Increased large conductance calcium-activated potassium (BK) channel expression accompanied by STREX variant downregulation in the developing mouse CNS

BACKGROUND: Large conductance calcium- and voltage activated potassium (BK) channels are important determinants of neuronal excitability through effects on action potential duration, frequency and synaptic efficacy. The pore- forming subunits are encoded by a single gene, KCNMA1, which undergoes extensive alternative pre mRNA splicing. Different splice variants can confer distinct properties on BK channels. For example, insertion of the 58 amino acid stress-regulated exon (STREX) insert, that is conserved throughout vertebrate evolution, encodes channels with distinct calcium sensitivity and regulation by diverse signalling pathways compared to the insertless (ZERO) variant. Thus, expression of distinct splice variants may allow cells to differentially shape their electrical properties during development. However, whether differential splicing of BK channel variants occurs during development of the mammalian CNS has not been examined. RESULTS: Using quantitative real-time polymerase chain reaction (RT-PCR) Taqman™ assays, we demonstrate that total BK channel transcripts are up regulated throughout the murine CNS during embryonic and postnatal development with regional variation in transcript levels. This upregulation is associated with a decrease in STREX variant mRNA expression and an upregulation in ZERO variant expression. CONCLUSION: As BK channel splice variants encode channels with distinct functional properties the switch in splicing from the STREX phenotype to ZERO phenotype during embryonic and postnatal CNS development may provide a mechanism to allow BK channels to control distinct functions at different times of mammalian brain development

Validating CFD predictions of flow over an escarpment using ground-based and airborne measurement devices

Micrometeorological observations from a tower, an eddy-covariance (EC) station and an unmanned aircraft system (UAS) at the WINSENT test-site are used to validate a computational fluid dynamics (CFD) model, driven by a mesoscale model. The observation site is characterised by a forested escarpment in a complex terrain. A two-day measurement campaign with a flow almost perpendicular to the escarpment is analysed. The first day is dominated by high wind speeds, while, on the second one, calm wind conditions are present. Despite some minor differences, the flow structure, analysed in terms of horizontal wind speeds, wind direction and inclination angles shows similarities for both days. A real-time strategy is used for the CFD validation with the UAS measurement, where the model follows spatially and temporally the aircraft. This strategy has proved to be successful. Stability indices such as the potential temperature and the bulk Richardson number are calculated to diagnose atmospheric boundary layer (ABL) characteristics up to the highest flight level. The calculated bulk Richardson values indicate a dynamically unstable region behind the escarpment and near the ground for both days. At higher altitudes, the ABL is returning to a near neutral state. The same characteristics are found in the model but only for the first day. The second day, where shear instabilities are more dominant, is not well simulated. UAS proves its great value for sensing the flow over complex terrains at high altitudes and we demonstrate the usefulness of UAS for validating and improving models

An Investigation into the Oil Transport and Starvation of Piston-Ring Pack

In order to accurately predict the lubricant film thickness and generated friction in any tribological contact, it is important to determine appropriate boundary conditions, taking into account the oil availability and extent of starvation. This paper presents a two-dimensional hydrodynamic model of a piston ring pack for prediction of lubricant film thickness, friction and total power loss. The model takes into account starvation caused by reverse flow at the conjunctional inlet wedge, and applied to a ring pack, comprising a compression and scraper ring. Inlet boundaries are calculated for an engine cycle of a four-cylinder, four-stroke gasoline engine operating at 1500 r/min with conditions pertaining to the New European Drive Cycle. The analysis shows the two main sources of starvation: first, due to a physical lack of inlet meniscus and second, due to reverse flow at the inlet wedge significantly affecting the prevailing conditions from the generally assumed idealised boundary conditions. Such an approach has not hitherto been reported in literature

Defining language impairments in a subgroup of children with autism spectrum disorder

