The role of VIP/PACAP receptor subtypes in spinal somatosensory processing in rats with an experimental peripheral mononeuropathy

Chronic constriction injury (CCI) of the rat sciatic nerve, produces an animal model ofperipheral neuropathy exhibiting abnormal pain states similar to those seen in man, including behavioural signs of spontaneous pain, hyperalgesia and allodynia. Many components ofneuropathic pain are resistant to classical opioid analgesics, and anaesthetic nerve blocks or surgical sympathectomies often provide only temporary relief. Since the expression ofVasoactive Intestinal Polypeptide (VIP) and Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) is markedly up-regulated in dorsal root ganglia following peripheral nerve injury, we investigated whether VIP/PACAP receptors are important regulators of the amplified sensory responses which develop following neuropathy.This study addressed the role of VIP₁, VIP₂ and PACAP receptors with regard to the responses of dorsal horn neurones in normal compared to CCI animals, using novel selective agonists and antagonists. In electrophysiological experiments on anaesthetised rats, the effects of ionophoretic application of VIP₁, VIP₂ and PACAP receptor antagonists were investigated on neuronal activity induced by innocuous brushing or cold stimulation of the cutaneous receptive field, or following peripheral application of the chemical algogen mustard oil. In normal rats, VIP₁ and PACAP receptor antagonists appeared to exert a general modification of dorsal horn neurone responses, inhibiting both brush- and mustard oil-induced activity to similar extents. In contrast, a novel VIP₂ receptor antagonist selectively inhibited mustard oil-evoked activity, whilst showing negligible effects on brush-evoked activity.The effects of the VIP/PACAP receptor antagonists changed markedly in CCI animals so that antagonists for all three receptor subtypes showed negligible effects on brush-induced activity of dorsal horn neurones. In contrast, VIP,/PACAP receptor antagonists significantly inhibited cold-induced activity, while a VIP₂ receptor antagonist had little effect. However, mustard oil-induced activity was significantly inhibited by all three receptor antagonists in CCI animals.The activity of single, multireceptive dorsal horn neurones was markedly increased following ionophoretic administration of selective VIP₁, VIP₂ and PACAP receptor agonists both in normal and CCI rats. Following nerve injury however, two main differences were apparent, and these may reflect changes in receptor expression: the number of dorsal horn neurones activated by the VIP2 receptor agonist doubled (these neurones also showed a greater extent of cell activation than those excited in normal animals), while the percentage of neurones activated by the VIP, receptor agonist was seen to decrease. The proportion of cells activated by the PACAP receptor agonist remained unchanged.In addition, in situ hybridisation histochemistry (ISHH) detection ofmRNA for the three receptor subtypes, was employed to monitor any changes in receptor expression following nerve injury. This study revealed that CCI of the rat sciatic nerve produced a significant increase in the expression of VIP₂ receptor mRNA in laminae III/IV of the spinal dorsal horn. In contrast, VIP₁ receptor mRNA was seen to markedly decrease, while the expression of mRNA for the PACAP receptor appeared to be unchanged.In conclusion, these results provide evidence that VIP/PACAP receptors may be important mediators/modulators ofthe transmission of sensory information at the spinal cord level, underlining the potential for VIP/PACAP receptor antagonists as new analgesics, particularly for use in currently intractable neuropathic pain states. These data demonstrate the involvement of the VIP₂ receptor in the transmission of nociceptive (C-fibre-mediated) information, both in normal and neuropathic animals. Although VIP, and PACAP receptor antagonists are rather non-selective inhibitors of sensory inputs in normal states, they may represent useful analgesics for certain aspects of allodynia (for example cold) as well as for polymodal C-fibre responses in neuropathy

Social work students' feedback about students' suitability for field education and the profession

Many students successfully complete placement while for a minority of students placement may be a time when questions are asked about suitability for placement and professional practice. Research undertaken with final year social work students examined their ideas about suitability and unsuitability for field education and practice and presented them with a model developed with field educators in an earlier phase of the research. The aim of the study was to incorporate students’ understanding into the discourse of suitability/unsuitability to further develop a suitability/unsuitability model for collaborative discussions between students, educators and supervisors. Twenty-eight students responded to an online survey. The results show that students identify a critical understanding of self, skills, knowledge, attitudes and contextual factors as important in assessing students’ suitability for field education. Identified indicators of ‘unsuitability’ included lack of preparedness to learn, lack of capacity to demonstrate an understanding of professional values and ethics and inability to maintain professional boundaries or demonstrate basic practice skills. Students overwhelmingly supported the use of the presented model and made suggestions for further development of the model. The discussion emphasises the importance of using a pedagogically informed formative assessment strategy in a timely manner to address professional suitability with students

