Orexin/hypocretin receptor signalling cascades

Orexin (hypocretin) peptides and their two known G-protein-coupled receptors play essential roles in sleep–wake control and powerfully influence other systems regulating appetite/metabolism, stress and reward. Consequently, drugs that influence signalling by these receptors may provide novel therapeutic opportunities for treating sleep disorders, obesity and addiction. It is therefore critical to understand how these receptors operate, the nature of the signalling cascades they engage and their physiological targets. In this review, we evaluate what is currently known about orexin receptor signalling cascades, while a sister review (Leonard & Kukkonen, this issue) focuses on tissue-specific responses. The evidence suggests that orexin receptor signalling is multifaceted and is substantially more diverse than originally thought. Indeed, orexin receptors are able to couple to members of at least three G-protein families and possibly other proteins, through which they regulate non-selective cation channels, phospholipases, adenylyl cyclase, and protein and lipid kinases. In the central nervous system, orexin receptors produce neuroexcitation by postsynaptic depolarization via activation of non-selective cation channels, inhibition of K⁺ channels and activation of Na⁺/Ca²⁺ exchange, but they also can stimulate the release of neurotransmitters by presynaptic actions and modulate synaptic plasticity. Ca²⁺ signalling is also prominently influenced by these receptors, both via the classical phospholipase C−Ca²⁺ release pathway and via Ca²⁺ influx, mediated by several pathways. Upon longer-lasting stimulation, plastic effects are observed in some cell types, while others, especially cancer cells, are stimulated to die. Thus, orexin receptor signals appear highly tunable, depending on the milieu in which they are operating.Linked ArticlesThis article is part of a themed section on Orexin Receptors. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-2     

Post‐implantation events of swan‐neck catheters for PD

The first step in PD is the implantation of a peritoneal catheter, a technique that is subject to different possible incidences. We have studied the non‐infectious events or incidences (pericatheter leakage, blood tinged dialysate, catheter displacement, omental wrapping and extra‐peritoneal placement) registered in our unit during a five‐year period (1992–1996) after the implantation of 144 swan‐neck curled catheters in 100 peritoneal dialysis patients, 49 males and 51 females. 70 catheters (48.61 %) were implanted using the blind puncture method and 74 (51.39 %) with the surgical method. All the incidence rates were compared between the two methods to analyse the possible influence of the implantation technique. 21 pericatheter leaks, 19 episodes of blood tinged dialysate, 10 displacements, 7 cases of omental wrapping and 4 extra‐peritoneal placements (all of them after blind punctures carried out by young assistant doctors) were registered, with a total number of 61 incidences (0.42 per catheter). Statistically significant differences were not found either globally or for each type of event when comparing the incidence rates between the two implantation techniques, although extra‐peritoneal placement was close to significant (p = 0.053). None of the incidences were severe. 25 catheters (17.4%) had to be replaced with the removal rates being similar for both techniques. In conclusion, in our experience neither technique shows a clear advantage over the other. Experienced staff members should implant PD catheters.     

Development and validation of nail psoriasis quality of life scale (NPQ10)

Background The chronic and treatment‐resistant nature of nail psoriasis affects patients’ lives not only physically but also psychologically. Although there are scoring systems available for disease severity, there is as yet no scale to evaluate the impact of this condition upon the patients’ quality of life. Objectives This study aims to develop and validate a quality of life scale specifically for nail psoriasis. Methods A questionnaire was developed during a study conducted in France between 2004 and 2005. With the cooperation of l’Association Pour la Lutte Contre le Psoriasis, the questionnaire was sent to a random sample of 4000 of its 17 000 members. Results The response rate was 33%. Of the 1309 questionnaires returned, 795 showed the presence of nail psoriasis and these were eligible. The scale score is obtained by adding together the responses to the 10 questionnaire items and the result is expressed as a percentage. The value of the score obtained is proportional to the functional difficulty experienced. The determination of Cronbach's α coefficient and a Principal Component Factor Analysis show, respectively, very good internal consistency and the unidimensional nature of the scale. Test–retest results on 15 patients showed good reproducibility. Results were validated with reference to the Dermatology Life Quality Index. In this study, the NPQ10 score is significantly influenced by gender (women have a higher score) and by the duration of psoriasis (recent onset implies greater functional difficulty). Finally, the score is much higher when the nail psoriasis affects both the hands and the feet. Conclusion This study confirms a change in the quality of life of patients who have nail psoriasis. The NPQ10 scale, specific to this condition, is simple to use and has the attributes needed in a quality of life scale. The scale must now be tested in longitudinal studies (such as clinical trials) to confirm its ability to measure a change in status.     

