A 340 kDa hyaluronic acid secreted by human vascular smooth muscle cells regulates their proliferation and migration

The formation of atherosclerotic lesions is characterized by invasion of vascular smooth muscle cells (VSMC) into the tunica intima of the arterial wall and subsequently by increased proliferation of VSMC, a process apparently restricted to the intimal layer of blood vessels. Both events are preceded by the pathological overexpression of several growth factors, such as platelet-derived growth factor (PDGF) which is a potent mitogen for VSMC and can induce their chemotaxis. PDGF is generally not expressed in the normal artery but it is upregulated in atherosclerotic lesions. We have previously shown that PDGF-BB specifically stimulates proliferating VSMC to secrete a 340 kDa hyaluronic acid (HA-340). Here, we present evidence regarding the biological functions of this glycan. We observed that HA-340 inhibited the PDGF-induced proliferation of human VSMC in a dosedependent manner and enhanced the PDGF-dependent invasion of VSMC through a basement membrane barrier. These effects were abolished following treatment of HA-340 with hyaluronidase. The effect of HA-340 on the PDGF-dependent invasion of VSMC coincided with increased secretion of the 72-kDa type IV collagenase by VSMC and was completely blocked by GM6001, a hydroxamic acid inhibitor of matrix metalloproteinases. HA-340 did not exert any chemotactic potency, nor did it affect chemotaxis of VSMC along a PDGF gradient. In human atheromatic aortas, we found that HA-340 is expressed with a negative concentration gradient from the tunica media to the tunica intima and the atheromatic plaque. Our findings suggest that HA-340 may be linked to the pathogenesis of atherosclerosis, by modulating VSMC proliferation and invasio

Characterization of tailless functions during Drosophila optic lobe formation

AbstractBrain development goes through phases of proliferative growth and differentiation to ensure the formation of correct number and variety of neurons. How and when naïve neuroepithelial cells decide to enter a differentiation pathway remains poorly understood. In the Drosophila visual system, four optic ganglia emerge from neuroepithelia of the inner (IPC) and outer (OPC) proliferation centers. Here we demonstrate that the orphan nuclear receptor Tailless (Tll) is a key factor for the development of all optic ganglia. We describe tll expression during larval optic lobe development in unprecedented detail and find a spatiotemporally dynamic pattern. In the larval OPC, symmetrically dividing neuroepithelial cells transform into asymmetrically dividing medulla neuroblast and into lamina precursor cells in a precisely regulated fashion. Using genetic manipulations we found that tll is required for proper neuroepithelium morphology and neuroepithelial cell survival. We show that tll regulates the precise timing of the transition from neuroepithelial cells to medulla neuroblasts. In particular, however, we demonstrate that tll has a crucial role for the specification of lamina precursor cells. We propose that the Tll/Tlx transcription factors have an evolutionary conserved role in regulating neural precursor cell states in the Drosophila optic lobe and in the mammalian retina

Bupropion SR for smoking cessation in smokers with cardiovascular disease: a multicentre, randomised study

Aim To investigate the safety and efficacy of bupropion sustained release (bupropion SR) in promoting abstinence from smoking in subjects with cardiovascular disease (CVD). Methods Six hundred twenty-nine subjects with CVD who smoked ≥10 cigarettes/day were randomised in a double-blind, multicentre study to receive bupropion SR (150mg twice daily) or placebo for 7 weeks, with a follow-up of 52 weeks. Primary efficacy endpoint: continuous abstinence from smoking from weeks 4 to 7. Secondary endpoints: continuous abstinence (weeks 4-12, 4-26 and 4-52) and weekly point prevalence abstinence. All participants received brief motivational support. Safety was evaluated throughout the study. Results Continuous smoking abstinence rates from weeks 4 to 7 were significantly higher in subjects receiving bupropion SR compared with placebo (43 vs. 19%, odds ratio [OR]=3.27, 95% confidence interval [CI] 2.24-4.84; \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} $P{<}0.001$ \end{document}). Continuous abstinence rates from weeks 4 to 26 and 4 to 52 continued to be more than double for bupropion SR compared with placebo (27 vs. 11%; 22 vs. 9%, \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} $P{<}0.001$ \end{document}). Weekly point prevalence abstinence was significantly higher for participants who received bupropion SR compared with placebo at weeks 3, 7, 26 and 52 \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} $(P{<}0.001)$ \end{document}. In both groups, there were no clinically significant changes in blood pressure and heart rate throughout the treatment phase. Overall, 6% of the participants \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} $(n=36)$ \end{document} discontinued study medication due to an adverse event (bupropion SR, \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} $n=17$ \end{document}; placebo, \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} $n=19$ \end{document}). Conclusions After 7 weeks of bupropion SR treatment, more than twice as many smokers with CVD had quit smoking at 1 year compared with placebo. The safety profile of bupropion SR was similar to that previously observed in general smoking population

