P2Y₂ Nucleotide Receptors Expressed Heterologously in Sympathetic Neurons Inhibit Both N-Type Ca²⁺ and M-Type K⁺ Currents

The P2Y₂ receptor is a uridine/adenosine triphosphate (UTP/ATP)-sensitive G-protein-linked nucleotide receptor that previously has been reported to stimulate the phosphoinositide signaling pathway. Messenger RNA for this receptor has been detected in brain tissue. We have investigated the coupling of the molecularly defined rat P2Y₂ receptor to neuronal N-type Ca²⁺ channels and to M-type K⁺ channels by heterologous expression in rat superior cervical sympathetic (SCG) neurons. After the injection of P2Y₂cRNA, UTP inhibited the currents carried by both types of ion channel. As previously reported [Filippov AK, Webb TE, Barnard EA, Brown DA (1997) Inhibition by heterologously expressed P2Y₂nucleotide receptors of N-type calcium currents in rat sympathetic neurones. Br J Pharmacol 121:849–851], UTP inhibited the Ca²⁺ current (I_{Ca(N)} by up to 64%, with an IC₅₀ of ∼0.5 μm. We now find that UTP also inhibited the K⁺_{M} current (I_{K(M)} by up to 61%, with an IC₅₀ of ∼1.5 μm. UTP had no effect on either current in neurons not injected with P2Y₂ cRNA. Structure–activity relations for the inhibition of I_{Ca(N)} and I_{K(M)} in P2Y₂ cRNA-injected neurons were similar, with UTP ≥ ATP > ITP ≫ GTP,UDP. However, coupling to these two channels involved different G-proteins: pretreatment withPertussis toxin (PTX) did not affect UTP-induced inhibition of I_{K(M)} but reduced inhibition of I_{Ca(N)} by ∼60% and abolished the voltage-dependent component of this inhibition. In unclamped neurons, UTP greatly facilitated depolarization-induced action potential discharges. Thus, the single P2Y₂ receptor can couple to at least two G-proteins to inhibit both Ca²⁺_{N} and K⁺_{M} channels with near-equal facility. This implies that the P2Y₂ receptor may induce a broad range of effector responses in the nervous system

Perceived life expectancy among dialysis recipients: a scoping review

Rationale & Objective: Greater prognostic understanding is associated with higher quality care at the end of life. We undertook a scoping review to explore how long dialysis recipients expect to live. Study Design: Scoping Review Setting and Study Population: People with kidney failure over 18 years old. Search Strategy & Sources: Studies were identified by searching Medline, Embase, APA PsycINFO, HMIC and ProQuest Database for terms related to “life expectancy”, “self -estimated” and “end stage kidney disease”. Data Extraction: Search strategies yielded 349 unique, potentially eligible studies, with 8 meeting the inclusion criteria after screening. Results: Significant mismatches between dialysis recipients and their healthcare provider estimations of prognosis were reported, with patients predicting significantly higher life expectancies than healthcare professionals and almost no agreement between patient and nephrologist estimates of one-year survival. Documented cognitive impairment did not affect 1- or 5-year prognosis estimates, neither did gender, age, time on dialysis or discussing perceived life expectancy. Dialysis recipients who thought they were on the transplant-list or self-identified as black had higher perceived life expectancy: people who were 75 years or older, or with fair/ poor self-reported health status had lower. Those with lower perceived life expectancy preferred care focusing on relieving pain and discomfort: people who thought they had a higher chance of survival were significantly more likely to prefer life-extending care. Limitations: There is a marked paucity of research in this area with most studies conducted in North American cohorts. Conclusions: Optimistic patient prognostic expectations persist in dialysis recipients. Given the effects of perceived life expectancy on treatment choices and subsequent quality of life, it is important that transparent discussions regarding prognosis are conducted with people receiving dialysis and their families

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

Desmoglein 3 acts as a potential oncogene in promoting cancer cell migration and invasion through regulating AP-1 and PKC dependent-Ezrin activation

Conference: 20th Anniversary Conference of the British-Skin-Foundation on Skin Deep - 20 Years of Research Location: Roayl Coll Phys, London, ENGLAND Date: OCT 13, 2016British Skin Fd

Counting supersymmetric branes

Maximal supergravity solutions are revisited and classified, with particular emphasis on objects of co-dimension at most two. This class of solutions includes branes whose tension scales with g_s^{-\sigma} for \sigma>2. We present a group theory derivation of the counting of these objects based on the corresponding tensor hierarchies derived from E11 and discrete T- and U-duality transformations. This provides a rationale for the wrapping rules that were recently discussed for \sigma<4 in the literature and extends them. Explicit supergravity solutions that give rise to co-dimension two branes are constructed and analysed.Comment: 1+33 pages. To the memory of Laurent Houart. v2: Published version with added reference

Automation and data processing with the immucor Galileo (R) system in a university blood bank

Background: The implementation of automated techniques improves the workflow and quality of immuno-hematological results. The workflows of our university blood bank were reviewed during the implementation of an automated immunohematological testing system. Methods: Work impact of blood grouping and subgrouping, cross- matching and antibody search using the Immucor Galileo system was compared to the previous used standard manual and semi- automated methods. Results: The redesign of our workflow did not achieve a significant reduction of the specimen's working process time, the operator's time however was reduced by 23%. Corresponding results were achieved for blood grouping, Rhesus typing, antibody screen and for autocontrol when changing from two semi- automated to the Galileo system. Because of the higher sensitivity of the Immucor antibody detection system, the rate of the initial positive antibody screens rose from 4 to 6% Conclusion: The Immucor Galileo system automates routine blood bank testing with high reliability, specificity and higher sensitivity compared to our previous used standard manual and semi- automated methods

Pressure ulcer related pain in community populations: a prevalence survey.