Sexual selection protects against extinction

Reproduction through sex carries substantial costs, mainly because only half of sexual adults produce offspring1. It has been theorized that these costs could be countered if sex allows sexual selection to clear the universal fitness constraint of mutation load2,3,4. Under sexual selection, competition between (usually) males and mate choice by (usually) females create important intraspecific filters for reproductive success, so that only a subset of males gains paternity. If reproductive success under sexual selection is dependent on individual condition, which is contingent to mutation load, then sexually selected filtering through ‘genic capture’5 could offset the costs of sex because it provides genetic benefits to populations. Here we test this theory experimentally by comparing whether populations with histories of strong versus weak sexual selection purge mutation load and resist extinction differently. After evolving replicate populations of the flour beetle Tribolium castaneum for 6 to 7 years under conditions that differed solely in the strengths of sexual selection, we revealed mutation load using inbreeding. Lineages from populations that had previously experienced strong sexual selection were resilient to extinction and maintained fitness under inbreeding, with some families continuing to survive after 20 generations of sib × sib mating. By contrast, lineages derived from populations that experienced weak or non-existent sexual selection showed rapid fitness declines under inbreeding, and all were extinct after generation 10. Multiple mutations across the genome with individually small effects can be difficult to clear, yet sum to a significant fitness load; our findings reveal that sexual selection reduces this load, improving population viability in the face of genetic stress.We thank the Natural Environment Research Council and the Leverhulme Trust for financial support, D. Edward for statistical advice and colleagues at the 2013 Biology of Sperm meeting for comments that improved analytical design and interpretation.Peer reviewedPeer Reviewe

Over-The-Counter Codeine: Can Community Pharmacy Staff Nudge Customers into Its Safe and Appropriate Use?

The misuse of opioids, including codeine which is sold over-the-counter (OTC) in United Kingdom (UK) community pharmacies, is a growing public health concern. An educational Patient Safety Card was developed and piloted to see if it nudged customers into the safe and appropriate use of OTC codeine. Exploratory analysis was conducted by (i) recording quantitative interactions for people requesting OTC codeine in community pharmacies; and (ii) a web-based pharmacy staff survey. Twenty-four pharmacies submitted data on 3993 interactions using the Patient Safety Card. Staff found the majority of interactions (91.3%) to be very or quite easy. Following an interaction using the card, customers known to pharmacy staff as frequent purchasers of OTC codeine were more likely not to purchase a pain relief medicine compared to customers not known to staff (5.5% of known customers did not purchase any pain relief product versus 1.1% for unknown customers (χ2 = 41.73, df = 1, p [less than] 0.001)). These results support both the use of a visual educational intervention to encourage appropriate use of OTC codeine in community pharmacy and the principles behind better self-care

Sexual selection protects against extinction

Reproduction through sex carries substantial costs, mainly because only half of sexual adults produce offspring. It has been theorised that these costs could be countered if sex allows sexual selection to clear the universal fitness constraint of mutation load. Under sexual selection, competition between (usually) males, and mate choice by (usually) females create important intraspecific filters for reproductive success, so that only a subset of males gains paternity. If reproductive success under sexual selection is dependent on individual condition, which depends on mutation load, then sexually selected filtering through ‘genic capture’ could offset the costs of sex because it provides genetic benefits to populations. Here, we test this theory experimentally by comparing whether populations with histories of strong versus weak sexual selection purge mutation load and resist extinction differently. After evolving replicate populations of the flour beetle Tribolium castaneum for ~7 years under conditions that differed solely in the strengths of sexual selection, we revealed mutation load using inbreeding. Lineages from populations that had previously experienced strong sexual selection were resilient to extinction and maintained fitness under inbreeding, with some families continuing to survive after 20 generations of sib × sib mating. By contrast, lineages derived from populations that experienced weak or non-existent sexual selection showed rapid fitness declines under inbreeding, and all were extinct after generation 10. Multiple mutations across the genome with individually small effects can be difficult to clear, yet sum to a significant fitness load; our findings reveal that sexual selection reduces this load, improving population viability in the face of genetic stress

Mixed-Method Evaluation of a Community Pharmacy Antimicrobial Stewardship Intervention (PAMSI)

