Distinct forms of synaptic inhibition and neuromodulation regulate calretinin positive neuron excitability in the spinal cord dorsal horn

The dorsal horn (DH) of the spinal cord contains a heterogenous population of neurons that process incoming sensory signals before information ascends to the brain. We have recently characterized calretinin-expressing (CR+) neurons in the DH and shown that they can be divided into excitatory and inhibitory subpopulations. The excitatory population receives high-frequency excitatory synaptic input and expresses delayed firing action potential discharge, whereas the inhibitory population receives weak excitatory drive and exhibits tonic or initial bursting discharge. Here, we characterize inhibitory synaptic input and neuromodulation in the two CR+ populations, in order to determine how each is regulated. We show that excitatory CR+ neurons receive mixed inhibition from GABAergic and glycinergic sources, whereas inhibitory CR+ neurons receive inhibition, which is dominated by glycine. Noradrenaline and serotonin produced robust outward currents in excitatory CR+ neurons, predicting an inhibitory action on these neurons, but neither neuromodulator produced a response in CR+ inhibitory neurons. In contrast, enkephalin (along with selective mu and delta opioid receptor agonists) produced outward currents in inhibitory CR+ neurons, consistent with an inhibitory action but did not affect the excitatory CR+ population. Our findings show that the pharmacology of inhibitory inputs and neuromodulator actions on CR+ cells, along with their excitatory inputs can define these two subpopulations further, and this could be exploited to modulate discrete aspects of sensory processing selectively in the DH

Reconciling diverse lacustrine and terrestrial system response to penultimate deglacial warming in southern Europe

Unlike the most recent deglaciation, the regional expression of climate changes during the penultimate deglaciation remains understudied, even though it led into a period of excess warmth with estimates of global average temperature 1–2 °C, and sea level ∼6 m, above pre-industrial values. We present the first complete high-resolution southern European diatom record capturing the penultimate glacial-interglacial transition, from Lake Ioannina (northwest Greece). It forms part of a suite of proxies selected to assess the character and phase relationships of terrestrial and aquatic ecosystem response to rapid climate warming, and to resolve apparent conflicts in proxy evidence for regional paleohydrology. The diatom data suggest a complex penultimate deglaciation driven primarily by multiple oscillations in lake level, and provide firm evidence for the regional influence of abrupt changes in North Atlantic conditions. There is diachroneity in lake and terrestrial ecosystem response to warming at the onset of the last interglacial, with an abrupt increase in lake level occurring ∼2.7 k.y. prior to sustained forest expansion with peak precipitation. We identify the potentially important role of direct input of snow melt and glacial meltwater transfer to the subterranean karst system in response to warming, which would cause rising regional groundwater levels. This explanation, and the greater sensitivity of diatoms to subtle changes in temperature, reconciles the divergent lacustrine and terrestrial proxy evidence and highlights the sensitivity of lakes situated in mountainous karstic environments to past climate warming

The search for novel analgesics: re-examining spinal cord circuits with new tools

In this perspective, we propose the absence of detailed information regarding spinal cord circuits that process sensory information remains a major barrier to advancing analgesia. We highlight recent advances showing that functionally discrete populations of neurons in the spinal cord dorsal horn play distinct roles in processing sensory information. We then discuss new molecular, electrophysiological, and optogenetic techniques that can be employed to understand how dorsal horn circuits process tactile and nociceptive information. We believe this information can drive the development of entirely new classes of pharmacotherapies that target key elements in spinal circuits to selectively modify sensory function and blunt pain

Ring-fencing a budget for cancer drugs: is it fair?

Ring-fencing is defined as protecting funds for use in a specific area. In the NationalHealth Service in the UK, various methods to ring-fence cancer have beenemployed over the years; more recently the Cancer Drugs Fund in England hasenabled cancer drugs that would not normally be considered cost-effective to beprovided to patients. This has created variation in provision between England andthe devolved countries. While some would argue that ring-fencing allows majoradvances to be made in the treatment of a particular condition, others wouldargue that it is intrinsically unfair. In this debate, Graham and Cassidy have writtenan article arguing the affirmative position and Hughes and Duerden were invitedto respond directly to their arguments. As with all the RCPE's 'Currentcontroversies', the authors have been asked to take a deliberately polarisedposition and so the views they express may be somewhat overstated

Contrasting alterations to synaptic and intrinsic properties in upper-cervical superficial dorsal horn neurons following acute neck muscle inflammation

Background: Acute and chronic pain in axial structures, like the back and neck, are difficult to treat, and have incidence as high as 15%. Surprisingly, most preclinical work on pain mechanisms focuses on cutaneous structures in the limbs and animal models of axial pain are not widely available. Accordingly, we developed a mouse model of acute cervical muscle inflammation and assessed the functional properties of superficial dorsal horn (SDH) neurons.<p></p> Results: Male C57/Bl6 mice (P24-P40) were deeply anaesthetised (urethane 2.2?g/kg i.p) and the rectus capitis major muscle (RCM) injected with 40??l of 2% carrageenan. Sham animals received vehicle injection and controls remained anaesthetised for 2?hrs. Mice in each group were sacrificed at 2?hrs for analysis. c-Fos staining was used to determine the location of activated neurons. c-Fos labelling in carrageenan-injected mice was concentrated within ipsilateral (87% and 63% of labelled neurons in C1 and C2 segments, respectively) and contralateral laminae I - II with some expression in lateral lamina V. c-Fos expression remained below detectable levels in control and sham animals. In additional experiments, whole cell recordings were obtained from visualised SDH neurons in transverse slices in the ipsilateral C1 and C2 spinal segments. Resting membrane potential and input resistance were not altered. Mean spontaneous EPSC amplitude was reduced by ~20% in neurons from carrageenan-injected mice versus control and sham animals (20.63???1.05 vs. 24.64???0.91 and 25.87???1.32 pA, respectively). The amplitude (238???33 vs. 494???96 and 593???167 pA) and inactivation time constant (12.9???1.5 vs. 22.1???3.6 and 15.3???1.4?ms) of the rapid A type potassium current (IAr), the dominant subthreshold current in SDH neurons, were reduced in carrageenan-injected mice.<p></p> Conclusions: Excitatory synaptic drive onto, and important intrinsic properties (i.e., IAr) within SDH neurons are reduced two hours after acute muscle inflammation. We propose this time point represents an important transition period between peripheral and central sensitisation with reduced excitatory drive providing an initial neuroprotective mechanism during the early stages of the progression towards central sensitisation

