Role of the Drosophila Non-Visual ß-Arrestin Kurtz in Hedgehog Signalling

The non-visual ß-arrestins are cytosolic proteins highly conserved across species that participate in a variety of signalling events, including plasma membrane receptor degradation, recycling, and signalling, and that can also act as scaffolding for kinases such as MAPK and Akt/PI3K. In Drosophila melanogaster, there is only a single non-visual ß-arrestin, encoded by kurtz, whose function is essential for neuronal activity. We have addressed the participation of Kurtz in signalling during the development of the imaginal discs, epithelial tissues requiring the activity of the Hedgehog, Wingless, EGFR, Notch, Insulin, and TGFβ pathways. Surprisingly, we found that the complete elimination of kurtz by genetic techniques has no major consequences in imaginal cells. In contrast, the over-expression of Kurtz in the wing disc causes a phenotype identical to the loss of Hedgehog signalling and prevents the expression of Hedgehog targets in the corresponding wing discs. The mechanism by which Kurtz antagonises Hedgehog signalling is to promote Smoothened internalization and degradation in a clathrin- and proteosomal-dependent manner. Intriguingly, the effects of Kurtz on Smoothened are independent of Gprk2 activity and of the activation state of the receptor. Our results suggest fundamental differences in the molecular mechanisms regulating receptor turnover and signalling in vertebrates and invertebrates, and they could provide important insights into divergent evolution of Hedgehog signalling in these organisms

Difference in the Surgical Outcome of Unilateral Cleft Lip and Palate Patients with and without Pre-Alveolar Bone Graft Orthodontic Treatment.

Presurgical orthodontic treatment before secondary alveolar bone grafting (SABG) is widely performed for cleft lip/palate patients. However, no randomized controlled trial has been published comparing SABG outcomes in patients with, and without, presurgical orthodontic treatment. This randomized, prospective, single-blinded trial was conducted between January 2012 and April 2015 to compare ABG volumes 6 months postoperatively between patients with and without presurgical orthodontic treatment. Twenty-four patients were enrolled and randomized and 22 patients completed follow-up. Patients who had presurgical orthodontics before SABG had significantly improved inclination (p < 0.001) and rotation (p < 0.001) of the central incisor adjacent to the defect, significantly improved ABG fill volume (0.81 ± 0.26 cm(3) at 6 months compared to 0.59 ± 0.22 cm(3); p < 0.05) and less residual alveolar bone defect (0.31 ± 0.08 cm(3) at 6 months compared to s 0.55 ± 0.14 cm(3); p < 0.001) compared to patients who did not have presurgical orthodontic treatment. In conclusion, orthodontic treatment combined with SABG results in superior bone volume when compared with conventional SABG alone.This article is freely available via Open Access. Click on the 'Additional Link' above to access the full-text via the publisher's site.Published (Open Access

Arrhythmia and death following percutaneous revascularization in ischemic left ventricular dysfunction: Prespecified analyses from the REVIVED-BCIS2 trial

BACKGROUND: Ventricular arrhythmia is an important cause of mortality in patients with ischemic left ventricular dysfunction. Revascularization with coronary artery bypass graft or percutaneous coronary intervention is often recommended for these patients before implantation of a cardiac defibrillator because it is assumed that this may reduce the incidence of fatal and potentially fatal ventricular arrhythmias, although this premise has not been evaluated in a randomized trial to date. METHODS: Patients with severe left ventricular dysfunction, extensive coronary disease, and viable myocardium were randomly assigned to receive either percutaneous coronary intervention (PCI) plus optimal medical and device therapy (OMT) or OMT alone. The composite primary outcome was all-cause death or aborted sudden death (defined as an appropriate implantable cardioverter defibrillator therapy or a resuscitated cardiac arrest) at a minimum of 24 months, analyzed as time to first event on an intention-to-treat basis. Secondary outcomes included cardiovascular death or aborted sudden death, appropriate implantable cardioverter defibrillator (ICD) therapy or sustained ventricular arrhythmia, and number of appropriate ICD therapies. RESULTS: Between August 28, 2013, and March 19, 2020, 700 patients were enrolled across 40 centers in the United Kingdom. A total of 347 patients were assigned to the PCI+OMT group and 353 to the OMT alone group. The mean age of participants was 69 years; 88% were male; 56% had hypertension; 41% had diabetes; and 53% had a clinical history of myocardial infarction. The median left ventricular ejection fraction was 28%; 53.1% had an implantable defibrillator inserted before randomization or during follow-up. All-cause death or aborted sudden death occurred in 144 patients (41.6%) in the PCI group and 142 patients (40.2%) in the OMT group (hazard ratio, 1.03 [95% CI, 0.82–1.30]; P =0.80). There was no between-group difference in the occurrence of any of the secondary outcomes. CONCLUSIONS: PCI was not associated with a reduction in all-cause mortality or aborted sudden death. In patients with ischemic cardiomyopathy, PCI is not beneficial solely for the purpose of reducing potentially fatal ventricular arrhythmias. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01920048

