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Background: Aprepitant is a neurokinin 1 receptor (NK1R) antagonist used for its antipruritic properties in dermatoses and systemic diseases. The mode of action is still unclear. A peripheral effect is assumed as aprepitant shows efficacy in inflammatory skin diseases including prurigo nodularis (PN). Objectives: To investigate the peripheral effects of NK1R antagonism in PN and cell culture models. Methods: Subjects with PN received an aprepitant treatment. Clinical, morphological and immunohistochemical changes were investigated in skin biopsies before and after treatment. Expression of NK1R was analysed by immunohistochemistry and for downstream pathways ((p)ERK1/2) by Western blotting in PN patients and matched healthy volunteers. Effects of NK1R blocking were analysed in cell cultures of primary keratinocytes by Western blotting for (p)ERK1/2 and by qPCR for NK1R, interleukin (IL)‐1beta, IL‐6, IL‐8 and TNFalpha. Results: Aprepitant treatment showed significant reduction in pruritus intensity (P < 0.05) in PN and relevant immunohistochemical changes (down: CD5, CD25, up: CD79a, IL4). NK1R expression was higher in keratinocytes of PN patients compared to healthy controls. After treatment, epidermal NK1R expression increased while expression and activation of ERK1/2 decreased. In vitro, receptor up‐regulation and reduced expression and activation of ERK1/2 were confirmed and reduced IL‐expression shown when blocking NK1R. Conclusion: Our data confirm that NK1R antagonists such as aprepitant exhibit effects in the skin. Epidermal receptor expression, epidermal inflammatory ILs, ERK1/2 MAPK signalling and cutaneous inflammatory infiltrate were targets of NK1R antagonism. This may explain partly the antipruritic effect of NK1R antagonists next to its role in the central nervous system. Linked Commentary: J.Wallengren. J Eur Acad Dermatol Venereol 2019; 33: 2221–2222. https://doi.org/10.1111/jdv.16031. [ABSTRACT FROM AUTHOR]

Background: Although chronic pruritus affects a large part of the population, its reliable assessment remains difficult. Electronical diaries (eDiaries) are often used in multicentre clinical trials. The ItchApp© for Android was developed to assess itch intensity and course and was validated for the German language in 2017. Objective: To validate ItchApp© for the use in the Polish and US English languages. Methods: Fifty‐three subjects in Poland and thirty subjects in the USA with chronic pruritus completed the paper‐based and app‐based questionnaires. These questionnaires contained items for measuring the itch intensity, including a numerical rating scale (NRS) and verbal rating scale (VRS), and for detecting the change of pruritus since the beginning of treatment. Results: The ItchApp© showed a high level of test–retest reliability [Intraclass correlation, Kappa and Kendall‐Tau B coefficients: 0.915–1.000 (Poland) and 0.863–1.000 (USA)]. The convergent validity showed strong correlation between the itch intensity scales on the ItchApp© (Items II‐IV = VRS mean, NRS mean and NRS worst) and the paper‐based itch intensity scales (mean and worst: VRS, NRS, VAS) [Spearman‐Rho and Pearson correlation coefficients: 0.710–0.987 (Poland) and 0.646–0.954 (USA)]. The ItchApp© items moderately correlated with the ItchyQol scores [Spearman‐Rho and Pearson correlation coefficients: 0.303–0.554 (Poland) and 0.275–0.447 (USA)]. After completing the ItchApp© questionnaire, a feasibility questionnaire was completed and showed that subjects feel the app is well suited for assessing pruritus. Conclusion: We provide evidence for the ItchApp© as a validated eDiary for the assessment of pruritus in Polish and US English languages, enabling its use in multicentre international clinical trials. [ABSTRACT FROM AUTHOR]

