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Aims: PRRX1 -rearranged mesenchymal tumours are a recently identified and rare subgroup of soft tissue neoplasms with distinct morphological features and genetic alterations. This study aims to further investigate the immunohistochemical profile and underlying genetic alterations in these tumours in order to get more insight on their underlying biology and the unique profile of these tumours., Methods: Two new molecular confirmed cases of PRRX1 -rearranged mesenchymal tumours were thoroughly studied with immunohistochemical stainings (RB1, CD34, ALK and pan-TRK), fluorescence in situ hybridisation (FISH) RB1/13q12 and RNA-based next-generation sequencing., Results: Both cases exhibited typical morphological and molecular features, confirming the diagnosis of PRRX1 -rearranged mesenchymal tumours. Immunohistochemistry revealed RB1 loss in both cases, which was subsequently confirmed through FISH analysis. Additionally, one case showed focal positivity for CD34, ALK and pan-TRK on immunohistochemistry., Conclusions: We identified loss of RB1 in two cases of PRRX1-rearranged mesenchymal tumours. This could suggest a potential association with RB1 -deficient soft tissue tumours, although further research is necessary. Furthermore, the finding of focal positivity for CD34, ALK and pan-TRK on immunohistochemistry enriches the immunohistochemical profile of these tumours., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To quantitatively investigate the effect of mandibular advancement devices (MADs) on pharyngeal airway dimensions in a transverse plane as measured during drug-induced sleep endoscopy (DISE)., Methods: Data from 56 patients, treated with MAD at 75% maximal protrusion and with baseline Apnea-Hypopnea Index ≥10 events/h, were analyzed. For each patient, three snapshots were selected from DISE video footage at baseline, with MAD presence, and during chin lift, resulting in 498 images (168/168/162, baseline/MAD/chin lift). Cross-sectional areas, anteroposterior (AP) and laterolateral (LL) dimensions on both retroglossal and retro-epiglottic levels were measured. To define the effect of MAD and chin lift on pharyngeal dimensions, linear mixed-effect models were built. Associations between MAD treatment response and pharyngeal expansion (MAD/chin lift) were determined., Results: Significant differences were found between retroglossal cross-sectional areas, AP, and LL dimensions at baseline and with MAD presence. At a retro-epiglottic level, only LL dimensions differed significantly with MAD presence compared to baseline, with significant relation of LL expansion ratio to treatment response (p = 0.0176). After adjusting the response definition for the sleeping position, greater retroglossal expansion ratios were seen in responders (1.32 ± 0.48) compared to non-responders (1.11 ± 0.32) (p = 0.0441). No significant association was found between response and pharyngeal expansion by chin lift., Conclusion: Our observations highlight the additional value of quantitative pharyngeal airway measurements during DISE with MAD presence in evaluating MAD treatment outcome. These findings demonstrate an increase in retroglossal airway dimensions during DISE, with MAD presence, and more pronounced increase in retroglossal expansion ratios in MAD treatment responders compared to non-responders after sleeping position correction., Level of Evidence: 3 Laryngoscope, 133:3619-3627, 2023., (© 2023 The Authors. The Laryngoscope published by Wiley Periodicals LLC on behalf of The American Laryngological, Rhinological and Otological Society, Inc.)

Mandibular advancement device (MAD) treatment outcome for obstructive sleep apnea (OSA) is variable and patient dependent. A global, clinically applicable predictive model is lacking. Our aim was to combine characteristics obtained during drug-induced sleep endoscopy (DISE), awake nasendoscopy, and computed tomography scan-based computational fluid dynamic (CFD) measurements in one multifactorial model, to explain MAD treatment outcome. A total of 100 patients with OSA were prospectively recruited and treated with a MAD at fixed 75% protrusion. In all, 72 underwent CFD analysis, DISE, and awake nasendoscopy at baseline in a blinded fashion and completed a 3-month follow-up polysomnography with a MAD. Treatment response was defined as a reduction in the apnea-hypopnea index (AHI) of ≥50% and deterioration as an increase of ≥10% during MAD treatment. To cope with missing data, multiple imputation with predictive mean matching was used. Multivariate logistic regression, adjusting for body mass index and baseline AHI, was used to combine all potential predictor variables. The strongest impact concerning odds ratios (ORs) was present for complete concentric palatal collapse (CCCp) during DISE on deterioration (OR 28.88, 95% confidence interval [CI] 1.18-704.35; p = 0.0391), followed by a C-shape versus an oval shape of the soft palate during wakefulness (OR 8.54, 95% CI 1.09-67.23; p = 0.0416) and tongue base collapse during DISE on response (OR 3.29, 95% CI 1.02-10.64; p = 0.0464). Both logistic regression models exhibited excellent and fair predictive accuracy. Our findings suggest DISE to be the most robust examination associated with MAD treatment outcome, with tongue base collapse as a predictor for successful MAD treatment and CCCp as an adverse DISE phenotype., (© 2022 The Authors. Journal of Sleep Research published by John Wiley & Sons Ltd on behalf of European Sleep Research Society.)

