Fixed combination of perindopril and indapamide at low dose improves endothelial function in essential hypertensive patients after acute administration

BACKGROUND: Fixed combination of angiotensin-converting enzyme inhibitors (ACEIs) with thiazide-type diuretics at low dose has been used as first-line therapy for the treatment of essential hypertension but their effect on conduit artery endothelial dysfunction remains unknown. METHODS: Thirteen hypertensive patients were assessed after acute administration of a placebo, fixed combination of perindopril-indapamide at low dose: D1 (2 mg/0.625 mg) and twice this dose: D2 (4 mg/1.25 mg), during a double-blind, randomized, crossover study, and were compared with 13 matched controls. Mean arterial pressure (MAP), radial artery diameter (echotracking) and flow (Doppler) were measured during flow-mediated dilatation (FMD) induced by post-ischemic hyperemia (PIH). PIH was characterized by peak flow and duration of hyperemia (t(1/2)). Endothelium-independent dilatation was assessed by trinitrine. RESULTS: In hypertensive patients compared with controls, basal radial artery diameter and flow, peak flow, and trinitrine responses were similar while MAP was increased (115 +/- 3 vs. 87 +/- 2 mm Hg), t(1/2) was decreased (11.1 +/- 1.9 vs. 17.2 +/- 2.2 s), and FMD was altered (radial diameter increase: 203 +/- 14 vs. 304 +/- 15 microm). Compared with placebo, only D2 decreased MAP (placebo: 115 +/- 3; D1: 112 +/- 4; D2: 103 +/- 4 mm Hg) and increased t(1/2) (placebo: 11.1 +/- 1.9; D1: 8.7 +/- 1.5; D2:13.0 +/- 1.9 s). Conversely, D1 and D2 increased FMD (placebo: 203 +/- 14; D1: 218 +/- 22; D2: 227 +/- 23 microm) with no change in basal diameter and flow, peak flow, and trinitrine responses. CONCLUSION: These results demonstrate that a fixed combination of ACEI/diuretic at low dose significantly improves radial artery FMD in hypertensive patients and suggest a direct effect on conduit artery endothelium that may contribute to vascular protection.     

Critical roles for IL-4, IL-5, and eosinophils in chronic skin allograft rejection

C57BL/6 mice injected with the 145-2C11 anti-CD3 mAb and grafted with MHC class II disparate bm12 skin develop a chronic rejection characterized by interstitial dermal fibrosis, a marked eosinophil infiltrate, and an obliterative intimal vasculopathy. Because these changes occur in the absence of alloreactive antibodies, we examined the contribution of cytokines in their pathogenesis. Chronically rejected grafts showed a marked accumulation of both IL-4 and IL-5 mRNA. Mixed lymphocyte reaction experiments established that mice undergoing chronic rejection were primed for IL-4, IL-5, and IL-10 secretion. In vivo administration of anti-IL-4 mAb completely prevented allograft vasculopathy as well as graft eosinophil infiltration and dermal fibrosis. Injection of anti-IL-5 mAb or the use of IL-5-deficient mice as recipients also resulted in the lack of eosinophil infiltration or dermal fibrosis, but these mice did develop allograft vasculopathy. Administration of anti-IL-10 mAb did not influence any histologic parameter of chronic rejection. Thus, in this model, IL-4- and IL-5-mediated tissue allograft eosinophil infiltration is associated with interstitial fibrosis. IL-4, but not eosinophils, is also required for the development of obliterative graft arteriolopathy.     

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.     

Measurement of glomerular filtration rate in obese patients: pitfalls and potential consequences on drug therapy

Epidemiological studies have shown that obesity is associated with chronic kidney disease and end stage renal disease. These studies have used creatinine derived equations to estimate glomerular filtration rate (GFR) and have indexed GFR to body surface area (BSA). However, the use of equations using creatinine as a surrogate marker of glomerular filtration and the indexation of GFR for BSA can be questioned in the obese population. First, these equations lack precision when they are compared to gold standard GFR measurements such as inulin clearances; secondly, the indexation of GFR for 1.73 m(2) of BSA leads to a systematic underestimation of GFR compared to absolute GFR in obese patients who have BSA that usually exceed 1.73 m(2). Obesity is also associated with pathophysiological changes that can affect the pharmacokinetics of drugs. The effect of obesity on both renal function and drug pharmacokinetics raises the issue of correct drug dosage in obese individuals. This may be particularly relevant for drugs known to have a narrow therapeutic range or excreted by the kidney.     

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.