The community pharmacy antimicrobial stewardship intervention (PAMSI) is multi-faceted and underpinned by behavioural science, consisting of the TARGET Antibiotic Checklist, staff e-Learning, and patient-facing materials. This mixed-method study evaluated the effect of PAMSI on community pharmacy staffs' self-reported antimicrobial stewardship (AMS) behaviours. Data collection included staff pre- and post-intervention questionnaires, qualitative interviews, and TARGET Antibiotic Checklists. Quantitative data were analysed by a multivariate ordinal linear mixed effect model; qualitative data were analysed thematically. A total of 101 staff participated from 66 pharmacies, and six completed semi-structured interviews. The statistical model indicated very strong evidence ( < 0.001) that post-intervention, staff increased their antibiotic appropriateness checks and patient advice, covering antibiotic adherence, antibiotic resistance, infection self-care, and safety-netting. Staff reported feeling empowered to query antibiotic appropriateness with prescribing clinicians. The TARGET Antibiotic Checklist was completed with 2043 patients. Topics patients identified as requiring advice from the pharmacy team included symptom duration, alcohol and food consumption guidance, antibiotic side-effects, and returning unused antibiotics to pharmacies. Pharmacy staff acknowledged the need for improved communication across the primary care pathway to optimise antimicrobial use, and PAMSI has potential to support this ambition if implemented nationally. To support patients not attending a pharmacy in person, an online information tool will be developed

Clinical Relevance of Dissolution Testing in Quality by Design

Quality by design (QbD) has recently been introduced in pharmaceutical product development in a regulatory context and the process of implementing such concepts in the drug approval process is presently on-going. This has the potential to allow for a more flexible regulatory approach based on understanding and optimisation of how design of a product and its manufacturing process may affect product quality. Thus, adding restrictions to manufacturing beyond what can be motivated by clinical quality brings no benefits but only additional costs. This leads to a challenge for biopharmaceutical scientists to link clinical product performance to critical manufacturing attributes. In vitro dissolution testing is clearly a key tool for this purpose and the present bioequivalence guidelines and biopharmaceutical classification system (BCS) provides a platform for regulatory applications of in vitro dissolution as a marker for consistency in clinical outcomes. However, the application of these concepts might need to be further developed in the context of QbD to take advantage of the higher level of understanding that is implied and displayed in regulatory documentation utilising QbD concepts. Aspects that should be considered include identification of rate limiting steps in the absorption process that can be linked to pharmacokinetic variables and used for prediction of bioavailability variables, in vivo relevance of in vitro dissolution test conditions and performance/interpretation of specific bioavailability studies on critical formulation/process variables. This article will give some examples and suggestions how clinical relevance of dissolution testing can be achieved in the context of QbD derived from a specific case study for a BCS II compound

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Persistent frequent attenders in primary care: costs, reasons for attendance, organisation of care and potential for cognitive behavioural therapeutic intervention

<p><b>Abstract</b></p> <p>Background</p> <p>The top 3% of frequent attendance in primary care is associated with 15% of all appointments in primary care, a fivefold increase in hospital expenditure, and more mental disorder and functional somatic symptoms compared to normal attendance. Although often temporary if these rates of attendance last more than two years, they may become persistent (persistent frequent or regular attendance). However, there is no long-term study of the economic impact or clinical characteristics of regular attendance in primary care. Cognitive behaviour formulation and treatment (CBT) for regular attendance as a motivated behaviour may offer an understanding of the development, maintenance and treatment of regular attendance in the context of their health problems, cognitive processes and social context.</p> <p>Methods/design</p> <p>A case control design will compare the clinical characteristics, patterns of health care use and economic costs over the last 10 years of 100 regular attenders (≥30 appointments with general practitioner [GP] over 2 years) with 100 normal attenders (6–22 appointments with GP over 2 years), from purposefully selected primary care practices with differing organisation of care and patient demographics. Qualitative interviews with regular attending patients and practice staff will explore patient barriers, drivers and experiences of consultation, and organisation of care by practices with its challenges. Cognitive behaviour formulation analysed thematically will explore the development, maintenance and therapeutic opportunities for management in regular attenders. The feasibility, acceptability and utility of CBT for regular attendance will be examined.</p> <p>Discussion</p> <p>The health care costs, clinical needs, patient motivation for consultation and organisation of care for persistent frequent or regular attendance in primary care will be explored to develop training and policies for service providers. CBT for regular attendance will be piloted with a view to developing this approach as part of a multifaceted intervention.</p