Processing of the oxytocin precursor by carboxypeptidase E

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The Development of the Genital Psoriasis Sexual Frequency Questionnaire (GenPs-SFQ) to Assess the Impact of Genital Psoriasis on Sexual Health

INTRODUCTION: Patient-reported outcome measures (PROs) exist for psoriasis but not genital psoriasis (GenPs). METHODS: This cross-sectional, qualitative study in patients with moderate-to-severe GenPs was conducted to support development of a PRO for measuring the impact of GenPs on sexual activity and to establish content validity. The impacts of GenPs were identified in a literature review. Findings from the literature review were discussed with clinicians, and then patients with GenPs were interviewed. RESULTS: From the literature review, 52 articles, 44 abstracts, and 41 clinical trials met predefined search criteria. Of these, 11 concepts emerged as having theoretical support for use as measurable impacts of psoriasis symptoms on patients; these concepts included sexual functioning and general health-related quality of life (HRQoL). These concepts were confirmed and expanded upon by two clinicians who routinely care for patients with GenPs. Interviews were then conducted with GenPs patients (n = 20) to discuss the impact of GenPs on their HRQoL. Eighty percent of patients reported that GenPs impacted sexual frequency. The two-item GenPs Sexual Frequency Questionnaire (GenPs-SFQ) was developed to assess limitations on sexual activity frequency because of GenPs. Cognitive debriefing with an additional 50 patients with GenPs confirmed the utility and understandability of the GenPs-SFQ. CONCLUSION: The GenPs-SFQ may have utility in clinical trials involving GenPs patients and in routine clinical practice. FUNDING: Eli Lilly and Company. Plain language summary available for this article

The Development of a Patient-Reported Outcome Measure for Assessment of Genital Psoriasis Symptoms: The Genital Psoriasis Symptoms Scale (GPSS)

INTRODUCTION: Patient-reported outcome measures (PROs) specific for genital psoriasis (GenPs) have not been described. METHODS: In this cross-sectional, qualitative study in patients with moderate-to-severe GenPs, we sought to develop a PRO useful for GenPs symptom assessment. A literature review was performed to identify relevant psoriasis or GenPs symptoms and existing PROs that may be useful in the evaluation of symptom severity in GenPs patients. The literature review findings were discussed with clinicians, and then patients with GenPs. RESULTS: Relevant psoriasis or GenPs symptoms from the literature review included itch, pain, scaling, redness/erythema, and stinging/burning. The validity of these symptoms for GenPs and potentially relevant PROs was corroborated by clinical experts. After gap analysis, a draft symptom scale consisting of Numeric Rating Scale (NRS) items was constructed. We then conducted interviews with GenPs patients (n = 20) to support content validity and use of the draft symptom NRS items in routine practice and in clinical trials. Participants identified and confirmed relevant symptoms and evaluated the utility of the draft PRO. A new PRO was developed: the Genital Psoriasis Symptoms Scale (GPSS). Cognitive debriefing and cultural adaptation/translation interviews with a second group of patients confirmed cultural appropriateness of the GPSS. CONCLUSION: The GPSS may be useful for assessing symptoms before, during, and after treatment in routine clinical practice and in clinical trials involving patients with GenPs. FUNDING: Eli Lilly & Company. Plain language summary available for this article

The atypical 'hippocampal' glutamate receptor coupled to phospholipase D that controls stretch-sensitivity in primary mechanosensory nerve endings is homomeric purely metabotropic GluK2

ACKNOWLEDGEMENTS We would like to thank: Prof. Christophe Mulle, University of Bordeaux, France for the generous donation of the GluK2-Neo mice; Prof. Roberto Pellicciari and Prof. Maura Marinozzi, University of Perugia, Italy for the generous gift of PCCG-13; the Microscopy and Histology core facility at the Institute of Medical Sciences, University of Aberdeen for their support and assistance in some of the imaging in this work. We would also like to thank Prof. Gernot Riedel, University of Aberdeen UK and Prof. David Jane, University of Bristol UK for helpful comments during the work and discussion about drafts of this manuscript.Peer reviewedPublisher PD

Effects of the noncompetitive N‐methyl‐d‐aspartate receptor antagonists ketamine and MK‐801 on pain‐stimulated and pain‐depressed behaviour in rats

