder with a radiolabelled murine tumour-associated monoclonal antibody and the measurement of the absolute uptake of the antibody by the tumour. Fourteen patients with transitional cell carcinoma of the bladder received 3–6 mCi (111–222 MBq) of technetium-99m labelled HMFG1 monoclonal antibody intravesically and one patient, 2 mCi (74 MBq) of iodine-131 labelled 11.4.1, which is a non-tumour-specific monoclonal antibody. Four of the 15 patients were evaluated with singlephoton emission tomography (SPET) 1 1/2 to 2 h post administration. All patients underwent transurethral resection of the bladder tumour within 12–20 h following intravesical administration of the radiolabelled antibody. The radioactivity of biopsy specimens from normal urothelium and tumour areas were counted in a gamma counter. The mean uptake of the radiolabelled antibodies from normal and tumour sites was expressed as a percentage of the administered dose per kilogram of tissue. Conventional histology and immunohistochemistry using HMFGI monoclonal antibody were performed on paraffin sections of the biopsy specimens. Although our results are preliminary, it can be concluded that: (a) bladder tumours are well imaged by SPET when using^99mTc-HMFG1; (b) intravesically administered radiolabelled antibody remains on the bladder tissue and does not escape into the systemic circulation; (c) the wide range of tumour uptake values (0%–9.3% administered dose/kg) observed probably can be attributed to heterogeneity of the antigenic expression of the tumour; (d) values of^99mTc-HMFGI monoclonal antibody uptake by the tumour do not justify future attempts at radioimmunotherapy.     

Fascia lata allograft bridging of a rotator cuff tear in a rabbit animal model

Purpose:

Despite advances in surgical treatment options, large rotator cuff (r-c) tears still represent a challenge for orthopedic surgeons. The purpose of this study was to evaluate the temporary and spatial histological incorporation of fascia lata allografts, used for bridging artificially created defects of the r-c.

Materials and Methods:

Seventy-two rabbits were divided into two groups and a supraspinatus tendinous defect was created. Half of the rabbit population underwent repair only, while in the other half, the defect was bridged utilizing fascia lata allograft. The animals were euthanized at 2, 4, and 6 weeks postoperative. Half of the specimens were evaluated histologically and the other half underwent mechanical testing.

Results:

There was an increased remodeling activity, fibroblastic in growth and strong presence of collagen fibers observed at 6 weeks on both groups. A gradually increasing mechanical strength was noticed by week 6 and increased toughness was also found at the same time period. There was no significant difference observed between the two groups regarding their histological and mechanical properties.

Conclusions:

In the difficult scenario of a large irreparable tear where the simple suture of the remaining r-c is impossible, allograft bridging, could be used with satisfactory results.

Clinical Relevance:

Treatment Study, Level 1.     

Evaluation of the polymorphisms associated with tandem repeats for Pseudomonas aeruginosa strain typing

We report on the development of a scheme for the typing of Pseudomonas aeruginosa, multiple-locus variable number of tandem repeat (VNTR) analysis (MLVA). We first evaluated the polymorphisms of 201 tandem repeat loci selected from more than 3,000 such sequences present in strain PAO1 with a test collection of 12 genotypically distinct clinical strains. Seven VNTR loci which can be easily scored with the technology used here were identified and used to genotype a collection of 89 clinical isolates that had previously been classified into 46 ribotypes, including 2 widespread ribotypes. Seventy-one different MLVA genotypes could be distinguished. With only two exceptions, strains with identical ribotypes were grouped together upon cluster analysis of the MLVA data. The 27 isolates with the most frequent ribotype were divided into 14 MLVA types, and the 18 isolates with the second most frequent ribotype were divided into 15 MLVA types. Analysis of a subset of 17 strains belonging to the major ribotype by pulsed-field gel electrophoresis with the enzyme SpeI distinguished seven types, identical to the number of MLVA types in this subset. Our data show that MLVA typing of P. aeruginosa based on the first set of loci has a high discriminatory power. Because MLVA is highly reproducible and easily portable among laboratories, it represents a very promising tool for the molecular surveillance of P. aeruginosa. A free, online strain identification service based on the genotyping data produced herein has been developed.     

Arthroscopic debridement of the osteoarthritic knee under local anaesthesia

This prospective study compared the efficacy of arthroscopic debridement in osteoarthritic knees under local, general or peridural anaesthesia. Between 1997 and 2001, 201 arthroscopic debridements were performed in 197 patients (173 partial meniscectomies, 192 articular trimmings, 119 microfractures, 201 lavage procedures) in 197 patients. Patients were treated under local (Group "L", n = 67), general (Group "G", n = 65) or peridural anesthesia ( Group "P", n = 65). No tourniquet was used. The follow-up ranged from 24 to 72 months (mean: 32 months). No major complication was noted. Results were assessed according to the scale of Baumgaertner et al independently from the type of anaesthesia used (p = 0.71). Results were excellent in 85 cases (L: 30, G: 27, E: 28), good in 75 (L: 25, G: 24, E: 26), fair in 27 (L: 9, G: 8, E: 10), poor in 14 (L: 7, G: 4, E: 3). Arthroscopic debridement of the osteoarthritic knee under local anaesthesia appears as an efficient, simple, safe, painless and cost-effective method of treatment.     

Partial excision of discoid meniscus: Arthroscopic operation of 10 patients

10 patients underwent arthroscopic removal of the central and torn portions of the lateral discoid meniscus, leaving a semilunar-shaped peripheral portion. All but one of the knees were asymptomatic at follow-up.