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

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

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

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

Leveraging the Variability of Pharmacovigilance Disproportionality Analyses to Improve Signal Detection Performances

Background: A plethora of methods and models of disproportionality analyses for safety surveillance have been developed to date without consensus nor a gold standard, leading to methodological heterogeneity and substantial variability in results. We hypothesized that this variability is inversely correlated to the robustness of a signal of disproportionate reporting (SDR) and could be used to improve signal detection performances. Methods: We used a validated reference set containing 399 true and false drug-event pairs and performed, with a frequentist and a Bayesian disproportionality method, seven types of analyses (model) for which the results were very unlikely to be related to actual differences in absolute risks of ADR. We calculated sensitivity, specificity and plotted ROC curves for each model. We then evaluated the predictive capacities of all models and assessed the impact of combining such models with the number of positive SDR for a given drug-event pair through binomial regression models. Results: We found considerable variability in disproportionality analysis results, both positive and negative SDR could be generated for 60% of all drug-event pairs depending on the model used whatever their truthfulness. Furthermore, using the number of positive SDR for a given drug-event pair largely improved the signal detection performances of all models. Conclusion: We therefore advocate for the pre-registration of protocols and the presentation of a set of secondary and sensitivity analyses instead of a unique result to avoid selective outcome reporting and because variability in the results may reflect the likelihood of a signal being a true adverse drug reaction.MIAI @ Grenoble Alpe

Oestrogen metabolites in relation to isoprostanes as a measure of oxidative stress

Objective  Oestradiol (E2) and its metabolites 2-hydroxyoestrone (2-OHE1) and 16Α-hydroxyoestrone (16Α-OHE1) are thought to curtail the greater oxidative stress found in the development and progression of disease conditions including atherosclerosis. We related oestrogen levels to F 2a -isoprostane levels, a biomarker of oxidative stress. Design and participants  Data were obtained from 1647 women, aged 47–57 years, participating in the fifth annual follow-up of the Study of Women's Health Across the Nation (SWAN), a study of the menopausal transition. Measurements  Serum E2 and urinary 2-OHE1 and 16Α-OHE1 concentrations were determined by enzyme-linked immunosorbent assay (ELISA) and urinary F 2a -isoprostanes were measured by enzyme immunoassay (EIA). Results  F 2a -isoprostane concentrations were elevated in women who smoked, a behaviour associated with increased oxidative stress, but not in stages of the natural menopause. Mean F 2a -isoprostane concentrations among pre- and postmenopausal women who smoked were 1082 and 1064 pg/ml, respectively, values double those in pre- (343 pg/ml) and postmenopausal (379 pg/ml) nonsmoking women. 2-OHE1 and F 2a -isoprostane concentrations were positively and highly correlated (partial correlations Ρ Y|X  = 0·44 and Ρ Y|X  = 0·43 in pre- and postmenopausal women, respectively). Similarly, 16Α-OHE1 concentrations were positively and highly correlated with F 2a -isoprostane concentrations (Ρ Y|X  = 0·52 and Ρ Y|X  = 0·59 in pre- and postmenopausal women, respectively). E2 was significantly correlated with F 2a -isoprostanes only in postmenopausal women (Ρ Y|X  = 0·20). Associations were adjusted for age, body mass index (BMI), race/ethnicity, lipids, physical activity level and alcohol consumption. Conclusions  This study does not support the commonly held hypothesis that levels of endogenous E2 or its oestrone metabolites favourably modify oxidative stress by decreasing F2 a -isoprostane levels.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/74943/1/j.1365-2265.2007.03108.x.pd

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