KCNQ/M currents in sensory neurons: Significance for pain therapy

Neuronal hyperexcitability is a feature of epilepsy and both inflammatory and neuropathic pain. M currents [I-K(M)] play a key role in regulating neuronal excitability, and mutations in neuronal KCNQ2/3 subunits, the molecular correlates of I-K(M), have previously been linked to benign familial neonatal epilepsy. Here, we demonstrate that KCNQ/M channels are also present in nociceptive sensory systems. I-K(M) was identified, on the basis of biophysical and pharmacological properties, in cultured neurons isolated from dorsal root ganglia (DRGs) from 17-d-old rats. Currents were inhibited by the M-channel blockers linopirdine (IC50, 2.1 muM) and XE991 (IC50, 0.26 muM) and enhanced by retigabine (10 muM). The expression of neuronal KCNQ subunits in DRG neurons was confirmed using reverse transcription-PCR and single-cell PCR analysis and by immunofluorescence. Retigabine, applied to the dorsal spinal cord, inhibited C and Adelta fiber-mediated responses of dorsal horn neurons evoked by natural or electrical afferent stimulation and the progressive "windup" discharge with repetitive stimulation in normal rats and in rats subjected to spinal nerve ligation. Retigabine also inhibited responses to intrapaw application of carrageenan in a rat model of chronic pain; this was reversed by XE991. It is suggested that I-K(M) plays a key role in controlling the excitability of nociceptors and may represent a novel analgesic target

Distributed design of product oriented manufacturing systems

Manufacturing leanness and agility are requirements of today’s manufacturing systems. Leanness call for a best fit of the manufacturing systems to products, therefore requiring product oriented manufacturing systems (POMS). Manufacturing agility can be achieved through easy systems reconfiguration to fit changing manufacturing requirements, which may mean dynamically configuring POMS. For this a suitable design system is required. Due to complexity of this design, and to the need for using suitable design methods, which may not be available locally, distributed sources of design services can be used. This paper presents and describes a prototype of a Distributed Design system for POMS based on a POMS design methodology and distributed suppliers of design services

Massive stars as thermonuclear reactors and their explosions following core collapse

Nuclear reactions transform atomic nuclei inside stars. This is the process of stellar nucleosynthesis. The basic concepts of determining nuclear reaction rates inside stars are reviewed. How stars manage to burn their fuel so slowly most of the time are also considered. Stellar thermonuclear reactions involving protons in hydrostatic burning are discussed first. Then I discuss triple alpha reactions in the helium burning stage. Carbon and oxygen survive in red giant stars because of the nuclear structure of oxygen and neon. Further nuclear burning of carbon, neon, oxygen and silicon in quiescent conditions are discussed next. In the subsequent core-collapse phase, neutronization due to electron capture from the top of the Fermi sea in a degenerate core takes place. The expected signal of neutrinos from a nearby supernova is calculated. The supernova often explodes inside a dense circumstellar medium, which is established due to the progenitor star losing its outermost envelope in a stellar wind or mass transfer in a binary system. The nature of the circumstellar medium and the ejecta of the supernova and their dynamics are revealed by observations in the optical, IR, radio, and X-ray bands, and I discuss some of these observations and their interpretations.Comment: To be published in " Principles and Perspectives in Cosmochemistry" Lecture Notes on Kodai School on Synthesis of Elements in Stars; ed. by Aruna Goswami & Eswar Reddy, Springer Verlag, 2009. Contains 21 figure

Radio emission from Supernova Remnants

The explosion of a supernova releases almost instantaneously about 10^51 ergs of mechanic energy, changing irreversibly the physical and chemical properties of large regions in the galaxies. The stellar ejecta, the nebula resulting from the powerful shock waves, and sometimes a compact stellar remnant, constitute a supernova remnant (SNR). They can radiate their energy across the whole electromagnetic spectrum, but the great majority are radio sources. Almost 70 years after the first detection of radio emission coming from a SNR, great progress has been achieved in the comprehension of their physical characteristics and evolution. We review the present knowledge of different aspects of radio remnants, focusing on sources of the Milky Way and the Magellanic Clouds, where the SNRs can be spatially resolved. We present a brief overview of theoretical background, analyze morphology and polarization properties, and review and critical discuss different methods applied to determine the radio spectrum and distances. The consequences of the interaction between the SNR shocks and the surrounding medium are examined, including the question of whether SNRs can trigger the formation of new stars. Cases of multispectral comparison are presented. A section is devoted to reviewing recent results of radio SNRs in the Magellanic Clouds, with particular emphasis on the radio properties of SN 1987A, an ideal laboratory to investigate dynamical evolution of an SNR in near real time. The review concludes with a summary of issues on radio SNRs that deserve further study, and analyzing the prospects for future research with the latest generation radio telescopes.Comment: Revised version. 48 pages, 15 figure

