Mixed-Valent Molecular Triple Deckers.

Two phenothiazine (PTZ) moieties were connected via naphthalene spacers to a central arene to result in stacked PTZ-arene-PTZ structure elements. Benzene and tetramethoxybenzene units served as central arenes mediating electronic communication between the two PTZ units. Based on cyclic voltammetry, UV/Vis-NIR absorption, EPR spectroscopy, and computational studies, the one-electron oxidized forms of the resulting compounds behave as class II organic mixed-valence species in which the unpaired electron is partially delocalized over both PTZ units. The barrier for intramolecular electron transfer depends on the nature of the central arene sandwiched between the two PTZ moieties. These are the first examples of rigid organic mixed-valent triple-decker compounds with possible electron-transfer pathways directly across a stacked structure, and they illustrate the potential of oligo-naphthalene building blocks for long-range electron transfer and a future molecular electronics technology.

EFFICACY OF AN ADDITIONAL MOBILE LEADED SHIELD ON OPERATOR RADIATION DURING PERCUTANEOUS CORONARY ANGIOGRAPHY.

Operator radiation protection during percutaneous coronary angiography (CA) is a growing concern in the catheterisation laboratory (cath lab). The purpose of this study was to evaluate the efficacy of an additional mobile leaded shield on operator radiation exposure during diagnostic CA. The study involved two operators from the same cath lab and patients scheduled for diagnostic coronary catheterisation over a period of 2 months. Procedures were performed with standard radiation equipment during the first month. An additional mobile lead shield was added during the second month. Radiation exposure was measured by three dosimeters positioned on the operator's left hand, on their chest under the lead apron and on lead glasses. The intra-operator results were compared. Ninety-nine per cent of the procedures were carried out by radial access. For Operators 1 and 2, the mobile shield, respectively, decreased the radiation dose to the eyes by 43 and 33 % and to the hands by 61 and 83 %. Thorax dose was less than the minimum measurable dose (<0.01 mSv) for each operator. There was no significant difference in total procedure duration, fluoroscopy time or contrast dose required between the two groups of patients. Improved operator radiation protection is an important issue in the face of increased occupational doses. Mobile leaded shield, combined with standard preventive measures, seems to be an effective additional option to reduce the radiation exposure during diagnostic CA.

Myofibrillar myopathy with congenital cataract and skeletal anomalies without mutations in the desmin, alphaB-crystallin, myotilin, LMNA or SEPN1 genes.

Myofibrillar myopathies are genetically heterogeneous. We present a sporadic case of an 8-year-old boy with unusual combination of congenital skeletal muscle myopathy, cataract and poly/syndactyly. Muscle pathology revealed a mild myopathic picture with hyaline plaques, showing dark green staining in modified trichrome reaction, and strong immunoreactivity for alphaB-crystallin, desmin and dystrophin. Analysis of the coding sequences of the desmin, alphaB-crystallin, SEPN1, lamin A/C genes and of exon 2 of the myotilin gene showed no abnormalities in the patient. Presented case expands the wide clinical spectrum of myofibrillar myopathies, reinforcing the need for further exploration of genetic causes for this group of disorders.

Nanoparticle-based highly sensitive MRI contrast agents with enhanced relaxivity in reductive milieu.

Current magnetic resonance imaging (MRI) contrast agents often produce insufficient contrast for diagnosis of early disease stages, and do not sense their biochemical environments. Herein, we report a highly sensitive nanoparticle-based MRI probe with r1 relaxivity up to 51.7 ± 1.2 mM(-1) s(-1) (3T). Nanoparticles were co-assembled from Gd(3+) complexed to heparin-poly(dimethylsiloxane) copolymer, and a reduction-sensitive amphiphilic peptide serving to induce responsiveness to environmental changes. The release of the peptide components leads to a r1 relaxivity increase under reducing conditions and increases the MRI contrast. In addition, this MRI probe has several advantages, such as a low cellular uptake, no apparent cellular toxicity (tested up to 1 mM Gd(3+)), absence of an anticoagulation property, and a high shelf stability (no increase in free Gd(3+) over 7 months). Thus, this highly sensitive T1 MRI contrast nanoparticle system represents a promising probe for early diagnosis through possible accumulation and contrast enhancement within reductive extracellular tumour tissue.

