Free Radical Copolymerization of 2,2,2-Trifluoroethyl a-Fluoroacrylate and tert-Butyl a-Trifluoromethylacrylate: Thermal and Optical Properties of the Copolymers

International audienceThe radical copolymerization of 2,2,2-trifluoroethyl a-fluoroacrylate (FATRIFE) with tert-butyl a-trifluoromethylacrylate (MAF-TBE) initiated by tertbutyl 2,2-dimethylperoxypropanoate was investigated in acetonitrile solution. A series of poly(FATRIFE-co-MAF-TBE) copolymers were synthesized with MAF-TBE compositions, determined by 19F NMR, ranging from 12 to 44 mol %. MAF-TBE incorporation was less than 50 mol % as this monomer underwent no radical homopolymerization. The obtained copolymers exhibited number-average molecular weights and polydispersity indexes ranging from 1.5 3 104 to 9.6 3 104 g/mol and from 1.5 to 3.1, respectively. The reactivity ratios were determined by the Kelen-Tu¨ dos method (rFATRIFE ¼ 1.71 6 0.01 and rMAF-TBE ¼ 0 at 74 8C) leading to random copolymers and alternating copolymers when the MAF-TBE molar ratio in copolymer is close to 50 mol %. Thermal and optical properties of the resulting polymers were examined. Glass transition temperatures of copolymers were varying from 89 to 108 8C. Modifying the compositions of these copolymers allowed a precise control over the refractive index measured at 633, 1320, and 1550 n

Acute black tea consumption improves cutaneous vascular function in healthy middle-aged humans.

BACKGROUND & AIMS: Dietary flavonoids, such as those present in black tea, are associated with reduced risk of cardiovascular disease (CVD), possibly through improving nitric oxide (NO) mediated vascular function. The aim of this study was to examine the effect of acute black tea ingestion on cutaneous microvascular function. METHODS: Twenty healthy participants (58 ± 5 y, 9 men) attended two experimental trials (tea, placebo), 7-days apart in a randomised, controlled, double-blind, cross-over design. Participants ingested a single dose of 200 ml black tea or placebo, followed by assessment of forearm cutaneous perfusion using laser-Doppler flowmetry (LDF) using three distinct heating protocols, enabling us to distinguish between axon- and endothelium-dependent vasodilation: 1. rapid 42°C, 2. rapid 39°C and 3. gradual 42°C. On the contralateral arm, full-field laser perfusion imaging (FLPI) was used to assess forearm perfusion during gradual 42°C. Data were presented as cutaneous vascular conductance (CVC; flux/mean arterial pressure, MAP) and CVC expressed as a percentage of maximal CVC (%CVCmax). RESULTS: Rapid local heating to 39°C or 42°C demonstrated no effect of tea for flux, CVC or %CVCmax (all P > 0.05). Gradual local heating to 42 °C, however, produced a higher skin blood flow following black tea ingestion for absolute CVC (P = 0.04) when measured by LDF, and higher absolute flux (P < 0.001) and CVC (P < 0.001) measured with FLPI. No effect of tea was found for %CVCmax when assessed by either LDF or FLPI. CONCLUSIONS: Acute tea ingestion enhanced cutaneous vascular responses to gradual local heating to 42 °C in healthy, middle-aged participants, possibly through a mechanism related to activation of endothelium-derived chemical mediators, such as NO. These improvements may contribute to the cardiovascular health benefits of regular tea ingestion

Role of cellular senescence and NOX4-mediated oxidative stress in systemic sclerosis pathogenesis.

Systemic sclerosis (SSc) is a systemic autoimmune disease characterized by progressive fibrosis of skin and numerous internal organs and a severe fibroproliferative vasculopathy resulting frequently in severe disability and high mortality. Although the etiology of SSc is unknown and the detailed mechanisms responsible for the fibrotic process have not been fully elucidated, one important observation from a large US population study was the demonstration of a late onset of SSc with a peak incidence between 45 and 54 years of age in African-American females and between 65 and 74 years of age in white females. Although it is not appropriate to consider SSc as a disease of aging, the possibility that senescence changes in the cellular elements involved in its pathogenesis may play a role has not been thoroughly examined. The process of cellular senescence is extremely complex, and the mechanisms, molecular events, and signaling pathways involved have not been fully elucidated; however, there is strong evidence to support the concept that oxidative stress caused by the excessive generation of reactive oxygen species may be one important mechanism involved. On the other hand, numerous studies have implicated oxidative stress in SSc pathogenesis, thus, suggesting a plausible mechanism in which excessive oxidative stress induces cellular senescence and that the molecular events associated with this complex process play an important role in the fibrotic and fibroproliferative vasculopathy characteristic of SSc. Here, recent studies examining the role of cellular senescence and of oxidative stress in SSc pathogenesis will be reviewed

Reproducibility of cutaneous vascular conductance responses to slow local heating assessed using 7-laser array probes.

