Patient and Public Involvement and Engagement for PhD Students

This paper aims to provide useful advice regarding the development of skills for patient and public involvement and engagement (PPIE) in research. The authors of this paper comprise experienced PhD supervisors and trainers, researchers leading PPIE activities including in the National Institute for Health and Social Care Research (NIHR) Nottingham Biomedical Research Centre (BRC), and experts in the conduct of PPIE. The paper arose from discussions in preparation for a programme of PPIE training for PhD students in the University of Nottingham, UK. We offer this advice on the basis that it is likely to be of use to others undertaking research training such as undergraduates or research associates moving into health-related research areas. Although the PPIE team of the NIHR Nottingham Biomedical Research Centre prepared this paper, we hope that it is of value across the whole spectrum of health research, not solely to experimental medicine and is of relevance to research more widely than that supported by the UK’s NIHR. The first section introduces PPIE, explains what it is and what it is not, and why it is important. The second section provides specific advice

Barriers to Accessing Treatment Services: Child Victims of Youths with Problematic Sexual Behavior

Child sexual abuse (CSA) remains a significant public health problem. Although the deleterious effects on the child victims could be mitigated through evidence-based interventions, victims often fail to be identified and receive clinical assessment and therapy services, particularly when they have been victimized by another youth. Given that at least a third of CSA cases are committed by another youth, understanding the process of identifying and addressing the needs of CSA victims of youth is the focus of the present study. Factors impacting services for child victims of youths with problematic sexual behavior (PSB) were examined through qualitative interviews (N = 226) with mental health agency administrators, direct service providers, and community stakeholders from eight geographically diverse communities across the United States. Responses focused on macro and micro level barriers to the identification and service provision for child victims of PSB of youths. Implications for clinicians and policymakers are discussed, along with strategies to enhance access and provision of services to meet the needs of the child victims

Selective potentiation by ouabain of naloxone-induced withdrawal contractions of isolated guinea-pig ileum following acute exposure to morphine

1. Ouabain, an inhibitor of Na(+)/K(+) ATPase induces the release of acetylcholine from central and myenteric cholinergic neurones principally due to partial depolarization of the cell membrane. The effect of ouabain has been examined on neurogenic contractions in the guinea-pig ileum arising from either electrical field stimulation or from naloxone in morphine-exposed preparations. 2. Guinea-pig isolated ileum preparations were stimulated transmurally (0.1 Hz, 0.3 ms, 200 mA) to elicit contractions of the myenteric plexus-longitudinal smooth muscle. 3. Incubation with morphine (0.3 μM, 60 min) was followed by naloxone (1 μM) which produced withdrawal contractions in 16/26 preparations (median of 10.7 [2.2–40.0]% of a maximal contracture to KCl (60 mM)). 4. In parallel experiments, ouabain (1 μM) was added to the tissue before exposure to morphine (0.3 μM, 60 min). Naloxone (1 μM) subsequently displayed a withdrawal contraction in all 26/26 tissues (57.9 [30.5–151.7]% of a maximal contracture to KCl (60 mM). 5. Ouabain neither affected the concentration-dependent contractions of guinea-pig ileum produced by carbachol nor the inhibition of electrically-evoked contraction produced by morphine (0.3 μM). 6. The muscarinic antagonist atropine (0.1 μM) antagonized control naloxone withdrawal responses. The atropine resistant component, evident in ouabain-treated tissues, was blocked by SR140333((S)1-{2-[3-(3,4-dichlorophenyl)-1-(3-isopropoxyphenylacetyl)piperidin-3-yl]ethyl}-4-phenyl-1-azoniabicyclo[2.2.2]octane, chloride), a substance P antagonist. 7. Clonidine (α(2)-adrenoceptor agonist) inhibited electrically-evoked contractions. Exposure to the α(2)-adrenoceptor antagonist RX811059 (2-(2-ethoxy-1,4-benzodioxan-2-yl)-2-imidazoline), resulted in a contracture which was not significantly enhanced by ouabain (1 μM). 8. Ouabain selectively potentiates the naloxone-induced withdrawal contraction following acute exposure to morphine the major components of which are mediated by both acetylcholine and substance P

Pharmacological examination of contractile responses of the guinea-pig isolated ileum produced by μ-opioid receptor antagonists in the presence of, and following exposure to, morphine