Long-term efficacy of myoblast transplantation on regional structure and function after myocardial infarction.

BACKGROUND: Transplantation (Tx) of skeletal myoblasts (SM) within an infarcted myocardium improves global left ventricular (LV) function, although a direct systolic effect remains controversial. METHODS AND RESULTS: Global and regional LV functions were studied in a sheep model (n=16) of infarction before (baseline), and 4 (M4), and 12 (M12) months after in-scar injections of autologous SM or culture medium (CM). LV end-diastolic volume (EDV), ejection fraction (EF), wall motion score (WMS), and systolic myocardial velocity gradient (MVG) across the scar were measured by echocardiography with tissue Doppler imaging. Parameters were similar at baseline between groups. At M4, Tx of SM reduced the postinfarction increase in EDV (72+/-8 versus 105+/-13 mL in the CM group, P<0.05) and the decrease in EF (48+/-5 versus 33+/-3% in the CM group, P=0.006) although it improved WMS (5.4+/-1.2 versus 13+/-2.2 in the CM group, P<0.01) and SMVG (0.60+/-0.13 versus -0.04+/-.13 seconds(-1) in the CM group, P<0.05). Results were similar at M12. In-scar accumulation of myotubes and SM were detected in all Tx animals up to M12, with co-expression of fast and slow isoforms of the myosin heavy chain (MHC) (30% of the fibers versus 0% in the normal skeletal muscle) and decreased collagen density (30+/-2% versus 73+/-3%, P<0.0001). CONCLUSIONS: For up to 1 year, Tx of SM limits postinfarction EF deterioration and improves systolic scar function through colonization of fibrosis by skeletal muscle cells with expression of both MHC isoforms, which may confer to the graft the ability to withstand a cardiac-type workload.

New concepts to fight oxidative stress: nanosized three-dimensional supramolecular antioxidant assemblies.

INTRODUCTION: Misregulation of reactive oxygen species and reactive nitrogen species by the body's antioxidant system results in oxidative stress, which is known to be associated with aging, and involved in various pathologies including cancer, neurodegenerative and cardiovascular diseases. A large variety of low-molecular-weight (LMW) antioxidant compounds and antioxidant enzymes have been proposed to alleviate oxidative stress, but their therapeutic efficacy is limited by their solubility, stability or bioavailability. In this respect, nanoscience-based systems are expected to provide more efficient mitigation of oxidative stress. AREAS COVERED: The main nanoscience-based three-dimensional (3D) supramolecular assemblies, decorated with, or entrapping antioxidant compounds, or which possess intrinsic antioxidant activity are discussed and illustrated with recent examples. Assemblies with different architectures and sizes in the nanometer range serve: i) to deliver LMW antioxidant compounds or enzymes; ii) as antioxidant systems due to their intrinsic activity; and recently iii) to provide a confined space where catalytic antioxidant reactions take place in situ (nanoreactors and artificial organelles). A few insights into the role of antioxidants in mitigating oxidative stress caused by therapeutic compounds or drug carriers are also discussed. EXPERT OPINION: Several challenges must still be overcome in the development of 3D supramolecular assemblies to efficiently fight oxidative stress. First, an improvement of the assemblies' properties and stability in biological conditions has to be addressed. Second, new systems based on the combination of biomolecules or mimics in supramolecular assemblies should provide multifunctionality, stimuli-responsiveness and targeting properties for a more efficient therapeutic effect. Third, comparative studies are necessary to evaluate these systems in a standardized manner both in vitro and in vivo.

