Fluorophosphonylated nucleoside derivatives as new series of thymidine phosphorylase multisubstrate inhibitors

The synthesis of new class of potential TPase inhibitors containing a difluoromethylphosphonate function as phosphate mimic is reported. This new series was prepared from a readily available fluorinated building block in few steps. Two series were evaluated as potential inhibitors: a linear series and a conformational constrained series. The activity of these multisubstrate inhibitors depends on the size of the spacer introduced between the pyrimidine ring and the phosphonate function. Best results were observed from triazolyl derivatives, easily obtained from propargylthymine and corresponding azides.     

Screening of alloantibodies: stability of false positive results as a quality indicator

Screening of alloantibodies is required before each transfusion. As part of our blood bank quality assurance, we have developed a quality indicator to monitor these false positive antibody results. We have studied 25.162 samples: sera were first screened by automated column agglutination technology (CAT). Positive results were found in 1.365 of the 25.162 samples. False positive results, ie positive screening test followed by a negative identification, were found in 271 (20%) cases. In the 116 patients remaining (43%) no factor could be evidenced. Interestingly, the percentage of patients with false positive antibody screening was stable month after month. In our experience, this percentage is very stable, it may be used as an indicator of quality laboratory and its unusual variation allows to suspect alterations of the reagents (hemolysis, loss of specificity, sensitivity).     

Unsatisfactory outcomes in myasthenia gravis: influence by care providers

Myasthenia gravis (MG) can be difficult to treat despite an available therapeutic armamentarium. Our aim was to analyze the factors leading to unsatisfactory outcome (UO). To this end we used the Myasthenia Gravis Foundation of America classification system. Forty one patients with autoimmune MG were followed prospectively from January 2003 to December 2007. Outcomes were assessed throughout follow-up and at a final visit. ‘Unchanged’, ‘worse’, ‘exacerbation’ and ‘died of MG’ post-intervention status were considered UOs. During follow-up, UO rates reached 54% and were related to undertreatment (41%), poor treatment compliance (23%), infections (23%), and adverse drug effects (13%). The UO rate at final study assessment was 20%. UO during follow-up was significantly (P = 0.004) predictive of UOs at final assessment. When care was provided by neuromuscular (NM) specialists, patients had significantly better follow-up scores (P = 0.01). At final assessment UO rates were 7% and significantly better in patients treated by NM specialists, compared to other physicians where UO rates reached 27%. UO was a frequent finding occurring in more than half our patients during follow-up. Nearly two-thirds of the UOs could have been prevented by appropriate therapeutic adjustments and improved compliance. The differential UO rates at follow-up, their dependency on the degree to which the management was specialized and their correlation with final outcomes suggest that specialized MG care improves outcomes.     

The EORTC Gastrointestinal Tract Cancer Group: 50 years of research contributing to improved gastrointestinal cancer management

During the last decades, the evolution of treatment - including radiotherapy, chemotherapy and targeted agents - has improved the cure and survival of patients with gastrointestinal (GI) cancer. Within the past 50 years of the EORTC's existence, significant progress has been made in the fight against cancer. During this time several cancer clinical trials were completed, and through these we are able to identify the most notable advances in GI cancer research done by the EORTC Gastrointestinal Tract Cancer Group (GI Group). Several EORTC clinical trials results have changed practice (e.g. standard of care of liver metastases of colorectal cancer has been changed by the EPOC trial) or have helped to support new treatment strategies in either early- or advanced-stage GI cancers. In addition to its clinical activities the group has started an extensive program of translational research. This changed strategy towards a translational, multidisciplinary program regarded as the basis for future developments. This review of the major achievements of the GI Group shows that it has played an important role in the scientific development of the understanding and treatment of GI cancer over the last 50 years.     

Reforming the Belgian market for orthotic braces: What can we learn from the international experience?

OBJECTIVES: This article aims to review regulation governing outpatient orthotic braces (neck, wrist and knee braces) in France, the Netherlands and Sweden with a view to reforming the Belgian market. METHODS: Information about the regulatory framework was derived from an analysis of legal texts and a survey completed by national experts. RESULTS: Strategies to keep down prices include public procurement in Sweden, maximum prices in France, and exclusion of expensive braces from reimbursement in the Netherlands. Reimbursement is linked to a medical indication or a chronic condition in France, the Netherlands and Sweden. To gain reimbursement, the cost-effectiveness of orthotic braces needs to be demonstrated in France and the Netherlands. Orthotic braces tend to be initially prescribed by a specialist physician and distributed by orthotists, medical equipment shops and/or community pharmacies. CONCLUSIONS: Extensive government intervention exists in the outpatient orthotic brace market in the countries studied. Our recommendations to reform the Belgian market for prefabricated orthotic braces are to separate reimbursement for service provision from reimbursement for braces; to set prices by means of a tendering process or an international price comparison; and to make reimbursement conditional on effectiveness and cost-effectiveness of braces.     