OBJECTIVE: Gradual local heating of the skin induces a largely nitric oxide(NO)-mediated vasodilatation. However, use of this assessment of microvascular health is limited because little is known about its reproducibility. METHODS: Healthy volunteers (n=9) reported twice to the laboratory. Cutaneous vascular conductance (CVC), derived from laser Doppler flux and mean arterial pressure, was examined in response to a standardised local heating protocol (0.5°C per 150s from 33-42°C, followed by 20-minutes at 44°C). Skin responses were examined at two locations on the forearm (between-site). Heating was repeated after a break of 24-72 hours (between-day). Reproducibility of skin-responses at 33-42°C is presented for absolute CVC and relative CVC-responses corrected for maximal CVC at 44°C (%CVCmax ). RESULTS: Between-day reproducibility of baseline CVC and %CVCmax for both sites was relatively poor (22-30%). At 42°C, CVC and %CVCmax responses showed less variation (9-19%), whilst absolute CVC-responses at 44°C were 14-17%. Between-day variation for %CVCmax increased when using data from site 1 on day 1, but site 2 on the subsequent day (25%). CONCLUSION: Day-to-day reproducibility of baseline laser Doppler-derived skin perfusion responses is poor, but acceptable when absolute and relative skin perfusion to a local gradual heating protocol is utilised and site-to-site variation is minimised. This article is protected by copyright. All rights reserved

Exploring venlafaxine pharmacokinetic variability with a phenotyping approach, a multicentric french-swiss study (MARVEL study).

It is well known that the standard doses of a given drug may not have equivalent effects in all patients. To date, the management of depression remains mainly empirical and often poorly evaluated. The development of a personalized medicine in psychiatry may reduce treatment failure, intolerance or resistance, and hence the burden and costs of mood depressive disorders. The Geneva Cocktail Phenotypic approach presents several advantages including the "in vivo" measure of different cytochromes and transporter P-gp activities, their simultaneous determination in a single test, avoiding the influence of variability over time on phenotyping results, the administration of low dose substrates, a limited sampling strategy with an analytical method developed on DBS analysis. The goal of this project is to explore the relationship between the activity of drug-metabolizing enzymes (DME), assessed by a phenotypic approach, and the concentrations of Venlafaxine (VLX) + O-demethyl-venlafaxine (ODV), the efficacy and tolerance of VLX. This study is a multicentre prospective non-randomized open trial. Eligible patients present a major depressive episode, MADRS over or equal to 20, treatment with VLX regardless of the dose during at least 4 weeks. The Phenotype Visit includes VLX and ODV concentration measurement. Following the oral absorption of low doses of omeprazole, midazolam, dextromethorphan, and fexofenadine, drug metabolizing enzymes activity is assessed by specific metabolite/probe concentration ratios from a sample taken 2 h after cocktail administration for CYP2C19, CYP3A4, CYP2D6; and by the determination of the limited area under the curve from the capillary blood samples taken 2-3 and 6 h after cocktail administration for CYP2C19 and P-gp. Two follow-up visits will take place between 25 and 40 days and 50-70 days after inclusion. They include assessment of efficacy, tolerance and observance. Eleven french centres are involved in recruitment, expected to be completed within approximately 2 years with 205 patients. Metabolic ratios are determined in Geneva, Switzerland. By showing an association between drug metabolism and VLX concentrations, efficacy and tolerance, there is a hope that testing drug metabolism pathways with a phenotypical approach would help physicians in selecting and dosing antidepressants. The MARVEL study will provide an important contribution to increasing the knowledge of VLX variability and in optimizing the use of methods of personalized therapy in psychiatric settings. ClinicalTrials.gov NCT02590185 (10/27/2015). This study is currently recruiting participants

Exercise training improves vascular function in adolescents with type 2 diabetes.

The impact of exercise training on vascular health in adolescents with type 2 diabetes has not been previously studied. We hypothesized that exercise training would improve micro- and macrovascular health in adolescents with type 2 diabetes. Thirteen adolescents (13-21 years, 10F) with type 2 diabetes were recruited from Princess Margaret Hospital. Participants were randomized to receive either an exercise program along with standard clinical care (n = 8) or standard care alone (n = 5). Those in the intervention group received 12 weeks of gym-based, personalized, and supervised exercise training. Those in the control group were instructed to maintain usual activity levels. Assessments were conducted at baseline and following week 12. The exercise group was also studied 12 weeks following the conclusion of their program. Assessments consisted of conduit artery endothelial function (flow-mediated dilation, FMD) and microvascular function (cutaneous laser Doppler). Secondary outcomes included body composition (dual-energy X-ray absorptiometry, DXA), glycemic control (whole body insulin sensitivity, M) assessed using the euglycemic-hyperinsulinemic clamp protocol, cardiorespiratory fitness (V˙O2peak), and muscular strength (1RM). Exercise training increased FMD (P < 0.05), microvascular function (P < 0.05), total lean mass (P < 0.05), and muscle strength (P < 0.001). There were no changes in cardiorespiratory fitness, body weight, BMI, or M. In the control group, body weight (P < 0.01), BMI (P < 0.01), and total fat mass (P < 0.05) increased. At week 24, improvements in vascular function were reversed. This study indicates that exercise training can improve both conduit and microvascular endothelial function and health, independent of changes in insulin sensitivity in adolescents with type 2 diabetes