Background: Currently available tools to monitor patients with chronic prurigo over time focus on pruritus and quality of life parameters, while no instrument objectively assessing the pruriginous lesions is yet available. Objective: The objective of this study was to develop a physician‐assessed Prurigo Activity Score (PAS), a new tool to monitor the distribution and activity of chronic prurigo lesions and to evaluate its reliability and validity. Methods: The 7‐item PAS questionnaire as well as validated pruritus intensity scales (VAS, NRS) and a skin‐related quality of life score (DLQI) were completed for 264 patients (172 females, age 61 years) at least twice over a period of 2 years. In addition, a 60‐min test–retest reliability test was performed by four experts for a random sample of 12 patients. Results: The PAS showed good test‐retest reliability (Cohens κ > 0.61; Cronbach‐alpha > 0.76), ordinal or metric items showed high inter‐rater reliability (Kendalls > 0.61) and items recording the number of lesions correlated significantly to each other (P < 0.001). The highest correlation to external constructs was achieved with DLQI. The feasibility test conducted by four raters indicated the suitability of PAS for tracking chronic prurigo in the clinical setting. Discussion: The PAS is a useful tool to objectively monitor pruriginous lesions in chronic prurigo patients over time. The sensitivity of change in the PAS score should be analysed in future studies. [ABSTRACT FROM AUTHOR]

In cynomolgus macaques ( Macaca fascicularis), widely used in drug metabolism studies, CYP2C9, CYP2C76, CYP2D6, CYP3A4, and CYP3A5, important drug-metabolizing enzymes, are abundantly expressed in liver and metabolize cytochrome P450 substrates. CYP2C9 (c.334A>C), CYP2C76 (c.449 TG>A), CYP2D6 (c.891A>G), CYP3A4 ( IVS3 + 1G>del), and CYP3A5 (c.625A>T) substantially influence metabolic activity of enzymes, and thus are important variants in drug metabolism studies. In this study, a real-time PCR method was developed for genotyping these variants. The validity of the methods was verified by genotyping two wild type, two heterozygous, and two homozygous DNAs and was used to genotype 41 cynomolgus macaques (from Cambodia, Indonesia, the Philippines, or Vietnam) for the five variants, along with another important variant CYP2C19 (c.308C>T). The CYP2C9 and CYP2C19 variants were found only in Cambodian and Vietnamese animals, while the CYP2C76 and CYP2D6 variants were found only in Indonesian and Philippine animals. The CYP3A4 and CYP3A5 variants were not found in any of the animals analyzed. Mauritian animals, genotyped using next-generation sequencing data for comparison, possessed the CYP2C19 and CYP2D6 variants, but not the other variants. These results indicated differences in prevalence of these important variants among animal groups. Therefore, the genotyping tool developed is useful for drug metabolism studies using cynomolgus macaques. [ABSTRACT FROM AUTHOR]

The hydrogen exosphere constitutes the uppermost atmospheric layer of the Earth, and its shape may reflect the last stage of the atmospheric escape process. The distribution of hydrogen in the outer exosphere remains unobserved because outer geocoronal emissions are difficult to observe from within the exosphere. In this study, we used the Lyman Alpha Imaging Camera on board the Proximate Object Close Flyby with Optical Navigation spacecraft, located outside the exosphere, to obtain the first image of the entire geocorona that extends to more than 38 Earth radii. The observed emission intensity distribution can be reproduced using our analytical model that has three parameters: exobase temperature, exobase density, and solar radiation pressure, which implies that hot hydrogen production in the magnetized plasmasphere is not the dominant process shaping the outer hydrogen exosphere. However, the role of the magnetic effect in determining the total escape flux cannot be ruled out. [ABSTRACT FROM AUTHOR]

