[Maternal-fetal therapy: from saving the fetus towards a better life for the future child]. / Ontwikkelingen in maternale-foetale therapie.

Maternal-fetal therapy (MFT) is special because treatment of the fetus is exclusively possible through the body of another person, the pregnant woman. MFT is a broad specialty with diverse interventions. In this manuscript several examples of innovations in MFT are discussed to illustrate the shift of lifesaving interventions to interventions aiming to improve morbidity of the future child. The broadening of the scope and shift towards prenatal treatments improving morbidity result in new ethical challenges. Particularly attention is needed for counseling and (the risk of) therapeutic misconception.

4q25 microdeletion encompassing PITX2: A patient presenting with tetralogy of Fallot and dental anomalies without ocular features.

Axenfeld-Rieger syndrome (ARS) is a heterogeneous clinical entity transmitted in an autosomal dominant manner. The main feature, Axenfeld-Rieger Anomaly (ARA), is a malformation of the anterior segment of the eye that can lead to glaucoma and impair vision. Extra-ocular defects have also been reported. Point mutations of FOXC1 and PITX2 are responsible for about 40% of the ARS cases. We describe the phenotype of a patient carrying a deletion encompassing the 4q25 locus containing PITX2 gene. This child presented with a congenital heart defect (Tetralogy of Fallot, TOF) and no signs of ARA. He is the first patient described with TOF and a complete deletion of PITX2 (arr[GRCh37]4q25(110843057-112077858)x1, involving PITX2, EGF, ELOVL6 and ENPEP) inherited from his ARS affected mother. In addition, to our knowledge, he is the first patient reported with no ocular phenotype associated with haploinsufficiency of PITX2. We compare the phenotype and genotype of this patient to those of five other patients carrying 4q25 deletions. Two of these patients were enrolled in the university hospital in Toulouse, while the other three were already documented in DECIPHER. This comparative study suggests both an incomplete penetrance of the ocular malformation pattern in patients carrying PITX2 deletions and a putative association between TOF and PITX2 haploinsufficiency.

Tuning the redox potential of vitamin K3 derivatives by oxidative functionalization using a Ag(i)/GO catalyst.

We propose herein initial results to develop optimum redox mediators by the combination of computational simulation and catalytic functionalization of the core structure of vitamin K3. We aim to correlate the calculated energy value of the LUMO of different vitamin K3 derivatives with their actual redox potential. For this, we optimized the catalytic alkylation of 1,4-naphthoquinones with a designed Ag(i)/GO catalyst and synthesized a series of molecules.

Continuous positive airway pressure devices for the treatment of obstructive sleep apnoea-hypopnoea syndrome: a systematic review and economic analysis.

OBJECTIVES: To determine the clinical effectiveness, safety and cost-effectiveness of continuous positive airway pressure (CPAP) devices for the treatment of obstructive apnoea-hypopnoea syndrome (OSAHS), compared with the best supportive care, placebo and dental devices. DATA SOURCES: The main search was of fifteen electronic databases, including MEDLINE, EMBASE and the Cochrane Library, up to November 2006. REVIEW METHODS: Randomised controlled trials (RCTs) comparing CPAP with best supportive/usual care, placebo, and dental devices in adults with a diagnosis of OSAHS were included. The primary outcomes of interest were subjective daytime sleepiness assessed by the Epworth Sleepiness Scale (ESS) and objective sleepiness assessed by the Maintenance of Wakefulness Test (MWT) and the Multiple Sleep Latency Test (MSLT). A new economic model was developed to assess incremental cost per quality-adjusted life-year (QALY). The cost-effectiveness of CPAP was compared with that of the use of dental devices and conservative management. The costs and QALYs were compared over a lifetime time horizon. Effectiveness was based on the RCT evidence on sleepiness symptoms (ESS), which was 'mapped' to utilities using individual patient data from a subset of studies. Utilities were expressed on the basis of generic HRQoL instruments [the EQ-5D (EuroQoL-5 Dimensions) in the base-case analysis]. The base-case analysis focused on a male aged 50. A series of subgroup and scenario analyses were also undertaken. RESULTS: The searches yielded 6325 citations, from which 48 relevant clinical effectiveness studies were identified, 29 of these providing data on daytime sleepiness. The majority of the included RCTs did not report using an adequate method of allocation concealment or use an intention-to-treat analysis. Only the studies using a sham CPAP comparator were double blinded. There was a statistically significant benefit with CPAP compared with control (placebo and conservative treatment/usual care) on the ESS [mean difference (MD) -2.7 points, 95% CI -3.45 to -1.96]. However, there was statistical heterogeneity, which was reduced when trials were subgrouped by severity of disease. There was also a significant benefit with CPAP compared with usual care on the MWT. There was a non-statistically significant difference between CPAP and dental devices (six trials) in the impact on daytime sleepiness (ESS) among a population with moderate symptom severity at baseline (MD -0.9, 95% CI -2.1 to 0.4). A review of five studies evaluating the cost-effectiveness of CPAP was undertaken. All existing cost-effectiveness studies had limitations; therefore a new economic model was developed, based on which it was found that, on average, CPAP was associated with higher costs and benefits than dental devices or conservative management. The incremental cost per QALY gained of CPAP was below 20,000 pounds in the base-case analysis and most alternative scenarios. There was a high probability of CPAP being more cost-effective than dental devices and conservative management for a cost-effectiveness threshold of 20,000 pounds per QALY gained. CONCLUSIONS: CPAP is an effective and cost-effective treatment for OSAHS compared with conservative/usual care and placebo in populations with moderate to severe daytime sleepiness, and there may be benefits when the disease is mild. Dental devices may be a treatment option in moderate disease but some uncertainty remains. Further research would be potentially valuable, particularly investigation of the effectiveness of CPAP for populations with mild sleepiness and further trials comparing CPAP with dental devices.