Autism spectrum disorder (ASD) is diagnosed on the basis of core impairments in pragmatic language skills, which are found across all ages and subtypes. In contrast, there is significant heterogeneity in language phenotypes, ranging from nonverbal to superior linguistic abilities, as defined on standardized tests of vocabulary and grammatical knowledge. The majority of children are verbal but impaired in language, relative to age-matched peers. One hypothesis is that this subgroup has ASD and co-morbid specific language impairment (SLI). An experiment was conducted comparing children with ASD to children with SLI and typically developing controls on aspects of language processing that have been shown to be impaired in children with SLI: repetition of nonsense words. Patterns of performance among the children with ASD and language impairment were similar to those with SLI, and contrasted with the children with ASD and no language impairment and typical controls, providing further evidence for the hypothesis that a subgroup of children with ASD has co-morbid SLI. The findings are discussed in the context of brain imaging studies that have explored the neural bases of language impairment in ASD and SLI, and overlap in the genes associated with elevated risk for these disorders.M01 RR00533 - NCRR NIH HHS; R01 DC10290 - NIDCD NIH HHS; U19 DC03610 - NIDCD NIH HH

Report of the study group on a superconducting proton linac as a PS Injector

A proposal was made at the end of 1996 to use the large inventory of RF hardware available after the decommissioning of LEP-2 for the construction of a 2 GeV Superconducting Proton Linac (SPL) to inject directly into the PS [1.1]. The brightness of the beam in the PS at low energy would double, helping the injector complex to satisfy the requirements of the LHC and benefiting the planned proton physics programme. Additional users could also be accommodated thanks to the capability of the SPL to operate at a much larger duty factor than that required for high-energy physics. Consequently, a small study group has been set up to analyse the major technical aspects of the SPL design as well as the processes of injection and capture in the PS. This report summarises the work done so far, and provides some information about the other possible uses of the SPL beam. The feasibility of such a cascade of accelerators is confirmed, although an in-depth design study is still required before the realistic performance and detailed design of that facility can be announced

A comparison between the APACHE II and Charlson Index Score for predicting hospital mortality in critically ill patients

<p>Abstract</p> <p>Background</p> <p>Risk adjustment and mortality prediction in studies of critical care are usually performed using acuity of illness scores, such as Acute Physiology and Chronic Health Evaluation II (APACHE II), which emphasize physiological derangement. Common risk adjustment systems used in administrative datasets, like the Charlson index, are entirely based on the presence of co-morbid illnesses. The purpose of this study was to compare the discriminative ability of the Charlson index to the APACHE II in predicting hospital mortality in adult multisystem ICU patients.</p> <p>Methods</p> <p>This was a population-based cohort design. The study sample consisted of adult (>17 years of age) residents of the Calgary Health Region admitted to a multisystem ICU between April 2002 and March 2004. Clinical data were collected prospectively and linked to hospital outcome data. Multiple regression analyses were used to compare the performance of APACHE II and the Charlson index.</p> <p>Results</p> <p>The Charlson index was a poor predictor of mortality (C = 0.626). There was minimal difference between a baseline model containing age, sex and acute physiology score (C = 0.74) and models containing either chronic health points (C = 0.76) or Charlson index variations (C = 0.75, 0.76, 0.77). No important improvement in prediction occurred when the Charlson index was added to the full APACHE II model (C = 0.808 to C = 0.813).</p> <p>Conclusion</p> <p>The Charlson index does not perform as well as the APACHE II in predicting hospital mortality in ICU patients. However, when acuity of illness scores are unavailable or are not recorded in a standard way, the Charlson index might be considered as an alternative method of risk adjustment and therefore facilitate comparisons between intensive care units.</p

External mechanical loading overrules cell-cell mechanical communication in sprouting angiogenesis during early bone regeneration

Sprouting angiogenesis plays a key role during bone regeneration. For example, insufficient early revascularization of the injured site can lead to delayed or non-healing. During sprouting, endothelial cells are known to be mechano-sensitive and respond to local mechanical stimuli. Endothelial cells interact and communicate mechanically with their surroundings, such as outer-vascular stromal cells, through cell-induced traction forces. In addition, external physiological loads act at the healing site, resulting in tissue deformations and impacting cellular arrangements. How these two distinct mechanical cues (cell-induced and external) impact angiogenesis and sprout patterning in early bone healing remains however largely unknown. Therefore, the aim of this study was to investigate the relative role of externally applied and cell-induced mechanical signals in driving sprout patterning at the onset of bone healing. To investigate cellular self-organisation in early bone healing, an in silico model accounting for the mechano-regulation of sprouting angiogenesis and stromal cell organization was developed. Computer model predictions were compared to in vivo experiments of a mouse osteotomy model stabilized with a rigid or a semirigid fixation system. We found that the magnitude and orientation of principal strains within the healing region can explain experimentally observed sprout patterning, under both fixation conditions. Furthermore, upon simulating the selective inhibition of either cell-induced or externally applied mechanical cues, external mechanical signals appear to overrule the mechanical communication acting on a cell-cell interaction level. Such findings illustrate the relevance of external mechanical signals over the local cell-mediated mechanical cues and could be used in the design of fracture treatment strategies for bone regeneration