BACKGROUND AND PURPOSE Chronic heart failure (CHF) is associated with action potential prolongation and Ca(2+) overload, increasing risk of ventricular tachyarrhythmias (VT). We therefore investigated whether I(Ca) blockade was anti-arrhythmic in an intact perfused heart model of CHF. EXPERIMENTAL APPROACH CHF was induced in rabbits after 4 weeks of rapid ventricular pacing. Hearts from CHF and sham-operated rabbits were isolated and perfused (Langendorff preparation), with ablation of the AV node. VT was induced by erythromycin and low [K(+) ] (1.5mM). Electrophysiology of cardiac myocytes, with block of cation currents, was simulated by a mathematical model. KEY RESULTS Repolarization was prolonged in CHF hearts compared with sham-operated hearts. Action potential duration (APD) and overall dispersion of repolarization were further increased by erythromycin (300 µM) to block I(Kr) in CHF hearts. After lowering [K(+) ] to 1.5mM, CHF and sham hearts showed spontaneous episodes of polymorphic non-sustained VT. Additional infusion of verapamil (0.75 µM) suppressed early afterdepolarizations (EAD) and VT in 75% of sham and CHF hearts. Verapamil shortened APD and dispersion of repolarization, mainly by reducing transmural dispersion of repolarization via shortening of endocardial action potentials. Mathematical simulations showed that EADs were more effectively reduced by verapamil assuming a state-dependent block than a simple block of I(Ca) . CONCLUSIONS AND IMPLICATIONS Blockade of I(Ca) was highly effective in suppressing VT via reduction of transmural dispersion of repolarization and suppression of EAD. Such blockade might represent a novel therapeutic option to reduce risk of VT in structurally normal hearts and also in heart failure. LINKED ARTICLE This article is commented on by Stams et al., pp. 554-556 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2011.01818.x. [ABSTRACT FROM AUTHOR]

BACKGROUND AND PURPOSE Chronic heart failure (CHF) is associated with action potential prolongation and Ca2+ overload, increasing risk of ventricular tachyarrhythmias (VT). We therefore investigated whether ICa blockade was anti-arrhythmic in an intact perfused heart model of CHF. EXPERIMENTAL APPROACH CHF was induced in rabbits after 4 weeks of rapid ventricular pacing. Hearts from CHF and sham-operated rabbits were isolated and perfused (Langendorff preparation), with ablation of the AV node. VT was induced by erythromycin and low [K+] (1.5mM). Electrophysiology of cardiac myocytes, with block of cation currents, was simulated by a mathematical model. KEY RESULTS Repolarization was prolonged in CHF hearts compared with sham-operated hearts. Action potential duration (APD) and overall dispersion of repolarization were further increased by erythromycin (300 µM) to block IKr in CHF hearts. After lowering [K+] to 1.5mM, CHF and sham hearts showed spontaneous episodes of polymorphic non-sustained VT. Additional infusion of verapamil (0.75 µM) suppressed early afterdepolarizations (EAD) and VT in 75% of sham and CHF hearts. Verapamil shortened APD and dispersion of repolarization, mainly by reducing transmural dispersion of repolarization via shortening of endocardial action potentials. Mathematical simulations showed that EADs were more effectively reduced by verapamil assuming a state-dependent block than a simple block of ICa. CONCLUSIONS AND IMPLICATIONS Blockade of ICa was highly effective in suppressing VT via reduction of transmural dispersion of repolarization and suppression of EAD. Such blockade might represent a novel therapeutic option to reduce risk of VT in structurally normal hearts and also in heart failure. LINKED ARTICLE This article is commented on by Stams et al., pp. 554-556 of this issue. To view this commentary visit [ABSTRACT FROM AUTHOR]

The aim of this study was to examine the effect of a 20° Trendelenburg position on the blockade of nerves that exit the brachial plexus proximally in patients undergoing single-injection axillary brachial plexus block. After a pilot study of eight cadavers suggested that a head-down and lateral position would encourage the proximal spread of local anaesthetic, 72 patients undergoing elective surgery were divided into two equal groups: a Supine group and a Modified Position group (lateral position, 20° head-down tilt). Patients were left in the allocated position for 30 min after an axillary block had been performed with alkalinised mepivacaine 1% 49.5 ml. Sensory and motor blockade evaluation showed that there was a significantly higher proportion of axillary nerve (76% vs. 0%, p < 0.001), thoracodorsal nerve (86% vs. 0%, p < 0.001) and subscapular nerve (89% vs. 0%, p < 0.001) blockade in the Modified Position group. Sensory block of the radial nerve was also improved by the modified position (100% vs. 86%, p < 0.05). [ABSTRACT FROM AUTHOR]

