Percutaneous mitral valve annuloplasty for functional mitral regurgitation: acute results of the first patient treated with the Viacor permanent device and future perspectives

BackgroundThere is a need to develop less invasive techniques to manage moderate or severe functional mitral regurgitation in patients at high surgical risk.ObjectiveWe report the acute results of the first patient treated with the permanent Viacor percutaneous transvenous mitral annuloplasty (PTMA) device in North America, introduce the PTOLEMY-2 protocol, and briefly discuss the current status of transvenous mitral valve techniques.Case reportAfter several episodes of pulmonary edema, an 87-year-old woman was referred for hemodynamic evaluation. Angiography revealed normal coronary arteries and severe mitral regurgitation. Baseline echocardiography showed severe (4+) functional mitral regurgitation. The coronary sinus was cannulated with a 9.5-Fr introducer from a left subclavian approach. After distal positioning of a coronary wire, the 7-Fr PTMA Viacor catheter was advanced to the anterior interventricular vein. Two 130 g/cm rods were then inserted resulting in an acute and dramatic reduction in mitral regurgitation as assessed by continuous transoesophageal echocardiography and which was associated with a sudden rise in arterial blood pressure. The next day, transthoracic echocardiogram showed a significant reduction in effective regurgitant orifice area (EROA) from 41 to 10 mm². The patient was discharged home the day following the procedure without complication. In accordance with the PTOLEMY-2 protocol, she will undergo 3-D transthoracic echocardiograms, quality of life assessments, and 6-min walk tests at regular intervals for the next 5 years.ConclusionPTMA is a promising technique for the treatment of severe mitral regurgitation in selected patients. Further ongoing research will determine the predictors of success and long-term safety and performance of this technique.     

The EULEV cohort study: rates of and factors associated with continuation of levetiracetam after 1 year

AIMS

To investigate real-life effectiveness of levetiracetam in patients initiating treatment in a stable market situation.

METHODS

Epileptic adults who had initiated levetiracetam between 1 January and 31 August in 2005 or 2006 were included and followed for 1 year by hospital or nonhospital neurologists practising in France. One-year continuation rates were estimated using Kaplan–Meier analysis. Among those still treated at end of study, treatment goals were investigated. Factors associated with discontinuation were investigated using Cox proportional hazards regression.

RESULTS

A total of 794 subjects were included in the cohort, and 753 subjects were followed up and included in the analysis. Among these, mean (SD) age was 42.6 (±17.0) years, 51.1% were female, 76.6% had partial epilepsy, 93.5% had seizures in the 6 months preceding levetiracetam initiation and 82.9% had at least one concomitant anti-epileptic drug when starting levetiracetam. One-year levetiracetam continuation rate was 83.5% (95% confidence interval, 80.5–86.0%). Of the 579 patients still using levetiracetam at end of study, 46.8% were seizure free during the last 6 months, and 24% were on levetiracetam monotherapy. Reasons for discontinuation (n = 122) were adverse events (45%), lack of efficacy (38%) or both (9%). Levetiracetam discontinuation was most strongly associated with previous exposure to more than four anti-epileptic drugs, whereas continuation was most strongly associated with presence of seizure-related falls in the 6 months preceding levetiracetam initiation.

CONCLUSIONS

This population-based cohort study in a stable market situation found a high 1 year levetiracetam continuation rate compared with previous studies done sooner after market introduction.     

Bioaccumulation and behavioral effects of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) in perinatally exposed mice

Polybrominated diphenyl ethers (PBDEs) are widely used flame retardants that have become pervasive environmental contaminants and may contribute to adverse health outcomes. We evaluated in mice the developmental neurotoxicity of 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47), one of the most abundant PBDE congeners detected in animal and human tissues. Female C57BL/6J mice were exposed to daily doses of 0, 0.03, 0.1 or 1 mg/kg beginning 4 weeks prior to conception, continuing through gestation and lactation, and ending at weaning on postnatal day (PND) 21. Levels of BDE-47 in blood, brain, liver and adipose tissues of dams were markedly increased after 4 weeks of exposure, around the time of mating, and continued to increase through the time of parturition. Blood levels of BDE-47 in the dosed dams were within the range reported in humans. BDE-47 tissue levels in the dams decreased between parturition and weaning, possibly reflecting mobilization during lactation. Brain BDE-47 levels in the offspring at PND 1 approached those of the dams at parturition. Perinatal exposure to BDE-47 resulted in significant dose dependent growth retardation, slower motor performance in several behavioral tests, and mice exposed to 1 mg/kg/day BDE-47 showed altered performance in the Morris water maze. There were no differences between groups in the numbers of pyramidal neurons in hippocampus CA1. These results document accumulation of BDE-47 in several organ systems following exposure to low-levels of BDE-47, and provide evidence that such exposure is associated with early behavioral deficits in exposed neonates.     