BACKGROUND: Pressure ulcers are costly to the healthcare provider and can have a major impact on patient's quality of life. One of the most distressing symptoms reported is pain. There is very little published data on the prevalence and details of pain experienced by patients with pressure ulcers, particularly in community populations. The study was conducted in two community NHS sites in the North of England. METHODS: The aim was to estimate the prevalence of pressure area related pain within a community population. We also explored the type and severity of the pain and its association with pressure ulcer classification. A cross-sectional survey was performed of community nurses caseloads to identify adult patients with pressure ulcers and associated pain. Consenting patients then had a full pain assessment and verification of pressure ulcer grade. RESULTS: A total of 287 patients were identified with pressure ulcers (0.51 per 1000 adult population). Of the 176 patients who were asked, 133 (75.6%) reported pain. 37 patients consented to a detailed pain assessment. Painful pressure ulcers of all grades and on nearly all body sites were identified. Pain intensity was not related to number or severity of pressure ulcer. Both inflammatory and neuropathic pain were reported at all body sites however the proportion of neuropathic pain was greater in pressure ulcers on lower limbs. CONCLUSIONS: This study has identified the extent and type of pain suffered by community patients with pressure ulcers and indicates the need for systematic and regular pain assessment and treatment

Endoscopic injection sclerotherapy for bleeding varices in children with intrahepatic and extrahepatic portal venous obstruction: Benefit of injection tract embolisation

Background. The outcome of sclerotherapy for bleeding oesophagealvarices may be influenced by injection technique. In a previous study at our institution, sclerotherapy was associated with a high re-bleeding rate and oesophageal ulceration. Embolisation of the injection tract was introduced in an attempt to reduce injectionrelated complications.Methods. To determine the outcome and effectiveness of injectiontract embolisation in reducing injection-related complications, weretrospectively reviewed a series of 59 children who underwent injection sclerotherapy for oesophageal varices (29 for extrahepatic portal vein obstruction (EHPVO) and 30 for intrahepatic disease) in our centre.Results. Sclerotherapy resulted in variceal eradication in only 11.8% of the children (mean follow-up duration: 38.4 months). Variceal eradication with sclerotherapy alone was achieved in 20.7% and 3.3% of EHPVO and intrahepatic disease patients, respectively. Injection tract embolisation was successful in reducing the number of complications and re-bleeding rates. Complications that arose included: transient pyrexia (16.7%); deep oesophageal ulcers (6.7%); stricture formation (3.3%); and re-bleeding before variceal sclerosis (23%).Conclusion. Injection sclerotherapy did not eradicate oesophageal varices in most children. Injection tract embolisation by sclerosant was associated with fewer complications and reduced re-bleeding rates

Gut thinking: the gut microbiome and mental health beyond the head

Background: In recent decades, dominant models of mental illness have become increasingly focused on the head, with mental disorders being figured as brain disorders. However, research into the active role that the microbiome-gut-brain axis plays in affecting mood and behaviour may lead to the conclusion that mental health is more than an internalised problem of individual brains. Objective: This article explores the implications of shifting understandings about mental health that have come about through research into links between the gut microbiome and mental health problems such as depression and anxiety. It aims to analyse the different ways that the lines between mind and body and mental and physical health are re-shaped by this research, which is starting to inform clinical and public understanding. Design: As mental health has become a pressing issue of political and public concern it has become increasingly constructed in socio-cultural and personal terms beyond clinical spaces, requiring a conceptual response that exceeds biomedical inquiry. This article argues that an interdisciplinary critical medical humanities approach is well positioned to analyse the impact of microbiome-gut-brain research on conceptions of mind. Results: The entanglement of mind and matter evinced by microbiome-gut-brain axis research potentially provides a different way to conceptualise the physical and social concomitants of mental distress. Conclusion: Mental health is not narrowly located in the head but is assimilated by the physical body and intermingled with the natural world, requiring different methods of research to unfold the meanings and implications of gut thinking for conceptions of human selfhood

AdS/BCFT Correspondence for Higher Curvature Gravity: An Example

We consider the effects of higher curvature terms on a holographic dual description of boundary conformal field theory. Specifically, we consider three-dimensional gravity with a specific combination of Ricci tensor square and curvature scalar square, so called, new massive gravity. We show that a boundary entropy and an entanglement entropy are given by similar expression with those of the Einstein gravity case when we introduce an {\it effective} Newton's constant and an {\it effective} cosmological constant. We also show that the holographic g-theorem still holds in this extension, and we give some comments about the central charge dependence of boundary entropy in the holographic construction. In the same way, we consider new type black holes and comment on the boundary profile. Moreover, we reproduce these results through auxiliary field formalism in this specific higher curvature gravity.Comment: 27pages, minor corrections, accepted in JHE