Study Objectives: Obstructive sleep apnea (OSA) is increasingly recognized as a complex and heterogenous disorder. As a result, a "one-size-fits-all" management approach should be avoided. Therefore, evaluation of pathophysiological endotyping in OSA patients is emphasized, with upper airway collapse during sleep as one of the main features. To assess the site(s) and pattern(s) of upper airway collapse, natural sleep endoscopy (NSE) is defined as the gold standard. As NSE is labor-intensive and time-consuming, it is not feasible in routine practice. Instead, drug-induced sleep endoscopy (DISE) is the most frequently used technique and can be considered as the clinical standard. Flow shape and snoring analysis are non-invasive measurement techniques, yet are still evolving. Although DISE is used as the clinical alternative to assess upper airway collapse, associations between DISE and NSE observations, and associated flow and snoring signals, have not been quantified satisfactorily. In the current project we aim to compare upper airway collapse identified in patients with OSA using endoscopic techniques as well as flow shape analysis and analysis of tracheal snoring sounds between natural and drug-induced sleep. Methods: This study is a blinded prospective comparative multicenter cohort study. The study population will consist of adult patients with a recent diagnosis of OSA. Eligible patients will undergo a polysomnography (PSG) with NSE overnight and a DISE within 3 months. During DISE the upper airway is assessed under sedation by an experienced ear, nose, throat (ENT) surgeon using a flexible fiberoptic endoscope in the operating theater. In contrast to DISE, NSE is performed during natural sleep using a pediatric bronchoscope. During research DISE and NSE, the standard set-up is expanded with additional PSG measurements, including gold standard flow and analysis of tracheal snoring sounds. Conclusions: This project will be one of the first studies to formally compare collapse patterns during natural and drug-induced sleep. Moreover, this will be, to the authors' best knowledge, the first comparative research in airflow shape and tracheal snoring sounds analysis between DISE and NSE. These novel and non-invasive diagnostic methods studying upper airway mechanics during sleep will be simultaneously validated against DISE and NSE. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT04729478., Competing Interests: AW reports grants and personal fees from SomniFix; grants from Sanofi and fees from Nox, Apnimed, Bayer, and Inspire Medical Systems outside the submitted work. JV reports grants and fees from SomnoMed, AirLiquide, Vivisol, Mediq Tefa, Medidis, OSG, Agfa-Gevaert, Accuramed, Bioprojet, Jazz Pharmaceutics, Desitin, Idorsia, Nightbalance, Inspire Medical Systems, Heinen and Löwenstein, Ectosense, Philips, and ResMed outside the submitted work. OV reports grants from Inspire Medical Systems, Nightbalance, GlaxoSmithKline, and LivaNova at the Antwerp University Hospital outside the submitted work. The funders were not involved in the study design, collection, the writing of this article or the decision to submit it for publication. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Van den Bossche, Van de Perck, Wellman, Kazemeini, Willemen, Verbraecken, Vanderveken, Vena and Op de Beeck.)