Simian retrovirus (SRV) is a type-D betaretrovirus infectious to the Old World monkeys causing a variety of symptoms. SRVs are also present in the Old World monkey genomes as endogenous forms, which are referred to as Simian endogenous retroviruses (SERVs). Although many SERV sequences have been identified in Cercopithecinae genomes, with potential of encoding all functional genes, the distribution of SERVs in genomes and evolutionary relationship between exogeneous SRVs and SERVs remains unclear. In this study, we comprehensively investigated seven draft genome sequences of the Old World monkeys, and identified a novel cluster of SERVs in the two Rhinopithecus (R. roxellana and R. bieti) genomes, which belong to the Colobinae subfamily. The Rhinopithecus genomes harbored higher copy numbers of SERVs than the Cercopithecinae genomes. A reconstructed phylogenetic tree showed that the Colobinae SERVs formed a distinct cluster from SRVs and Cercopithecinae SERVs, and more closely related to exogenous SRVs than Cercopithecinae SERVs. Three radical amino acid substitutions specific to Cercopithecinae SERVs, which potentially affect the infectious ability of SERVs, were also identified in the proviral envelope protein. In addition, we found many integration events of SERVs were genus- or species-specific, suggesting the recent activity of SERVs in the Old World monkey genomes. The results suggest that SERVs in Cercopithecinae and Colobinae monkeys were endogenized after the divergence of subfamilies and do not transmit across subfamilies. Our findings also support the hypothesis that Colobinae SERVs are direct ancestors of SRV-6, which has a different origin from the other exogenous SRVs. These findings shed novel insight into the evolutionary history of SERVs, and may help to understand the process of endogenization of SRVs., (© 2018 Wiley Periodicals, Inc.)

Purpose: To evaluate the anatomical success rate of scleral buckling surgery in the treatment of rhegmatogenous retinal detachment and to evaluate the differences in outcome between patients suffering macula-off retinal detachment and those without a macular involvement., Methods: As a retrospective interventional case series, Munster Study on Therapy Achievements in Retinal Detachment (MUSTARD) is one of the largest ever established of retinal detachment patients and their outcome after buckling surgery, with 4325 patients who underwent surgery between 1980 and 2001. In 53.94% (n = 2134) of 3956 patients with nontraumatic retinal detachment, the macula was involved. The main outcome measure was the achievement of dry anatomical attachment of the retina., Results: The success rate in patients with macula-off retinal detachment is 80.46% and thus 7.78% lower (p < 0.01) than that in those patients with their macula intact whose success rate amounted to 88.24%. The overall success rate of all 4325 MUSTARD patients was 83.98%., Conclusions: Scleral buckling is an established and mostly successful method for the treatment of retinal detachment. As our case series has demonstrated, even eyes with macula-off can be treated successfully by this procedure, thereby avoiding the complications of primary vitrectomy., (© 2010 The Authors. Journal compilation © 2010 Acta Ophthalmol.)

Schizophrenic patients with an onset before age 16 years (early-onset schizophrenia, EOS) would be a rare but attractive subpopulation for genetic studies. This study explored the relationship between the polymorphism of four dopamine-regulating-enzymes (tyrosine hydroxylase, dopamine-beta-hydroxylase, catechol-O-methyltransferase, monoamine oxidase-A) genes, four dopamine-receptors (dopamine D1, D2, D3, D4 receptors) genes and susceptibility to EOS in a Japanese sample. Subjects comprised 51 Japanese patients who met DSM-IV criteria for schizophrenia with an onset before age 16 (by age 15) and 148 Japanese healthy controls. DNA was extracted from whole blood and genotyping was carried out by PCR-RELP using each restriction endonuclease. No significant difference was found in the allele frequencies or genotype distributions of any of the eight genes examined between EOS and the control groups. We did not find the relationship between the polymorphism of eight dopamine-related genes and susceptibility to EOS in a Japanese sample., (Copyright 2002 Wiley-Liss, Inc.)