Ecosystem uptake and transfer of Sellafield-derived radiocarbon (14C). Part 1. The Irish Sea

Ecosystem uptake and transfer processes of Sellafield-derived radiocarbon (14C) within the Irish Sea were examined. Highly variable activities in sediment, seawater and biota indicate complex 14C dispersal and uptake dynamics. All east basin biota exhibited 14C enrichments above ambient background while most west basin biota had 14C activities close to background, although four organisms including two slow-moving species were significantly enriched. The western Irish Sea gyre is a suggested pathway for transfer of 14C to the west basin and retention therein. Despite ongoing Sellafield 14C discharges, organic sediments near Sellafield were significantly less enriched than associated benthic organisms. Rapid scavenging of labile, 14C-enriched organic material by organisms and mixing to depth of 14C-enriched detritus arriving at the sediment/water interface are proposed mechanisms to explain this. All commercially important fish, crustaceans and molluscs showed 14C enrichments above background; however, the radiation dose from their consumption is extremely low and radiologically insignificant

Integral Field Spectroscopy of 23 Spiral Bulges

We have obtained Integral Field Spectroscopy for 23 spiral bulges using INTEGRAL on the William Herschel Telescope and SPIRAL on the Anglo-Australian Telescope. This is the first 2D survey directed solely at the bulges of spiral galaxies. Eleven galaxies of the sample do not have previous measurements of the stellar velocity dispersion (sigma*). These data are designed to complement our Space Telescope Imaging Spectrograph program for estimating black hole masses in the range 10^6-10^8M_sun using gas kinematics from nucleated disks. These observations will serve to derive the stellar dynamical bulge properties using the traditional Mgb and CaII triplets. We use both Cross Correlation and Maximum Penalized Likelihood to determine projected sigma* in these systems and present radial velocity fields, major axis rotation curves, curves of growth and sigma* fields. Using the Cross Correlation to extract the low order 2D stellar dynamics we generally see coherent radial rotation and irregular velocity dispersion fields suggesting that sigma* is a non-trivial parameter to estimate.Comment: 11 pages, 30 figures, accepted for publication in ApJ

Intervention for Children Exposed to Interparental Violence (IPV): Assessment of Needs and Research Priorities

In this paper we review the development of interventions for children who have been exposed to interparental violence (IPV), assess current needs in the evaluation of interventions, and provide suggestions for research priorities in this area. Interventions for negative outcomes associated with exposure to IPV only recently have been carefully designed and evaluated, thus knowledge regarding program effectiveness is minimal. Three of the most comprehensive interventions that have been evaluated are presented. Each has demonstrated effectiveness, and focuses on children with different levels of symptoms and distress. However, many questions remain regarding which interventions are beneficial for diverse children with different kinds and intensities of problems. A number of research priorities and suggestions for further improvements in the evaluation of effectiveness of interventions are identified.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44276/1/10567_2004_Article_469659.pd

Making tea: a human centred approach to designing a pervasive smart lab notebook

The methodology used to design a useful and workable laboratory electronic notebook is described along with some of the technology needed to implement the smart lab systems

Development of antigen-specific ELISA for circulating autoantibodies to extracellular matrix protein 1 in lichen sclerosus

Lichen sclerosus is a common, acquired chronic inflammatory skin disease of unknown etiology, although circulating autoantibodies to the glycoprotein extracellular matrix protein 1 (ECM1) have been detected in most patients’ sera. We have examined the nature of ECM1 epitopes in lichen sclerosus sera, developed an ELISA system for serologic diagnosis, and assessed clinicopathological correlation between ELISA titer and disease. Epitope-mapping studies revealed that lichen sclerosus sera most frequently recognized the distal second tandem repeat domain and carboxyl-terminus of ECM1. We analyzed serum autoantibody reactivity against this immunodominant epitope in 413 individuals (95 subjects with lichen sclerosus, 161 normal control subjects, and 157 subjects with other autoimmune basement membrane or sclerosing diseases). The ELISA assay was highly sensitive; 76 of 95 lichen sclerosus patients (80.0%) exhibited IgG reactivity. It was also highly specific (93.7%) in discriminating between lichen sclerosus and other disease/control sera. Higher anti-ECM1 titers also correlated with more longstanding and refractory disease and cases complicated by squamous cell carcinoma. Furthermore, passive transfer of affinity-purified patient IgG reproduced some histologic and immunopathologic features of lichen sclerosus skin. This new ELISA is valuable for the accurate detection and quantification of anti-ECM1 autoantibodies. Moreover, the values may have clinical significance in patients with lichen sclerosus