Spectrum of Antley-Bixler Syndrome

Antley-Bixler syndrome (ABS) is an exceptionally rare craniosynostosis syndrome characterized by radiohumeral synostosis present from the perinatal period. There is a wide spectrum of anomalies seen within ABS, and other features include midface hypoplasia; choanal stenosis or atresia; multiple joint contractures; visceral anomalies, particularly of the genitourinary system; and impaired steroidogenesis. The condition of ABS is curious in that mutations of 2 separate genes have been identified and that there seem to be subtle phenotypic differences between the 2 genotypes. Mutations of the P450 oxidoreductase gene have been reported in those patients with genital anomalies and/or impaired steroidogenesis, and the S351C mutation of the fibroblast growth factor receptor 2 gene has been reported predominantly in those patients with normal genitalia and steroidogenesis. We report a series of 4 patients with ABS and review their main findings and management.Karen L. McGlaughlin, Helen Witherow, David J. Dunaway, David J. David and Peter J. Anderso

Relational Intimacy Mediates Sexual Outcomes Associated With Impaired Sexual Function: Examination in a Clinical Sample

Background Relational intimacy is hypothesized to underlie the association between female sexual functioning and various sexual outcomes, and married women and women with sexual dysfunction have been generally absent from prior studies investigating these associations, thus restricting generalizability. Aim To investigate whether relational intimacy mediates sexual outcomes (sexual satisfaction, coital frequency, and sexual distress) in a sample of married women with and without impaired sexual functioning presenting in clinical settings. Methods Using a cross-sectional design, 64 heterosexual married women with (n = 44) and without (n = 20) impaired sexual functioning completed a battery of validated measurements assessing relational intimacy, sexual dysfunction, sexual frequency, satisfaction, and distress. Intimacy measurements were combined using latent factor scores before analysis. Bias-corrected mediation models of the indirect effect were used to test mediation effects. Moderated mediation models examined whether indirect effects were influenced by age and marital duration. Outcomes Patients completed the Female Sexual Function Index, the Couple\u27s Satisfaction Index, the Sexual Satisfaction Scale for Women, the Inclusion of the Other in the Self Scale, and the Miller Social Intimacy Test. Results Mediation models showed that impaired sexual functioning is associated with all sexual outcomes directly and indirectly through relational intimacy. Results were predominantly independent of age and marital duration. Clinical Implications Findings have important treatment implications for modifying interventions to focus on enhancing relational intimacy to improve the sexual functioning of women with impaired sexual functioning. Strengths and Limitations The importance of the role relational intimacy plays in broad sexual outcomes of women with impaired sexual functioning is supported in clinically referred and married women. Latent factor scores to improve estimation of study constructs and the use of contemporary mediation analysis also are strengths. The cross-sectional design precludes any causal conclusions and it is unknown whether the results generalize to male partners, partners within other relationship structures, and non-heterosexual couples. Conclusion Greater relational intimacy mitigates the adverse impact of impaired sexual functioning on sexual behavior and satisfaction in women. Witherow MP, Chandraiah S, Seals SR, et al. Relational Intimacy Mediates Sexual Outcomes Associated With Impaired Sexual Function: Examination in a Clinical Sample. J Sex Med 2017;14:843–851