Associations between Extending Access to Primary Care and Emergency Department Visits: A Difference-In-Differences Analysis

Background: Health services across the world increasingly face pressures on the use of expensive hospital services. Better organisation and delivery of primary care has the potential to manage demand and reduce costs for hospital services, but routine primary care services are not open during evenings and weekends. Extended access (evening and weekend opening) is hypothesized to reduce pressure on hospital services from emergency department visits. However, the existing evidence-base is weak, largely focused on emergency out-of-hours services, and analysed using a before-and after-methodology without effective comparators. Methods and Findings: Throughout 2014, 56 primary care practices (346,024 patients) in Greater Manchester, England, offered 7-day extended access, compared with 469 primary care practices (2,596,330 patients) providing routine access. Extended access included evening and weekend opening and served both urgent and routine appointments. To assess the effects of extended primary care access on hospital services, we apply a difference-in-differences analysis using hospital administrative data from 2011 to 2014. Propensity score matching techniques were used to match practices without extended access to practices with extended access. Differences in the change in “minor” patient-initiated emergency department visits per 1,000 population were compared between practices with and without extended access. Populations registered to primary care practices with extended access demonstrated a 26.4% relative reduction (compared to practices without extended access) in patient-initiated emergency department visits for “minor” problems (95% CI -38.6% to -14.2%, absolute difference: -10,933 per year, 95% CI -15,995 to -5,866), and a 26.6% (95% CI -39.2% to -14.1%) relative reduction in costs of patient-initiated visits to emergency departments for minor problems (absolute difference: -£767,976, -£1,130,767 to -£405,184). There was an insignificant relative reduction of 3.1% in total emergency department visits (95% CI -6.4% to 0.2%). Our results were robust to several sensitivity checks. A lack of detailed cost reporting of the running costs of extended access and an inability to capture health outcomes and other health service impacts constrain the study from assessing the full cost-effectiveness of extended access to primary care. Conclusions: The study found that extending access was associated with a reduction in emergency department visits in the first 12 months. The results of the research have already informed the decision by National Health Service England to extend primary care access across Greater Manchester from 2016. However, further evidence is needed to understand whether extending primary care access is cost-effective and sustainable

Persistence of self-injurious behaviour in autism spectrum disorder over 3 years: a prospective cohort study of risk markers

BackgroundThere are few studies documenting the persistence of self-injury in individuals with autism spectrum disorder (ASD) and consequently limited data on behavioural and demographic characteristics associated with persistence. In this longitudinal study, we investigated self-injury in a cohort of individuals with ASD over 3 years to identify behavioural and demographic characteristics associated with persistence.MethodsCarers of 67 individuals with ASD (Median age of individuals with ASD in years = 13.5, Interquartile Range = 10.00–17.00), completed questionnaires relating to the presence and topography of self-injury at T1 and three years later at T2. Analyses were conducted to evaluate the persistence of self-injury and to evaluate the behavioural and demographic characteristics associated with persistence of self-injury.ResultsAt T2 self-injurious behaviour had persisted in 77.8 % of individuals. Behavioural correlates of being non-verbal, having lower ability and higher levels of overactivity, impulsivity and repetitive behaviour, were associated with self-injury at both time points. Risk markers of impulsivity (p = 0.021) and deficits in social interaction (p = 0.026) at T1 were associated with the persistence of self-injury over 3 years.ConclusionsImpulsivity and deficits in social interaction are associated with persistent self-injury in ASD and thus may act as behavioural risk markers. The identification of these risk markers evidences a role for behaviour dysregulation in the development and maintenance of self-injury. The findings have clinical implications for proactive intervention; these behavioural characteristics may be utilised to identify ‘at risk’ individuals for whom self-injury is likely to be persistent and therefore those individuals for whom early intervention may be most warranted.<br/

Discordance between accumulated p53 protein level and its transcriptional activity in response to u.v. radiation.