Impact of fondaparinux versus enoxaparin on in-hospital bleeding and 1-year death in non-ST-segment elevation myocardial infarction. FAST-MI (French Registry of Acute ST-elevation and non-ST-elevation Myocardial Infarction) 2010.

AIMS: Fondaparinux is an alternative to low molecular weight heparin (LMWH) for non-ST-elevation myocardial infarction (NSTEMI) with levels of recommendation that differ according to guidelines. The aim of this study was to assess outcomes in real world practice in NSTEMI patients participating in the French Registry of ST-elevation and non-ST-elevation Myocardial Infarction (FAST-MI) 2010 according to the use of fondaparinux, in comparison with patients receiving enoxaparin. METHODS AND RESULTS: FAST-MI 2010 is a nationwide French registry that included 4,169 patients with acute myocardial infarction at the end of 2010 in 213 centres (76% of active centres in France); 1,734 had NSTEMI, with 240 receiving fondaparinux and 1,027 enoxaparin. Patients receiving enoxaparin vs. fondaparinux had essentially characteristics with a similar GRACE (Global Registry of Acute Coronary Events) score. Invasive strategy was used in 69% in both groups. In-hospital bleeding was similar with both anticoagulant strategies and 1-year survival was 94.6% and 91.7%, respectively. Using fully adjusted Cox multivariate analysis, the use of fondaparinux was not associated with a reduced risk of death (hazard ratio: 1.35; 95% confidence interval: 0.70-2.51). After propensity score matching (207 patients per group), 1-year survival was similar with both strategies. There was, however, an interaction between fondaparinux and unfractionated heparin, with higher survival in fondaparinux-treated patients who received UFH, compared with those who did not. CONCLUSIONS: In this French cohort of NSTEMI patients, predominantly managed invasively, there was no evidence that fondaparinux was superior to enoxaparin as regards bleeding events or 1-year mortality (FAST-MI 2010; NCT01237418).

Thrombotic and bleeding events after coronary stenting according to clopidogrel and aspirin platelet reactivity: VerifyNow French Registry (VERIFRENCHY).

BACKGROUND: Dual antiplatelet therapy, comprising aspirin and clopidogrel, is recommended in patients undergoing coronary stenting to avoid the occurrence of stent thrombosis and others ischaemic events. Interindividual response to clopidogrel varies, however, with poor response associated with an increased risk of ischaemic events. New assays are available for testing aspirin and clopidogrel response routinely at the bedside. AIM: To evaluate the prognostic value of testing antiplatelet response in an intermediate-risk population undergoing stent implantation. METHODS: We prospectively assessed clopidogrel and aspirin response using the VerifyNow assay at the time of coronary stenting in 1001 patients who presented with stable coronary disease or non-ST-segment elevation acute coronary syndrome. The main ischaemic endpoint was the composite of definite and probable stent thrombosis, cardiovascular death or spontaneous myocardial infarction at one year. The safety endpoint was major bleeding. RESULTS: Overall, 36.0% of patients had high on-clopidogrel platelet reactivity (OCR) and 8.6% had high on-aspirin platelet reactivity (OAR). The main ischaemic composite endpoint occurred in 3.9% of patients with high vs. 2.3% of patients with normal OCR (hazard ratio 1.66, 95% confidence interval 0.78-3.54; P=0.18). Definite or probable stent thrombosis occurred in 1.1% of patients with high vs. 0.3% of patients with normal OCR (P=0.86). There was no significant difference in ischaemic endpoints according to OAR and there was no difference in rates of major bleeding between patients with high versus normal on-treatment platelet reactivity. CONCLUSIONS: On-treatment platelet reactivity was not associated with 1-year ischaemic or bleeding events in an intermediate-risk population undergoing stent implantation.

