Activation of Extracellular-signal Regulated Kinase (ERK1/2) by Fluid Shear is Ca\u3csup\u3e2+\u3c/sup\u3e- and ATP-dependent in MC3T3-E1 Osteoblasts

To determine the role of Ca2+ signaling in activation of the Mitogen-Activated Protein Kinase (MAPK) pathway, we subjected MC3T3-E1 pre-osteoblastic cells to inhibitors of Ca2+ signaling during application of fluid shear stress (FSS). FSS only activated ERK1/2, rapidly inducing phosphorylation within 5 min of the onset of shear. Phosphorylation of ERK1/2 (pERK1/2) was significantly reduced when Cai2+ was chelated with BAPTA or when Ca2+ was removed from the flow media. Inhibition of both the L-type voltage-sensitive Ca2+ channel and the mechanosensitive cation-selective channel blocked FSS-induced pERK1/2. Inhibition of phospholipase C with U73122 significantly reduced pERK1/2. This inhibition did not result from blockage of intracellular Ca2+ release, but a loss of PKC activation. Recent data suggests a role of ATP release and purinergic receptor activation in mechanotransduction. Apyrase-mediated hydrolysis of extracellular ATP completely blocked FSS-induced phosphorylation of ERK1/2, while the addition of exogenous ATP to static cells mimicked the effects of FSS on pERK1/2. Two P2 receptors, P2Y2 and P2X7, have been associated with the anabolic responses of bone to mechanical loading. Using both iRNA techniques and primary osteoblasts isolated from P2X7 knockout mice, we found that the P2X7, but not the P2Y2, purinergic receptor was involved in ERK1/2 activation under FSS. These data suggest that FSS-induced ERK1/2 phosphorylation requires Ca2+-dependent ATP release, however both increased Cai2+ and PKC activation are needed for complete activation. Further, this ATP-dependent ERK1/2 phosphorylation is mediated through P2X7, but not P2Y2, purinergic receptors

Parathyroid Hormone Enhances Mechanically Induced Bone Formation, Possibly Involving L-Type Voltage- Sensitive Calcium Channels

PTH and mechanical loading might act synergistically on bone formation. We tested the in vivo effect of the L-type voltage-sensitive calcium channel (VSCC) blocker, verapamil, on bone formation induced by human PTH-(1–34) (PTH) injection with or without mechanical loading. Adult rats were divided into eight groups: vehicle, verapamil, PTH, or verapamil plus PTH with or without mechanical loading. Verapamil (100 mg/kg) was given orally 90 min before loading. PTH (80 μg/kg) was injected sc 30 min before loading. Loading applied to tibia and ulna for 3 min significantly increased the bone formation rate on both the endocortical surface of tibia and the periosteal surface of ulna (P < 0.0001). Treatment with PTH enhanced load-induced bone formation by 53% and 76% (P < 0.001) on the endocortical and periosteal surfaces, respectively. Treatment with verapamil suppressed load-induced bone formation rate by 77% and 59% (P < 0.01). Furthermore, verapamil suppressed bone formation in rats subjected to PTH plus loading by 74% and 68% (P < 0.0001) at the tibia and ulna, respectively. In the groups without loading, neither verapamil nor PTH treatment significantly changed any bone formation parameter. This study indicates that L-type VSCCs mediate load-induced bone formation in vivo. Furthermore, PTH enhances load-induced bone adaptation through involvement of L-type VSCCs

Evolve therapeutic services: a 5-year outcome study of children and young people in out-of-home care with complex and extreme behavioural and mental health problems

Background: Little evaluation research has been conducted on the effectiveness of services and intervention provided to children in out-of-home care. This study evaluated an innovative Queensland, Australia program employing a collaborative wrap-round model of care in combination with a flexible intervention approach, individually tailored to children and young people in out-of-home care presenting with complex and extreme behavioural and mental health problems

Functional magnetic resonance imaging neurofeedback-guided motor imagery training and motor training for Parkinson's Disease: randomized trial

Objective: Real-time functional magnetic resonance imaging (rt-fMRI) neurofeedback (NF) uses feedback of the patient’s own brain activity to self-regulate brain networks which in turn could lead to a change in behavior and clinical symptoms. The objective was to determine the effect of NF and motor training (MOT) alone on motor and non-motor functions in Parkinson’s Disease (PD) in a 10-week small Phase I randomized controlled trial. Methods: Thirty patients with Parkinson’s disease (PD; Hoehn and Yahr I-III) and no significant comorbidity took part in the trial with random allocation to two groups. Group 1 (NF: 15 patients) received rt-fMRI-NF with MOT. Group 2 (MOT: 15 patients) received MOT alone. The primary outcome measure was the Movement Disorder Society—Unified PD Rating Scale-Motor scale (MDS-UPDRS-MS), administered pre- and post-intervention “off-medication”. The secondary outcome measures were the “on-medication” MDS-UPDRS, the PD Questionnaire-39, and quantitative motor assessments after 4 and 10 weeks. Results: Patients in the NF group were able to upregulate activity in the supplementary motor area (SMA) by using motor imagery. They improved by an average of 4.5 points on the MDS-UPDRS-MS in the “off-medication” state (95% confidence interval: −2.5 to −6.6), whereas the MOT group improved only by 1.9 points (95% confidence interval +3.2 to −6.8). The improvement in the intervention group meets the minimal clinically important difference which is also on par with other non-invasive therapies such as repetitive Transcranial Magnetic Stimulation (rTMS). However, the improvement did not differ significantly between the groups. No adverse events were reported in either group. Interpretation: This Phase I study suggests that NF combined with MOT is safe and improves motor symptoms immediately after treatment, but larger trials are needed to explore its superiority over active control conditions