Ethical procedures and patient consent differ in Europe

BACKGROUND: Research ethics approvals, procedures and requirements for institutional research ethics committees vary considerably by country and by type of organisation. OBJECTIVE: To evaluate the requirements and procedures of research ethics committees, details of patient information and informed consent based on a multicentre European trial. DESIGN: Survey of European hospitals participating in the prospective observational study on chronic postsurgical pain (euCPSP) using electronic questionnaires. SETTING: Twenty-four hospitals in 11 European countries. PARTICIPANTS: From the 24 hospitals, 23 local investigators responded; 23 answers were analysed. OUTCOME MEASURES: Comparison of research ethics procedures and committee requirements from the perspective of clinical researchers. Comparison of the institutions' procedures regarding patient information and consent. Description of further details such as costs and the duration of the approval process. RESULTS: The approval process lasted from less than 2 weeks up to more than 2 months with financial fees varying between 0 and 575 €. In 20 hospitals, a patient information sheet of variable length (half page up to two pages) was provided. Requirements for patients' informed consent differed. Written informed consent was mandatory at 12, oral at 10 and no form of consent at one hospital. Details such as enough time for consideration, possibility for withdrawal and risks/benefits of participation were provided in 25 to 30% of the institutions. CONCLUSION: There is a considerable variation in the administrative requirements for approval procedures by research ethics committees in Europe. This results in variation of the extent of information and consent procedures for the patients involved

Biomimetic rehabilitation engineering: the importance of somatosensory feedback for brain-machine interfaces.

Brain-machine interfaces (BMIs) re-establish communication channels between the nervous system and an external device. The use of BMI technology has generated significant developments in rehabilitative medicine, promising new ways to restore lost sensory-motor functions. However and despite high-caliber basic research, only a few prototypes have successfully left the laboratory and are currently home-deployed. The failure of this laboratory-to-user transfer likely relates to the absence of BMI solutions for providing naturalistic feedback about the consequences of the BMI's actions. To overcome this limitation, nowadays cutting-edge BMI advances are guided by the principle of biomimicry; i.e. the artificial reproduction of normal neural mechanisms. Here, we focus on the importance of somatosensory feedback in BMIs devoted to reproducing movements with the goal of serving as a reference framework for future research on innovative rehabilitation procedures. First, we address the correspondence between users' needs and BMI solutions. Then, we describe the main features of invasive and non-invasive BMIs, including their degree of biomimicry and respective advantages and drawbacks. Furthermore, we explore the prevalent approaches for providing quasi-natural sensory feedback in BMI settings. Finally, we cover special situations that can promote biomimicry and we present the future directions in basic research and clinical applications. The continued incorporation of biomimetic features into the design of BMIs will surely serve to further ameliorate the realism of BMIs, as well as tremendously improve their actuation, acceptance, and use

Body Context and Posture Affect Mental Imagery of Hands

Different visual stimuli have been shown to recruit different mental imagery strategies. However the role of specific visual stimuli properties related to body context and posture in mental imagery is still under debate. Aiming to dissociate the behavioural correlates of mental processing of visual stimuli characterized by different body context, in the present study we investigated whether the mental rotation of stimuli showing either hands as attached to a body (hands-on-body) or not (hands-only), would be based on different mechanisms. We further examined the effects of postural changes on the mental rotation of both stimuli. Thirty healthy volunteers verbally judged the laterality of rotated hands-only and hands-on-body stimuli presented from the dorsum- or the palm-view, while positioning their hands on their knees (front postural condition) or behind their back (back postural condition). Mental rotation of hands-only, but not of hands-on-body, was modulated by the stimulus view and orientation. Additionally, only the hands-only stimuli were mentally rotated at different speeds according to the postural conditions. This indicates that different stimulus-related mechanisms are recruited in mental rotation by changing the bodily context in which a particular body part is presented. The present data suggest that, with respect to hands-only, mental rotation of hands-on-body is less dependent on biomechanical constraints and proprioceptive input. We interpret our results as evidence for preferential processing of visual- rather than kinesthetic-based mechanisms during mental transformation of hands-on-body and hands-only, respectively

Procalcitonin and the early diagnosis of infective endocarditis

Background— Variability in the clinical presentation of infective endocarditis (IE) makes the diagnosis a clinical challenge. We hypothesized that serum procalcitonin, a marker of systemic bacterial infection, might be helpful in its diagnosis. Methods and Results— We conducted a prospective cohort study in 67 consecutive patients admitted to the hospital with the suspicion of IE or in whom the suspicion arose during the hospital course. IE was diagnosed by an interdisciplinary team that included an infectious disease specialist and a cardiologist who applied the Duke criteria. IE was confirmed in 21 patients. Procalcitonin was significantly higher in patients with IE (median 6.56 ng/mL) than in those with other final diagnoses (median 0.44 ng/mL, P<0.001). The area under the receiver operating characteristic curve that used procalcitonin to predict IE was 0.856 (95% CI 0.750 to 0.962), compared with 0.657 (95% CI 0.511 to 0.802) for C-reactive protein. The optimum concentration of procalcitonin for the calculation of positive and negative predictive accuracy as obtained from the receiver operating characteristic curve was 2.3 ng/mL. With this cutoff, the test characteristics of procalcitonin were as follows: sensitivity 81%, specificity 85%, negative predictive value 92%, and positive predictive value 72%. Multiple logistic regression analysis revealed that procalcitonin was the only significant independent predictor of IE on admission (OR 1.52, 95% CI 1.07 to 2.15, P=0.018). Conclusions— Procalcitonin may be a valuable additional diagnostic marker in patients with suspected IE