Pyrimidine-2,4,6-triones are a new class of voltage-gated L-type Ca(2+) channel activators.

Cav1.2 and Cav1.3 are the main L-type Ca(2+) channel subtypes in the brain. Cav1.3 channels have recently been implicated in the pathogenesis of Parkinson’s disease. Therefore, Cav1.3-selective blockers are developed as promising neuroprotective drugs. We studied the pharmacological properties of a pyrimidine-2,4,6-trione derivative (1-(3-chlorophenethyl)-3-cyclopentylpyrimidine-2,4,6-(1H,3H,5H)-trione, Cp8) recently reported as the first highly selective Cav1.3 blocker. Here we show, in contrast to this previous study, that Cp8 reproducibly increases inward Ca(2+) currents of Cav1.3 and Cav1.2 channels expressed in tsA-201 cells by slowing activation, inactivation and enhancement of tail currents. Similar effects are also observed for native Cav1.3 and Cav1.2 channels in mouse chromaffin cells, while non-L-type currents are unaffected. Evidence for a weak and non-selective inhibition of Cav1.3 and Cav1.2 currents is only observed in a minority of cells using Ba(2+) as charge carrier. Therefore, our data identify pyrimidine-2,4,6-triones as Ca(2+) channel activators

Noninvasive measurements of arterial stiffness: Repeatability and interrelationships with endothelial function and arterial morphology measures

Corey J Huck1, Ulf G Bronas1, Eric B Williamson1, Christopher C Draheim1, Daniel A Duprez2, Donald R Dengel1,31School of Kinesiology, University of Minnesota, Minneapolis, MN, USA; 2Cardiovascular Division, Department of Medicine, University of Minnesota, Minneapolis, MN; 3Research Service, Minneapolis Veterans Affairs Medical Center, Minneapolis, MN, USABackground: Many noninvasive arterial assessment techniques have been developed, measuring different parameters of arterial stiffness and endothelial function. However, there is little data available comparing different devices within the same subject. Therefore, the purpose of this study was to examine the repeatability and interrelationships between 3 different techniques to measure arterial stiffness and to compare this with forearm-mediated dilation.Methods: Carotid-radial pulse wave velocity was measured by the Sphygmocor (SPWV) and Complior (CPWV) devices, cardio-ankle vascular index (CAVI) was measured by the VaSera device, vascular structure and function was assessed using ultrasonography and evaluated for reliability and compared in 20 apparently healthy, college-aged men and women.Results: The intraclass correlation coefficient and standard error of the mean for the Sphygmocor (R = 0.56, SEM = 0.69), Complior (R = 0.62, SEM = 0.69), and VaSera (R = 0.60, SEM = 0.56), indicated moderate repeatability. Bland-Altman plots indicated a mean difference of 0.11 ± 0.84 for SPWV, 0.13 ± 1.15 for CPWV, and –0.43 ± 0.90 for CAVI. No significant interrelationships were found among the ultrasound measures and SPWV, CPWV, and CAVI.Conclusions: The three noninvasive modalities to study arterial stiffness reliably measures arterial stiffness however, they do not correlate with ultrasound measures of vascular function and structure in young and apparently healthy subjects.Keywords: Pulse wave velocity, intima-media thickness, flow-mediated dilatio

Antibacterial PMMA Composite Cements with Tunable Thermal and Mechanical Properties