What evidence is there on the effectiveness of different models of delivering urgent care? A rapid review

Objective The purpose of the evidence synthesis is to assess the nature and quality of the existing evidence base on delivery of emergency and urgent care services and identify gaps that require further primary research or evidence synthesis. Methods We have conducted a rapid framework-based evidence synthesis approach. Five separate reviews were conducted linked to themes in the NHS England review. A general and five theme specific database searches were conducted for the years 1995-2014. Relevant systematic reviews and additional primary research papers were included with narrative assessment of evidence quality was conducted for each review. Results The review was completed in six months. In total 45 systematic reviews and 102 primary research studies have been included across all 5 reviews. The key findings for each reviews were 1) Demand - there is little empirical evidence to explain increases in demand for urgent care, 2) Telephone triage - Overall, these services provide , appropriate and safe decision making with high patient satisfaction but required clinical skill mix and effectiveness in a system is unclear , 3) extended paramedic roles have been implemented in various health settings and appear to be successful at reducing transports to hospital, making safe decisions about the need for transport and delivering acceptable, cost-effective care out of hospital. 4)ED – The evidence on co-location of GP services with ED indicates there is potential to improve care. The attempt to summarise the evidence about wider ED operations proved to be too complex and further focused reviews are needed. 5) There is no empirical evidence to support the design and development of urgent care networks. Limitations Although there is a large body of evidence on relevant interventions much of it is weak with only very small numbers of randomised controlled trials identified. Evidence is dominated by single site studies many of which were uncontrolled. Conclusions The evidence gaps of most relevance to the delivery of services are 1) more detailed understanding and mapping of the characteristics of demand to inform service planning, 2) assessment of the current state of urgent care network development and evaluation of effectiveness of different models, and 3) Expanding the current evidence base on existing interventions that are viewed as central to delivery of the NHS England plan by assessing the implications of increasing interventions at scale and measuring costs and system impact. It would be prudent to develop a national picture of existing pilot projects or interventions in development to support decisions about research commissioning

The Period Changes of the Cepheid RT Aurigae

Observations of the light curve for the 3.7-day Cepheid RT Aur both before and since 1980 indicate that the variable is undergoing an overall period increase, amounting to +0.082 +-0.012 s/yr, rather than a period decrease, as implied by all observations prior to 1980. Superposed on the star's O-C variations is a sinusoidal trend that cannot be attributed to random fluctuations in pulsation period. Rather, it appears to arise from light travel time effects in a binary system. The derived orbital period for the system is P = 26,429 +-89 days (72.36 +-0.24 years). The inferred orbital parameters from the O-C residuals differ from those indicated by existing radial velocity data. The latter imply the most reasonable results, namely a1 sin i = 9.09 (+-1.81) x 10^8 km and a minimum secondary mass of M2 = 1.15 +-0.25 Msun. Continued monitoring of the brightness and radial velocity changes in the Cepheid are necessary to confirm the long-term trend and to provide data for a proper spectroscopic solution to the orbit.Comment: Accepted for publication in PASP (November 2007

The Ku-band Polarization Identifier

The Ku-band Polarization Identifier (KUPID) will integrate a very low noise 12-18 GHz, correlation polarimeter onto the Crawford Hill seven meter, millimeter-wave antenna. The primary components of the polarimeter will be built at the University of Miami and other key components, including the microwave horn and data acquisition system will be built at the University of Chicago and Princeton University. This project will measure the Q and U Stokes parameters in regions near the north celestial pole, in regions of low galactic contamination, and in regions near the galactic plane. The KUPID survey experiment makes use of many of the techniques employed in the Princeton IQU Experiment (PIQUE) that was developed by the members of this collaboration to detect CMB polarization at shorter wavelengths. The KUPID experiment will be constructed in parallel and on the same timescale as the CAPMAP experiment (see Barkats, this volume) which is the follow-on experiment to PIQUE. KUPID will observe on the Crawford Hill antenna from late spring until early autumn, while CAPMAP will observe during the lower water vapor months of late autumn until early spring.Comment: To be published in the proceedings of "The Cosmic Microwave Background and its Polarization", New Astronomy Reviews, (eds. S. Hanany and K. A. Olive