Bioreactor Conditioning of Valve Scaffolds Seeded Internally with Adult Stem Cells

The goal of this study was to test the hypothesis that stem cells, as a response to valve-specific extracellular matrix “niches” and mechanical stimuli, would differentiate into valvular interstitial cells (VICs). Porcine aortic root scaffolds were prepared by decellularization. After verifying that roots exhibited adequate hemodynamics in vitro, we seeded human adipose-derived stem cells (hADSCs) within the interstitium of the cusps and subjected the valves to in vitro pulsatile bioreactor testing in pulmonary pressures and flow conditions. As controls we incubated cell-seeded valves in a rotator device which allowed fluid to flow through the valves ensuring gas and nutrient exchange without subjecting the cusps to significant stress. After 24 days of conditioning, valves were analyzed for cell phenotype using immunohistochemistry for vimentin, alpha-smooth muscle cell actin (SMA) and prolyl-hydroxylase (PHA). Fresh native valves were used as immunohistochemistry controls. Analysis of bioreactor-conditioned valves showed that almost all seeded cells had died and large islands of cell debris were found within each cusp. Remnants of cells were positive for vimentin. Cell seeded controls, which were only rotated slowly to ensure gas and nutrient exchange, maintained about 50% of cells alive; these cells were positive for vimentin and negative for alpha-SMA and PHA, similar to native VICs. These results highlight for the first time the extreme vulnerability of hADSCs to valve-specific mechanical forces and also suggest that careful, progressive mechanical adaptation to valve-specific forces might encourage stem cell differentiation towards the VIC phenotype.

Usher syndrome type 1: early detection of electroretinographic changes.

BACKGROUND: Usher syndrome type 1 needs to be diagnosed at early age in order to timely manage speech therapy, cochlear implantation, and genetic counseling. Few data are available regarding electroretinographic testing before the age of six years. AIM: To describe electroretinographic changes in young children with Usher syndrome type 1. METHODS: Retrospective study of fourteen patients. Age at first neurophysiologic testing was between 17 months and 5 years 4 months. Electroretinogram was performed using flash stimulation in mesopic conditions in the conscious child. Analysis was focused on the amplitudes and latencies of a- and b-waves. RESULTS: Whatever the age, an abnormal fundus was always confirmed with an absent electroretinogram. The youngest patient with absent electroretinogram was 17 month-old. When recorded on and after the 29th month of age, electroretinogram was absent in all cases, including 6 patients with normal fundus. In three patients a low-amplitude electroretinogram was present at first recording within the 26th and 27th months. CONCLUSION: Electroretinogram showed retinopathy in young children with Usher syndrome type 1, even in the absence of fundoscopic signs of retinal degeneration.

Variation in AUDIT (Alcohol Use [correction of Used] Disorder Identification Test) scores within the first weeks of imprisonment.

AIMS: Although the prevalence of alcohol problems amongst detainees is suspected to be high, often only more flagrant problems are detected, restricting the possibilities for intervention in alcohol misuse and reducing opportunities for preventive efforts. This study examined the re-test reliability of AUDIT (the Alcohol Use Disorder Identification Test) in screening prisoners METHODS: AUDIT was administered for the first time on the day of entry to prison and again about 15 days later. The results were analysed according to two AUDIT thresholds: a score of 8 or higher and 12 or higher. RESULTS: Of 75 consecutive entrants tested, 47 male prisoners completed the study. At the first administration, 19.1% of these 47 men met criteria for a probable alcohol problem but this percentage rose to 59.6% on the second occasion (P = 0.0001). The proportion of subjects with a score 12 or higher (probably dependent) was 10.6% the first time versus 42.6% the second time (P = 0.0001). In the 19 who scored positive at the second administration only, changes in answers to the 10 items were coherent with a total score growing from 3.0 to 18.1 (P = 0.0001). No prisoner had a lower AUDIT score on the second administration. As alcohol problems are not routinely considered during the medical and biological examination at entry, no confirmation of the AUDIT results could be obtained, although those obtained at the second administration fitted well with the prevalence rates in previous reports. CONCLUSIONS: AUDIT, for the purpose of giving a prevalence estimate or to enter appropriate prisoners into more detailed assessment or interventions, should not be conducted immediately at entry, but some weeks later.