Development of animal models underlining mechanistic connections between prostate inflammation and cancer

The characterization of animal models has indicated that the genetic, dietary and environmental factors and hormonal imbalance may influence the risk to develop prostate inflammatory lesions and prostate cancer (PC) confirming human epidemiologic data. It is now established that the prostate inflammatory response typically results in major changes in the local microenvironment of epithelial cells of the prostate gland, including an intense stromal remodeling, activation of fibroblasts, infiltration of immune cells such as mast cells, macrophages and B and T lymphocytes and collagen deposition. The immune cells recruited at prostate inflammatory lesions and myofibroblasts may contribute to the release of numerous pro-inflammatory cytokines and chemokines that in turn can promote the oxidative stress, genomic instability and proliferation of epithelial cells. The accumulation of additional genetic and/or epigenetic alterations in prostatic stem/progenitor cells may subsequently culminate to their malignant transformation and PC initiation and progression and more particularly with advancing age. The potential mechanistic relationships between the molecular events associated with the persistent inflammatory response and prostate carcinogenesis have important implications for optimizing the current therapies against different prostatic disorders and PCs.     

Influence of visual inputs on quasi-static standing postural steadiness in individuals with spinal cord injury

Postural steadiness while standing is impaired in individuals with spinal cord injury (SCI) and could be potentially associated with increased reliance on visual inputs. The purpose of this study was to compare individuals with SCI and able-bodied participants on their use of visual inputs to maintain standing postural steadiness. Another aim was to quantify the association between visual contribution to achieve postural steadiness and a clinical balance scale. Individuals with SCI (n = 15) and able-bodied controls (n = 14) performed quasi-static stance, with eyes open or closed, on force plates for two 45 s trials. Measurements of the centre of pressure (COP) included the mean value of the root mean square (RMS), mean COP velocity (MV) and COP sway area (SA). Individuals with SCI were also evaluated with the Mini-Balance Evaluation Systems Test (Mini BESTest), a clinical outcome measure of postural steadiness. Individuals with SCI were significantly less stable than able-bodied controls in both conditions. The Romberg ratios (eyes open/eyes closed) for COP MV and SA were significantly higher for individuals with SCI, indicating a higher contribution of visual inputs for postural steadiness in that population. Romberg ratios for RMS and SA were significantly associated with the Mini-BESTest. This study highlights the contribution of visual inputs in individuals with SCI when maintaining quasi-static standing posture.     

Effects of exposure to DAMPS and GSM signals on ornithine decarboxylase (ODC) activity: I. L-929 mouse fibroblasts

Purpose: A temporary increase in ornithine decarboxylase (ODC) activity was reported in lysed L-929 fibroblasts after exposure to the microwaves emitted by Digital Advanced Mobile Phone System (DAMPS-835 MHz, 2.5 W/kg, 8 hours). Confirmation of these data was undertaken, given the suggested potential physiopathological consequences, i.e., tumour promotion.

Materials and methods: Murine L-929 fibroblasts were exposed at various Specific Absorption rates (SAR) to (DAMPS) or Global System for Mobile communications (GSM) signals using different set-ups. Cell ODC activities were assayed using ¹⁴CO₂ generation from ¹⁴C-labeled L-ornithine.

Results: ODC activity in live L-929 cells showed no significant alteration after exposure at an SAR of 2.5 W/kg, for one hour at the end of exposure to 50 Hz-modulated DAMPS-835 using Transverse Electro-Magnetic (TEM) cells. No significant alteration in ODC activity was observed at 6 W/kg, with active fans to regulate temperature (37°C). Tests using cell lysed after exposure in another temperature-controlled set-up (waveguides) did not confirm the published studies reporting increased ODC activity in Radio-Frequency radiation (RFR)-exposed L-929 cells. In the second part of the study, no alteration of ODC activity was detected when L-929 cells were exposed to different RFR signals: 217 Hz modulated GSM-900 (wire-patch antenna) or GSM-1800 (waveguides), and lysed before ODC measurement.

Conclusion: We conclude that under our exposure conditions, DAMPS-835 and GSM signals have no influence on ODC activity in L-929 cells.     

Antifungal Activity of 10 Guadeloupean Plants

Screening of the antifungal activities of ten Guadeloupean plants was undertaken to find new extracts and formulations against superficial mycoses such as onychomycosis, athlete's foot, Pityriasis versicolor, as well as the deep fungal infection Pneumocystis pneumonia. For the first time, the CMI of these plant extracts [cyclohexane, ethanol and ethanol/water (1:1, v/v)] was determined against five dermatophytes, five Candida species, Scytalidium dimidiatum, a Malassezia sp. strain and Pneumocystis carinii. Cytotoxicity tests of the most active extracts were also performed on an HaCat keratinocyte cell line. Results suggest that the extracts of Bursera simaruba, Cedrela odorata, Enterolobium cyclocarpum and Pluchea carolinensis have interesting activities and could be good candidates for developing antifungal formulations. Copyright © 2012 John Wiley & Sons, Ltd.