The EU paediatric regulation:: Effects on paediatric psychopharmacology in Europe

Child and adolescent psychiatry is a relatively young field and the recognition, classification, and treatment of disorders in children and adolescents lag behind those in adults. In recent years there is an increasing awareness of the differences between children and adults in psychopathology and pharmacology. Related to this new paediatric regulations have been introduced. This article reviews the regulatory and legislative measures that were adopted in the EU in 2007 and the subsequent impact of these measures on the field of paediatric psychopharmacology.The consequences of the paediatric regulation in the EU are reflected in several domains: regulatory, research aimed at drug development and clinical practices. In the regulatory domain, the consequences include: new paediatric indications, inclusion of special (class) warnings, specification of dose regimens, and information on safety specific to children and adolescents, and development of new medicinal formulations.The paediatric regulation leads to timely development of paediatric friendly formulations and better quality of the clinical evidence. In clinical practices, an increased awareness of the uniqueness of paediatric pharmacology is emerging among medical professionals, and subsequent improvement of medical care (i.e. correct doses, appropriate formulation, monitoring for expected adverse events). In addition, clinical guidelines will have to be revised more frequently in order to integrate the recently acquired knowledge.The new regulations stimulate transparency and discussions between academia, pharmaceutical industry, and regulators. The purpose is to optimize clinical research and obtain evidence for paediatric psychopharmacology, thereby providing adequate support for treatment.     

Assessment of RTG-W1, RTL-W1, and PLHC-1 fish cell lines for genotoxicity testing of environmental pollutants by means of a Fpg-modified comet assay

In a context of growing awareness of aquatic pollution impacts, there is an increasing need to develop methods for hazard and risk assessment of pollutants. For this purpose, in vitro models such as fish cell lines warrant to be evaluated as possible alternative to in vivo fish testing, and new toxicity endpoints such as genotoxicity deserve to be considered. This study assesses the interest of the formamido pyrimidine glycosylase (Fpg)-modified comet assay applied to three fish cell lines (RTL-W1, RTG-W1, and PLHC-1) regarding the sensitivity of the system for measuring genotoxicity of various classes of pollutants. Cytochrome P450-dependent EROD activity has also been measured to evaluate the importance of the biotransformation capacity of the cell lines in genotoxicity assessment. For all cell lines and chemicals tested, a concentration dependent genotoxic effect was observed with a 10- to 1000-fold increased sensitivity when using the Fpg-protocol compared to the standard comet assay. Such a modified assay led in particular to improve the detection threshold of oxidative and alkylating DNA damages following exposure at environmentally relevant contaminant concentrations and could partly compensate for the lower sensitivity of cell lines versus whole organism testing often cited as a limit of in vitro testing.     

Emergence of resistance to antibacterial agents: the role of quaternary ammonium compounds--a critical review

Quaternary ammonium compounds (QACs) are widely distributed in hospitals, industry and cosmetics. Little attention has been focused on the potential impact of QACs on the emergence of antibiotic resistance in patients and the environment. To assess this issue, we conducted a literature review on QAC chemical structure, fields of application, mechanism of action, susceptibility testing, prevalence, and co- or cross-resistance to antibiotics. Special attention was paid to the effects of QACs on microflora; in particular, the issue of the potential of QACs for applying selective pressure on multiple-antibiotic-resistant organisms was raised. It was found that there is a lack of standardised procedures for interpreting susceptibility test results. QACs have different impacts on the minimum inhibitory concentrations of antibacterials depending on the antibacterial compound investigated, the resistance genes involved, the measuring methodology and the interpretative criteria. The unmet needs for adequate detection of reduced susceptibility to QACs and antibiotics include (i) a consensus definition for resistance, (ii) epidemiological cut-off values and (iii) clinical resistance breakpoints. This review advocates the design of international guidelines for QAC use.     

Short-term uptake of microcystin-LR by Coregonus lavaretus: GST activity and genotoxicity

In the present study, juvenile whitefish weighing 2?g were exposed by force-feeding to two ecologically relevant doses (0.05 and 0.5?μg per fish) of microcystin-LR (MC-LR). Then over 96?h the MC uptake in fish liver and muscle was measured, as the activity of the detoxification enzyme glutathione S-transferase (GST) in the liver, and the genotoxicity impact on red blood cells. Results show that (1) the MC-LR equivalent concentrations increased for both doses and in both organs of whitefish with approximately threefold lower concentrations for the low dose compared to the high dose in both organs and threefold lower concentrations in the muscle compared to the liver for each dose (2) the liver GST activity increased during the first 48?h of exposure with fivefold higher GST activity for the highest dose at 48?h compared to control and (3) MC-LR leads to deoxyribonucleic acid strand breaks that were detected by the comet assay and shown to be partially repaired. This work demonstrates that European whitefish could be impacted by cyanobacteria toxins due to rapid microcystin uptake, especially in the context of chronic contamination, which can occur during long bloom episodes.     

Dendronized iron oxide nanoparticles for multimodal imaging

The synthesis of small-size dendrons and their grafting at the surface of iron oxide nanoparticles were achieved with the double objective to obtain a good colloidal stability with a mean hydrodynamic diameter smaller than 100 nm and to ensure the possibility of tuning the organic coating characteristics including morphology, functionalities, physico-chemical properties, grafting of fluorescent or targeting molecules. Magnetic resonance and fluorescence imaging are then demonstrated to be simultaneously possible using such versatile superparamagnetic iron oxide nanocrystals covered by a dendritic shell displaying either carboxylate or ammonium groups at their periphery which could be further labelled with a fluorescent dye. The grafting conditions of these functionalized dendrons at the surface of SPIO NPs synthesized by co-precipitation have been optimized as a function of the nature of the peripheral functional group. The colloidal stability has been investigated in water and osmolar media, and in vitro and in vivo MRI and optical imaging measurements have been performed showing encouraging biodistribution.