Cost-effectiveness of radiofrequency catheter ablation for the treatment of atrial fibrillation in the United Kingdom.

OBJECTIVE: To assess the cost-effectiveness of radiofrequency catheter ablation (RFCA) compared with anti-arrhythmic drug (AAD) therapy for the treatment of atrial fibrillation (AF) from the perspective of the UK NHS. DESIGN: Bayesian evidence synthesis and decision analytical model. METHODS: A systematic review and meta-analysis was conducted and Bayesian statistical methods used to synthesise the effectiveness evidence from randomised control trials. A decision analytical model was developed to assess the costs and consequences associated with the primary outcome of the trials over a lifetime time horizon. MAIN OUTCOME MEASURE: Costs from a health service perspective and outcomes measured as quality-adjusted life years (QALYs). RESULTS: The incremental cost-effectiveness ratio of RFCA varied between pound7763 and pound7910 for each additional QALY according to baseline risk of stroke, with a probability of being cost-effective from 0.98 to 0.99 for a cost-effectiveness threshold of pound20 000. Results were sensitive to the duration of quality of life benefits from treatment. CONCLUSIONS: RFCA is potentially cost-effective for the treatment of paroxysmal AF in patients' predominantly refractory to AAD therapy provided the quality-of-life benefits from treatment are maintained for more than 5 years. These findings remain subject to limitations in the existing evidence regarding the nature of life benefits and the prognostic importance of restoring normal sinus rhythm conferred using RFCA.

Curative catheter ablation in atrial fibrillation and typical atrial flutter: systematic review and economic evaluation.