BackgroundPain is a significant public health concern, and current pharmacological treatments have problematic side effects and limited effectiveness. N‐methyl‐d‐aspartate (NMDA) glutamate receptor antagonists have emerged as one class of candidate treatments for pain because of the significant contribution of glutamate signalling in nociceptive processing.MethodsThis study compared effects of the NMDA receptor antagonists ketamine and MK‐801 in assays of pain‐stimulated and pain‐depressed behaviour in rats. The nonsteroidal anti‐inflammatory drug ketoprofen was examined for comparison as a positive control. Intraperitoneal injection of dilute acid served as an acute visceral noxious stimulus to stimulate a stretching response or depress intracranial self‐stimulation (ICSS) in male Sprague–Dawley rats.ResultsKetamine (1.0–10.0 mg/kg) blocked acid‐stimulated stretching but failed to block acid‐induced depression of ICSS, whereas MK‐801 (0.01–0.1 mg/kg) blocked both acid‐stimulated stretching and acid‐induced depression of ICSS. These doses of ketamine and MK‐801 did not alter control ICSS in the absence of the noxious stimulus; however, higher doses of ketamine (10 mg/kg) and MK‐801 (0.32 mg/kg) depressed all behaviour. Ketoprofen (1.0 mg/kg) blocked both acid‐induced stimulation of stretching and depression of ICSS without altering control ICSS.ConclusionThese results support further consideration of NMDA receptor antagonists as analgesics; however, some NMDA receptor antagonists are more efficacious at attenuating pain‐depressed behaviours.What does this study addNMDA receptor antagonists produce dissociable effects on pain‐depressed behaviour.Provides evidence that pain‐depressed behaviours should be considered and evaluated when determining the antinociceptive effects of NMDA receptor antagonists.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/134264/1/ejp847_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/134264/2/ejp847.pd

Characterization of [beta]-endorphin-related peptides in the caudal medulla oblongata and hypothalamus of the prenatal, postnatal and adult rat

A comparison was made of [beta]-endorphin (B-END) concentrations versus post-translation products during the perinatal period in the hypothalamus and the caudal medulla oblongata. The concentration of B-END-like immunoreactivity did not differ statistically between embryonic day 21 (E21) and postnatal day 1 (P1) in either area. There were significant differences in forms, with a shift from larger precursors at E21 to smaller peptides at P1, with the predominant form of B-END being the 31 residue form at E21 in both regions. B-END varied between the two regions at P1, the 27-26 residue predominant in the hypothalamus, and the 31 residue in the caudal medulla.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/29130/1/0000169.pd

ω-conotoxin CVID inhibits a pharmacologically distinct voltage-sensitive calcium channel associated with transmitter release from preganglionic nerve terminals

Demonstration of a novel calcium channel antagonist, (omega)-conotoxin CVID, which selectively inhibits transmitter (ACh) release from mammalian preganglionic nerve terminals. DJ Adams conceived the project and contributed to data analysis and writing the paper. AB Smith, a postdoc, and CI Schroeder and T Yasuda, PhD students, carried out the experiments and analysed the data

Altered mRNA Editing and Expression of Ionotropic Glutamate Receptors after Kainic Acid Exposure in Cyclooxygenase-2 Deficient Mice

Kainic acid (KA) binds to the AMPA/KA receptors and induces seizures that result in inflammation, oxidative damage and neuronal death. We previously showed that cyclooxygenase-2 deficient (COX-2−/−) mice are more vulnerable to KA-induced excitotoxicity. Here, we investigated whether the increased susceptibility of COX-2−/− mice to KA is associated with altered mRNA expression and editing of glutamate receptors. The expression of AMPA GluR2, GluR3 and KA GluR6 was increased in vehicle-injected COX-2−/− mice compared to wild type (WT) mice in hippocampus and cortex, whereas gene expression of NMDA receptors was decreased. KA treatment decreased the expression of AMPA, KA and NMDA receptors in the hippocampus, with a significant effect in COX-2−/− mice. Furthermore, we analyzed RNA editing levels and found that the level of GluR3 R/G editing site was selectively increased in the hippocampus and decreased in the cortex in COX-2−/− compared with WT mice. After KA, GluR4 R/G editing site, flip form, was increased in the hippocampus of COX-2−/− mice. Treatment of WT mice with the COX-2 inhibitor celecoxib for two weeks decreased the expression of AMPA/KA and NMDAR subunits after KA, as observed in COX-2−/− mice. After KA exposure, COX-2−/− mice showed increased mRNA expression of markers of inflammation and oxidative stress, such as cytokines (TNF-α, IL-1β and IL-6), inducible nitric oxide synthase (iNOS), microglia (CD11b) and astrocyte (GFAP). Thus, COX-2 gene deletion can exacerbate the inflammatory response to KA. We suggest that COX-2 plays a role in attenuating glutamate excitotoxicity by modulating RNA editing of AMPA/KA and mRNA expression of all ionotropic glutamate receptor subunits and, in turn, neuronal excitability. These changes may contribute to the increased vulnerability of COX-2−/− mice to KA. The overstimulation of glutamate receptors as a consequence of COX-2 gene deletion suggests a functional coupling between COX-2 and the glutamatergic system