1. We have assessed the potential of several μ-opioid receptor antagonists to elicit a response in the guinea-pig isolated ileum in the presence of, and following overnight exposure to, morphine. 2. Naloxone, D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH(2) (CTOP), (−)-5,9α-diethyl-2-(3-furyl-methyl)-2′-hydroxy-6,7-benzomorphan (MR2266), but not D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH(2) (CTAP), produced a transient inhibition of electrically-evoked contractions of the guinea-pig ileum. The effect of 1 μM CTOP, but not that to MR2266, was inhibited by 1 μM somatostatin. 3. Naloxone (0.3 μM), CTOP (3 μM), CTAP (3 μM) and MR2266 (0.3 μM) antagonized the inhibitory effect of morphine on electrically-evoked contractions of the guinea-pig to a similar degree and, following 60 min exposure to morphine, produced non-sustained contractions. The response to 3 μM CTOP was significantly smaller than that to 3 μM CTAP. None of the antagonists produced a response in the absence of morphine. 4. Following overnight exposure of the ileum to 0.3 μM morphine (4°C), and repeated washing to remove the agonist, all four antagonists elicited non-sustained contractions. However, the responses to 3 μM CTOP and 0.3 μM MR2266 were significantly smaller than those elicited by 0.3 μM naloxone and 3 μM CTAP. Somatostatin (1 μM) significantly reduced naloxone-induced contractions, but not those to CTAP. 5. While all four μ-opioid antagonists elicited contractions in the presence of, and following prolonged exposure to, morphine, differences between them were noted which may be a consequence of non-opioid actions

Pharmacological characterization of neurogenic responses of the sheep isolated internal anal sphincter

1. The aim of the study was to establish the nature of the neurogenic responses of the sheep isolated anal sphincter. 2. Isolated strips of sheep internal anal sphincter develop intrinsic contractile tone following the application of stretch tension. On transmural stimulation (1–20 Hz, 10 V pulse strength, 0.5 ms pulse width, 1 s every 180 s) transient relaxations were observed. 3. The amplitude of the relaxations were frequency-dependent reaching a maximal response at 10–20 Hz and were inhibited by tetrodotoxin (0.3 μM). Neither atropine (0.3 μM) nor phentolamine (1 μM) affected control responses. 4. The nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME, 100 μM) and the selective inhibitor of soluble guanylyl cyclase ODQ, (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one) (1 μM) completely inhibited the neurogenic relaxations and uncovered contractions that were abolished by 1 μM phentolamine and 0.1 μM prazosin. The effect of L-NAME, but not that of ODQ, was partially reversed by the addition of L-arginine (1 mM). 5. Sodium nitroprusside (10 nM–10 μM) caused concentration-dependent inhibition of myogenic tone and this effect was significantly reduced by ODQ. Calcium-free Krebs-Henseleit solution also reduced myogenic tone by 85%. 6. Transmural electrical stimulation of the sheep isolated internal anal sphincter causes a transient relaxation of myogenic tone that appears to involve nitric oxide from non-adrenergic, non-cholinergic nerves and, to a lesser degree, noradrenaline from sympathetic nerves. The characteristics of the preparation compares well with that of human tissue and may prove to be a suitable animal based model for further studies

Pharmacological comparison of the effect of ibogaine and 18-methoxycoronaridine on isolated smooth muscle from the rat and guinea-pig

1. Ibogaine and 18-methoxycoronaridine are naturally occurring alkaloids reported to possess antiaddictive properties in several models of drug dependence. We have examined their effect at μ-opioid receptors regulating neurogenic contractions of several smooth muscle preparations and also against spontaneous contractions of the rat isolated portal vein. 2. Ibogaine (pIC(50) 5.28) and 18-methoxycoronaridine (pIC(50) 5.05) caused a concentration-dependent inhibition of cholinergic contractions of the guinea-pig ileum which was not affected by the opioid receptor antagonist naloxone (1 μM). 3. In the rat isolated vas deferens ibogaine and 18-methoxycoronaridine caused a concentration-dependent enhancement of purinergic contractions. Both agents (30 μM) caused a 3–5 fold rightward displacement of DAMGO-induced inhibition of purinergic contractions, but similar effects were observed for ibogaine against α(2)-adrenoceptor-mediated inhibition of neurogenic responses. 4. In the guinea-pig isolated bladder both ibogaine (10 μM) and 18-methoxycoronaridine (10 μM) caused a 2 fold increase in the purinergic component of neurogenic contractions without significantly altering cholinergic contractions or responses to exogenous ATP. In contrast, ibogaine (1–30 μM), but not 18-methoxycoronaridine, caused a concentration-dependent enhancement of spontaneous contractions of the rat isolated portal vein. 5. In summary, while ibogaine and 18-methoxycoronaridine modulated electrically-evoked contractions in the three preparations examined, we have no evidence for a selective interaction with pre-junctional μ-opioid receptors. The pronounced enhancement of purinergic contractions produced by both agents is a novel finding and worthy of further investigation