In response to DNA damage, the transcriptional activity of p53 rises. This has been thought to be due to an increase in the level of p53 protein. By comparing the p53 protein level and its ability to transactivate target genes Waf1/Cip1 and mdm2 in both T22 and NIH3T3 cells irradiated with u.v., a discordance between the p53 protein level and its transcriptional activity was observed. When the cells were irradiated with 10 J/m2 of u.v., there was a substantial increase in expression of Waf1/ Cip1 and mdm2. However, little increase in Waf1/Cip1 and mdm2 expression was observed in T22 and NIH3T3 cells 8 or 9 h after exposure to 50 J/m2 of u.v., although the p53 protein level accumulated to its highest level under these conditions. Interestingly, a significant increase in Waf1/Cip1 expression was seen 24 h after irradiation in NIH3T3 cells, indicating that the inhibition of p53 transcriptional activity is reversible. Discordance between the transcriptional activity of p53 and its protein level was further studied using a cell line expressing the p53 reporter plasmid RGC delta fosLacZ. Using double immunofluorescence staining, the coexpression of p53 and beta-galactosidase from the reporter plasmid in the same cells was investigated. The observed lack of correlation between the elevated p53 and beta-galactosidase and expression in u.v. irradiated cells strongly indicates that the ability of p53 to transactivate its target genes is not simply correlated to its protein level. The results indicate that the transcriptional activity of p53 may be negatively regulated

Discordance between accumulated p53 protein level and its transcriptional activity in response to u.v. radiation.

In response to DNA damage, the transcriptional activity of p53 rises. This has been thought to be due to an increase in the level of p53 protein. By comparing the p53 protein level and its ability to transactivate target genes Waf1/Cip1 and mdm2 in both T22 and NIH3T3 cells irradiated with u.v., a discordance between the p53 protein level and its transcriptional activity was observed. When the cells were irradiated with 10 J/m2 of u.v., there was a substantial increase in expression of Waf1/ Cip1 and mdm2. However, little increase in Waf1/Cip1 and mdm2 expression was observed in T22 and NIH3T3 cells 8 or 9 h after exposure to 50 J/m2 of u.v., although the p53 protein level accumulated to its highest level under these conditions. Interestingly, a significant increase in Waf1/Cip1 expression was seen 24 h after irradiation in NIH3T3 cells, indicating that the inhibition of p53 transcriptional activity is reversible. Discordance between the transcriptional activity of p53 and its protein level was further studied using a cell line expressing the p53 reporter plasmid RGC delta fosLacZ. Using double immunofluorescence staining, the coexpression of p53 and beta-galactosidase from the reporter plasmid in the same cells was investigated. The observed lack of correlation between the elevated p53 and beta-galactosidase and expression in u.v. irradiated cells strongly indicates that the ability of p53 to transactivate its target genes is not simply correlated to its protein level. The results indicate that the transcriptional activity of p53 may be negatively regulated

Individual behavioural differences in pigs: intra- and inter-test consistency

Two studies have been carried out in pigs to determine the relation between escape behaviour and production parameters and between escape behaviour and other factors. In the first, 823 piglets were tested with the backtest at 10 and 17 days of age. Production parameters, such as average daily weight gain and lean meat percentage, were recorded. In the second, the backtest was performed on 566 piglets at 3, 10 and 17 days of age. Escape behaviour in the backtest (backtest score) of the mother was known for 364 piglets. Parameters concerning the health of sow and piglets were recorded, as well as the sow's reaction on piglet removal for testing. Relations between production parameters and backtest scores of the animals were calculated, as well as the influence of birth weight, gender tall males were castrated), parents and health parameters on backtest scores. Backtest scores were fairly consistent over successive tests. Males had higher backtest scores than females, and piglets from sows with low backtest scores had low scores themselves. Finally, a higher backtest score gave a higher lean meat percentage and a better carcass grading at slaughter. No relation with daily weight gain was found. It is concluded that there are individual differences between the ways in which pigs cope with a stressful situation, as is measured with the backtest, and that this coping behaviour is consistent. A positive relation exists between backtest scores and lean meat percentage, and a heritability of backtest scores is assumed. (C) 2000 Elsevier Science B.V. All rights reserved