PMMA-based cements are the most used bone cements in vertebroplasty and total hip arthroplasty. However, they present several drawbacks, including susceptibility to bacterial infection, monomer leakage toxicity, and high polymerization temperature, which can all lead to damage to the surrounding tissues and their failure. In the present study, silver nanowires (AgNWs) have been introduced to bestow antibacterial properties; chitosan (CS) to promote porosity and to reduce the polymerization temperature, without negatively affecting the mechanical performance; and methacryloyl chitosan (CSMCC) to promote cross-linking with methyl methacrylate (MMA) and reduce the quantity of monomer required for polymerization. Novel PMMA cements were formulated containing AgNWs (0 and 1% w/w) and CS or CSMCC at various concentrations (0, 10, 20, and 30% w/w), testing two different ratios of powder and MMA (P/L). Mechanical, thermal, antibacterial, and cytotoxic properties of the resulting composite cements were tested. Cements with concentrations of CS > 10% presented a significantly reduced polymerization temperature. The mechanical performances were affected for concentrations > 20% with a P/L concentration equal to 2:1. Concentrations of AgNWs as low as 1% w/w conferred antimicrobial activity against S. aureus, whereas biofilm formation on the surface of the cements was increased when CS was included in the preparation. The combination of CS and AgNWs allowed a higher concentration of Ag+ to be released over time with enhanced antimicrobial activity. Inclusion of AgNWs did not affect cell viability on the scaffolds. In conclusion, a combination of CS and AgNWs may be beneficial for reducing both polymerization temperature and biofilm formation, without significantly affecting mesenchymal stem cell proliferation on the scaffolds. No advantages have been noticed as a result of the reducing P/L ratio or using CSMCC instead of CS

Walk well:a randomised controlled trial of a walking intervention for adults with intellectual disabilities: study protocol

Background - Walking interventions have been shown to have a positive impact on physical activity (PA) levels, health and wellbeing for adult and older adult populations. There has been very little work carried out to explore the effectiveness of walking interventions for adults with intellectual disabilities. This paper will provide details of the Walk Well intervention, designed for adults with intellectual disabilities, and a randomised controlled trial (RCT) to test its effectiveness. Methods/design - This study will adopt a RCT design, with participants allocated to the walking intervention group or a waiting list control group. The intervention consists of three PA consultations (baseline, six weeks and 12 weeks) and an individualised 12 week walking programme. A range of measures will be completed by participants at baseline, post intervention (three months from baseline) and at follow up (three months post intervention and six months from baseline). All outcome measures will be collected by a researcher who will be blinded to the study groups. The primary outcome will be steps walked per day, measured using accelerometers. Secondary outcome measures will include time spent in PA per day (across various intensity levels), time spent in sedentary behaviour per day, quality of life, self-efficacy and anthropometric measures to monitor weight change. Discussion - Since there are currently no published RCTs of walking interventions for adults with intellectual disabilities, this RCT will examine if a walking intervention can successfully increase PA, health and wellbeing of adults with intellectual disabilities

Predominant Functional Expression of Kv1.3 by Activated Microglia of the Hippocampus after Status epilepticus

BACKGROUND:Growing evidence indicates that the functional state of microglial cells differs according to the pathological conditions that trigger their activation. In particular, activated microglial cells can express sets of Kv subunits which sustain delayed rectifying potassium currents (Kdr) and modulate differently microglia proliferation and ability to release mediators. We recently reported that hippocampal microglia is in a particular activation state after a status epilepticus (SE) and the present study aimed at identifying which of the Kv channels are functionally expressed by microglia in this model. METHODOLOGY/PRINCIPAL FINDINGS:SE was induced by systemic injection of kainate in CX3CR1(eGFP/+) mice and whole cell recordings of fluorescent microglia were performed in acute hippocampal slices prepared 48 h after SE. Microglia expressed Kdr currents which were characterized by a potential of half-maximal activation near -25 mV, prominent steady-state and cumulative inactivations. Kdr currents were almost abolished by the broad spectrum antagonist 4-Aminopyridine (1 mM). In contrast, tetraethylammonium (TEA) at a concentration of 1 mM, known to block Kv3.1, Kv1.1 and 1.2 subunits, only weakly reduced Kdr currents. However, at a concentration of 5 mM which should also affect Kv1.3 and 1.6, TEA inhibited about 30% of the Kdr conductance. Alpha-dendrotoxin, which selectively inhibits Kv1.1, 1.2 and 1.6, reduced only weakly Kdr currents, indicating that channels formed by homomeric assemblies of these subunits are not important contributors of Kdr currents. Finally, agitoxin-2 and margatoxin strongly inhibited the current. CONCLUSIONS/SIGNIFICANCE:These results indicate that Kv1.3 containing channels predominantly determined Kdr currents in activated microglia after SE