Enzyme self-label-bound ATTO700 in single-molecule and super-resolution microscopy

Herein, we evaluate near-infrared ATTO700 as an acceptor in SNAP- and Halo-tag protein labelling for Förster Resonance Energy Transfer (FRET) by ensemble and single molecule measurements. Microscopy of cell surface proteins in live cells is perfomed including super-resolution stimulated emission by depletion (STED) nanoscopy

Elevated hemostasis markers after pneumonia increases one-year risk of all-cause and cardiovascular deaths

Background: Acceleration of chronic diseases, particularly cardiovascular disease, may increase long-term mortality after community-acquired pneumonia (CAP), but underlying mechanisms are unknown. Persistence of the prothrombotic state that occurs during an acute infection may increase risk of subsequent atherothrombosis in patients with pre-existing cardiovascular disease and increase subsequent risk of death. We hypothesized that circulating hemostasis markers activated during CAP persist at hospital discharge, when patients appear to have recovered clinically, and are associated with higher mortality, particularly due to cardiovascular causes. Methods: In a cohort of survivors of CAP hospitalization from 28 US sites, we measured D-Dimer, thrombin-antithrombin complexes [TAT], Factor IX, antithrombin, and plasminogen activator inhibitor-1 at hospital discharge, and determined 1-year all-cause and cardiovascular mortality. Results: Of 893 subjects, most did not have severe pneumonia (70.6% never developed severe sepsis) and only 13.4% required intensive care unit admission. At discharge, 88.4% of subjects had normal vital signs and appeared to have clinically recovered. D-dimer and TAT levels were elevated at discharge in 78.8% and 30.1% of all subjects, and in 51.3% and 25.3% of those without severe sepsis. Higher D-dimer and TAT levels were associated with higher risk of all-cause mortality (range of hazard ratios were 1.66-1.17, p = 0.0001 and 1.46-1.04, p = 0.001 after adjusting for demographics and comorbid illnesses) and cardiovascular mortality (p = 0.009 and 0.003 in competing risk analyses). Conclusions: Elevations of TAT and D-dimer levels are common at hospital discharge in patients who appeared to have recovered clinically from pneumonia and are associated with higher risk of subsequent deaths, particularly due to cardiovascular disease. © 2011 Yende et al

Comparison of severity of illness scoring systems for patients with nosocomial bloodstream infection due to Pseudomonas aeruginosa

BACKGROUND: Several acute illness severity scores have been proposed for evaluating patients on admission to intensive care units but these have not been compared for patients with nosocomial bloodstream infection (nBSI). We compared three severity of illness scoring systems for predicting mortality in patients with nBSI due to Pseudomonas aeruginosa. METHODS: We performed a historical cohort study on 63 adults in intensive care units with P. aeruginosa monomicrobial nBSI. RESULTS: The Acute Physiology, Age, Chronic Health Evaluation II (APACHE II), Sequential Organ Failure Assessment (SOFA), and Simplified Acute Physiologic Score (SAPS II), were calculated daily from 2 days prior through 2 days after the first positive blood culture. Calculation of the area under the receiver operating characteristic (ROC) curve confirmed that APACHE II and SAPS II at day -1 and SOFA at day +1 were better predictors of outcome than days -2, 0 and day 2 of BSI. By stepwise logistic regression analysis of these three scoring systems, SAPS II (OR: 13.03, CI95% 2.51–70.49) and APACHE II (OR: 12.51, CI95% 3.12–50.09) on day -1 were the best predictors for mortality. CONCLUSION: SAPS II and APACHE II are more accurate than the SOFA score for predicting mortality in this group of patients at day -1 of BSI