Local hyperhemia to heating is impaired in secondary Raynaud's phenomenon

Accurate and sensitive measurement techniques are a key issue in the quantification of the microvascular and endothelial dysfunction in systemic sclerosis (SSc). Thermal hyperhemia comprises two separate mechanisms: an initial peak that is axon reflex mediated; and a sustained plateau phase that is nitric oxide dependent. The main objective of our study was to test whether thermal hyperhemia in patients with SSc differed from that in patients with primary Raynaud's phenomenon (RP) and healthy controls. In a first study, we enrolled 20 patients suffering from SSc, 20 patients with primary RP and 20 healthy volunteers. All subjects were in a fasting state. Post-occlusive hyperhemia, 0.4 mg sublingual nitroglycerin challenge and thermal hyperhemia were performed using laser Doppler flowmetry on the distal pad of the third left finger. In a second study, thermal hyperhemia was performed in 10 patients with rheumatoid arthritis and 10 patients with primary RP. The thermal hyperhemia was dramatically altered in terms of amplitude and kinetics in patients with SSc. Whereas 19 healthy volunteers and 18 patients with primary RP exhibited the classic response, including an initial peak within the first 10 minutes followed by a nadir and a second peak, this occurred only in four of the SSc patients (p < 0.0001). The 10 minutes thermal peak was 43.4 (23.2 to 63), 42.6 (31 to 80.7) and 27 (14.7 to 51.4) mV/mm Hg in the healthy volunteers, primary RP and SSc groups, respectively (p = 0.01), while the 44°C thermal peak was 43.1 (21.3 to 62.1), 42.6 (31.6 to 74.3) and 25.4 (15 to 52.4) mV/mm Hg, respectively (p = 0.01). Thermal hyperhemia was more sensitive and specific than post-occlusive hyperhemia for differentiating SSc from primary RP. In patients with rheumatoid arthritis, thermal hyperhemia was also altered in terms of amplitude. Thermal hyperhemia is dramatically altered in patients with secondary RP in comparison with subjects with primary RP. Further studies are required to determine the mechanisms of this altered response, and whether it may provide additional information in a clinical setting

Sample entropy of laser Doppler flowmetry signals increases in patients with systemic sclerosis

Associated to reactivity tests, laser Doppler flowmetry (LDF) emphasizes abnormal skin microvascular function in diseases affecting digits, such as Raynaud\u27s phenomenon (RP) and systemic sclerosis (SSc). However, baseline perfusion value does not discriminate between disease states. We study if LDF sample entropy (SampEn) allows distinguishing healthy subjects, RP and SSc patients. LDF measurements were performed on finger pad and forearm of 108 subjects (27 controls, 28 RP patients, 53 SSc patients), before and after local thermal hyperemia. We also assessed the reproducibility of SampEn [expressed as within-subject coefficients of variation (CV) and intra-class correlation coefficients (ICC)]. Baseline SampEn is significantly increased in patients with SSc compared to RP and controls on finger pad [0.49 (0.19), 0.38 (0.14) and 0.36 (0.15), respectively; P &lt; 0.002], but not on forearm. However, local thermal hyperemia increased SampEn at all sites and for all groups. Finally, reproducibility of SampEn computed on two baseline segments was acceptable (CV = 26%, ICC = 0.63). SampEn of skin blood flow at rest is increased on finger pad of patients with SSc but not on forearm. This is consistent with the pathophysiology of the disease, which predominantly affects digital microcirculation in most patients. SampEn of LDF signal could be a reproducible tool to predict digital microvascular impairment

Assessment right atrial thrombus by real-time three dimensional transthoracic echocardiography in patient with dilated cardiomyopathy

We report a case of a 52-year-old patient with dilated cardiomyopathy who presented with worsening heart failure. Two-dimensional transthoracic echocardiography and real-time three dimensional transthoracic echocardiography showed severe dilated cardiac chambers, impaired ejection fraction and a mobile right atrial thrombus 2.6 × 1.0 cm in size, traversing the right atrial cavity during the whole cardiac cycle. After one week therapeutic anticoagulation, echocardiography confirmed no evidence of residual thrombus