OBJECTIVES: To determine the safety, clinical effectiveness and cost-effectiveness of radio frequency catheter ablation (RCFA) for the curative treatment of atrial fibrillation (AF) and typical atrial flutter. DATA SOURCES: For the systematic reviews of clinical studies 25 bibliographic databases and internet sources were searched in July 2006, with subsequent update searches for controlled trials conducted in April 2007. For the review of cost-effectiveness a broad range of studies was considered, including economic evaluations conducted alongside trials, modelling studies and analyses of administrative databases. REVIEW METHODS: Systematic reviews of clinical studies and economic evaluations of catheter ablation for AF and typical atrial flutter were conducted. The quality of the included studies was assessed using standard methods. A decision model was developed to evaluate a strategy of RFCA compared with long-term antiarrhythmic drug (AAD) treatment alone in adults with paroxysmal AF. This was used to estimate the cost-effectiveness of RFCA in terms of cost per quality-adjusted life-year (QALY) under a range of assumptions. Decision uncertainty associated with this analysis was presented and used to inform future research priorities using the value of information analysis. RESULTS: A total of 4858 studies were retrieved for the review of clinical effectiveness. Of these, eight controlled studies and 53 case series of AF were included. Two controlled studies and 23 case series of typical atrial flutter were included. For atrial fibrillation, freedom from arrhythmia at 12 months in case series ranged from 28% to 85.3% with a weighted mean of 76%. Three RCTs suggested that RFCA is more effective than long-term AAD therapy in patients with drug-refractory paroxysmal AF. Single RCTs also suggested superiority of RFCA over electrical cardioversion followed by long-term AAD therapy and of RFCA plus AAD therapy over AAD maintenance therapy alone in drug-refractory patients. The available RCTs provided insufficient evidence to determine the effectiveness of RFCA beyond 12 months or in patients with persistent or permanent AF. Adverse events and complications were generally rare. Mortality rates were low in both RCTs and case series. Cardiac tamponade and pulmonary vein stenosis were the most frequently recorded complications. For atrial flutter, freedom from arrhythmia at 12 months in case series ranged from 85% to 92% with a weighted mean of 88%. Neither of the atrial flutter RCTs reported freedom from arrhythmia at 12 months. One RCT found a statistically significant benefit favouring ablation over AADs in terms of freedom from arrhythmia at a mean follow-up of 22 months. A second RCT reported a more modest effect favouring ablation in terms of freedom from atrial flutter at follow-up in older patients (mean age 78 years) after their first episode of flutter. In the atrial flutter case series, mortality was rare and the most frequent complications were atrioventricular block and haematomas. Complications in the RCTs were similar, except for those events likely to have been caused by AAD therapy (e.g. thyroid dysfunction). The review of cost-effectiveness evidence found one relevant study, which from a UK NHS perspective had a number of important limitations. The base-case analysis in the decision model demonstrated that if the quality of life benefits of RFCA are maintained over the remaining lifetime of the patient then the cost-effectiveness of RFCA appears clear. These findings were robust over a wide range of alternative assumptions, being between 7763 and 7910 pounds per additional QALY with very little uncertainty. If the quality of life benefits of RFCA are assumed to be maintained for no more than 5 years, cost-effectiveness of RFCA is dependent on a number of factors. Estimates of cost-effectiveness that explored the influence of these factors ranged from 23,000 to 38,000 pounds per QALY. CONCLUSIONS: RFCA is a relatively safe and efficacious procedure for the therapeutic treatment of AF and typical atrial flutter. There is some randomised evidence to suggest that RFCA is superior to AADs in patients with drug-refractory paroxysmal AF in terms of freedom from arrhythmia at 12 months. RFCA appears to be cost-effective if the observed quality of life benefits are assumed to continue over a patient's lifetime. However, there remain uncertainties around longer-term effects of the intervention and the extent to which published effectiveness findings can be generalised to 'typical' UK practice. All catheter ablation procedures for the treatment of AF or atrial flutter undertaken in the UK should be recorded prospectively and centrally and measures to increase compliance in recording RFCA procedures may be needed. This would be of particular value in establishing the long-term benefits of RFCA and the true incidence and impact of any complications. Collection of appropriate quality of life data within any such registry would also be of value to future clinical and cost-effectiveness research in this area. Any planned multicentre RCTs comparing RFCA against best medical therapy for the treatment of AF and/or atrial flutter should be conducted among 'non-pioneering' centres using the techniques and equipment typically employed in UK practice and should measure relevant outcomes.

Activity of benzothiazoles and chemical derivatives on Plasmodium falciparum.

Malaria is a major health concern particularly in Africa which has about 90% of the worldwide annual clinical cases. The increasing number of drug-resistant Plasmodium falciparum justifies the search for new drugs in this field. Antimalarial activity of 2-substituted 6-nitro- and 6-amino-benzothiazoles and their anthranilic acids has been tested. An in vitro study has been performed on W2 and 3D7 strains of P. falciparum and on clinical isolates from malaria-infected patients. Toxicity has been assessed on THP1 human monocytic cells. For the most active drug candidates, the in vitro study was followed by in vivo assays on P. berghei-infected mice and by in vitro assays in order to determine the stage-dependency and the mechanism of action. Of 39 derivatives tested in vitro, 2 had specific antimalarial properties. Each compound was active on all stages of the parasite, but one was markedly active on mature schizonts, while the other was more active on young schizont forms. Both drugs were also active on mitochondrial membrane potential. In vivo data confirmed efficiency with a sustained decrease of parasitaemia. Products A12 and C7 may be considered as potential antimalarial worthy of further chemical and biological research.