No association between nickel allergy and reporting cosmetic dermatitis from mascara or eye shadow: a cross‐sectional general population study

Background In theory, all pigmented make‐up products may contain metal allergens including nickel. Eyelid dermatitis has previously been observed among nickel allergic dermatitis patients following exposure to nickel containing mascara and eye shadow. However, an association between nickel eyelid dermatitis and nickel in make‐up products remains controversial. Objective This cross‐sectional patch test study investigated whether the frequency of self‐reported cosmetic dermatitis from mascara or eye shadow use was higher among nickel allergic Danish women than women without nickel allergy. Methods In 2006, a total of 1843 18–69 year old women completed a postal questionnaire including questions on cosmetic dermatitis and were patch tested with nickel sulphate. Data were analysed by logistic regression analyses and associations were expressed as odds ratios (ORs) with 95% confidence intervals (CIs). Results The prevalence of nickel allergy was similar among women who reported cosmetic dermatitis from eye shadow or mascara and among women who did not report such symptoms. Cosmetic dermatitis was positively associated with self‐reported atopic dermatitis and age. Conclusion Overall, no association between having nickel allergy and reporting cosmetic dermatitis from mascara or eye shadow use was found in the general population. This does not exclude a causal relationship in selected cases.     

Feasibility of identifying plasma donors with high measles neutralizing antibody concentrations for the use of producing a measles hyperimmune globulin for postexposure prophylaxis

Immune globulin (IG) is administered as measles postexposure prophylaxis (PEP) in people with primary immunodeficiency disorders or individuals not eligible for live virus vaccination. However, measles virus (MeV) neutralizing antibody (nAb) levels in plasma for fractionation and IG products fractionated thereof have declined. Here, the feasibility of producing a measles hyperimmune globulin (HIG) for PEP of high-risk individuals was investigated. Plasma samples (n?=?384) were selected based on donor self-identification for previous MeV infection or vaccination, to determine the MeV-nAb content and compare it to the potency of plasma pools (n?=?13) from the current IG manufacture. Convalescent donors have higher mean MeV-nAb concentrations (3.9 IU/mL) than vaccinated donors (2.5 IU/mL), as previously reported. However, their selection would only result in a 1.4-fold elevated nAb concentration compared to current plasma pools, which is not sufficient for HIG production. Interestingly, thirty-two donors (8%) had a MeV-nAb concentration of?≥?8 IU/mL. The selective use of these plasma donations would result in sixfold higher plasma pool concentrations, which should permit the manufacture of the measles HIG. Further, the longitudinal analysis of a subset of individuals who repeatedly donated plasma at a high frequency revealed only a minor decline (~?30%) of MeV-nAb levels. Repeat donations of such high-potency donors would thus facilitate the production of the measles HIG. Due to its markedly raised MeV-nAb concentration compared to standard IG, such preparation could significantly shorten infusion time and thus improve the treatment experience for both physicians and patients, especially infants.

     

Cerebrovascular reactivity in retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations

Retinal Vasculopathy with Cerebral Leukoencephalopathy and Systemic manifestations (RVCL-S) is a small vessel disease caused by TREX1 mutations. RVCL-S is characterized by retinal vasculopathy and brain white matter lesions with and without contrast enhancement. We aimed to investigate cerebrovascular reactivity (CVR) in RVCL-S. In this cross-sectional observational study, 21 RVCL-S patients, 23 mutation-negative family members, and 31 healthy unrelated controls were included. CVR to a hypercapnic challenge was measured using dual-echo arterial spin labeling magnetic resonance imaging. Stratified analyses based on age were performed. We found that CVR was decreased in gray and white matter of RVCL-S patients compared with family members and healthy controls (ANCOVA; P < 0.05 for all comparisons). This was most noticeable in RVCL-S patients aged ≥40 years (ANCOVA, P < 0.05 for all comparisons). In RVCL-S patients aged < 40 years, only CVR in white matter was lower when compared to healthy controls (P < 0.05). Gray matter CVR was associated with white matter lesion volume in RVCL-S patients (r = –0.527, P = 0.01). In conclusion, impaired cerebrovascular reactivity may play an important role in the pathophysiology of RVCL-S and may be an useful early biomarker of cerebrovascular disease severity.     

Interference Screw vs. Suture Anchor Fixation for Open Subpectoral Biceps Tenodesis: Does it Matter?

Background  

Bioabsorbable interference screw fixation has superior biomechanical properties compared to suture anchor fixation for biceps tenodesis. However, it is unknown whether fixation technique influences clinical results.     

Variations in clinical decision-making between cardiologists and cardiac surgeons; a case for management by multidisciplinary teams?

Objective  

To assess variations in decisions to revascularise patients with coronary heart disease between general cardiologists, interventional cardiologists and cardiac surgeons     

Stiff skin syndrome

Stiff skin syndrome is a rare disorder characterized by pronounced skin induration, mild hypertrichosis and limited joint mobility, predominantly on the buttocks and thighs. Many heterogeneous cases have been reported under the name of stiff skin syndrome. We present a case of stiff skin syndrome from China, the diagnosis based on the patient's typical clinical and histopathological features.