This study's objective is to systematically review the literature on natural sleep endoscopy (NSE), including the set-up, different scoring systems, visualized collapse patterns during natural sleep, additional measurements, and comparison of upper airway collapse between NSE and drug-induced sleep endoscopy (DISE). A computerized search on Medline, Web of Science and the Cochrane library was conducted, obtaining 39 hits. Ten prospective studies were included in which NSE was performed in adults with obstructive sleep apnea (OSA). This study's findings suggest the soft palate to be the most frequent site of obstruction (58.8 %), followed by the tongue base (43.2 %), lateral walls (29.9 %), and epiglottis (22.4 %), which is in line with previous findings during DISE. Based on this literature review, the authors conclude that at this stage high quality, comparative research between DISE and NSE is missing. To adequately compare findings between OSA patients, endoscopic classification of upper airway collapse should be standardized. Non-invasive predictive tools to determine pharyngeal collapse are currently under investigation and may obviate the need for invasive endoscopy. This review highlights the contribution of NSE in validating such novel diagnostic methods and in studying upper airway mechanics in a research setting, yet larger and adequately powered studies are needed., Competing Interests: Conflicts of interest The authors do not have any conflicts of interest to disclose., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Abstract: Cutaneous clear cell proliferations encompass a heterogenous group of several primary cutaneous neoplasms and metastatic tumors with different histogenesis. Many of these clear cell proliferations may seem strikingly similar under the microscope resulting in challenging diagnosis. In many of these clear cell lesions, the reason for the clear or pale appearance of proliferating cells is unknown, whereas in other ones, this clear cell appearance is due to intracytoplasmic accumulation of glycogen, mucin, or lipid. Artifacts of tissue processing and degenerative phenomenon may also be responsible for the clear cell appearance of proliferating cells. Awareness of the histopathologic findings as well as histochemical and immunohistochemical techniques are crucial to the accurate diagnosis. This review details the histopathologic features of clear cell cutaneous proliferations, classifying them according their type of differentiation and paying special attention to the histopathologic differential diagnosis among them., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Sleep disturbances are features of Parkinson's disease (PD), that can already occur before PD diagnosis. The most investigated prodromal PD sleep disorder is REM sleep behavior disorder (RBD). The relation between other polysomnographic (PSG) alterations and the prediagnostic stages of PD, however, is less clear., Methods: We performed a retrospective case-control study to characterize polysomnographic alterations in PD and prediagnostic PD. We included 63 PD subjects (33 subjects that underwent a video-PSG before PD diagnosis [13 with and 20 without RBD] and 30 subjects that underwent a PSG after PD diagnosis) and 30 controls. PSGs were analyzed for sleep stages, different RSWA variables, body position, arousals, periodic limb movements, and REM density., Results: Higher subscores of all RSWA variables were observed in subjects with PD and prediagnostic PD (with and without RBD). Total RSWA, tonic RSWA and chin RSWA severity were significant predictors for all PD and prediagnostic PD groups. Our study also shows a higher percentage of nocturnal supine body position in all PD and prediagnostic PD groups. Supine body position percentage is the highest in the PD group and has a positive correlation with time since diagnosis., Conclusions: These findings suggest that increased total, tonic and chin RSWA as well as nocturnal supine body position are already present in prediagnostic PD, independently of RBD status. Prospective longitudinal studies are necessary to confirm the additional value of these PSG abnormalities as prodromal PD biomarkers., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Geographic variations in management and outcomes of individuals supported by continuous-flow left ventricular assist devices (CF-LVAD) between the United States (US) and Europe (EU) is largely unknown., Methods: We created a retrospective, multinational registry of 524 patients who received a CF-LVAD (either HVAD or Heartmate II) between January 2008 and April 2017. Follow up spanned from date of CF-LVAD implant to post-HTx period with a median follow up of 44.8 months., Results: The cohort included 299 (57.1%) EU and 225 (42.9%) US patients. Although the US cohort was significantly older with a higher prevalence of comorbidities, survival was similar between the cohorts (US 63.1%, EU 68.4% at 5 years, unadjusted log-rank test p = 0.43).Multivariate analyses suggested that older age, higher body mass index, elevated creatinine, use of temporary mechanical circulatory support prior CF-LVAD, and implantation of HVAD were associated with increased mortality. Among CF-LVAD patients undergoing HTx, the median time on CF-LVAD support was shorter in the US, meanwhile US donors were younger. Finally, the pattern of adverse events (stroke, gastrointestinal bleedings, late right ventricular failure, and driveline infection) during support differed significantly between US and EU., Conclusions: Although waitlisted patients in the US on CF-LVAD have higher risk comorbid conditions, the overall outcome is similar in US and EU. Geographic variations with regards to donor characteristics, duration of CF-LVAD support prior to transplant, and adverse events on support can explain the disparity in the utilization of mechanical bridge to transplant strategy between US and EU., Competing Interests: Declaration of Competing interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objectives: Weight change after left ventricular assist device implantation may influence outcomes and can affect transplant candidacy. We questioned if there is a systematic weight change after left ventricular assist device implantation and examined the evolution in functional capacity., Methods: A retrospective analysis of 84 patients who received a left ventricular assist device in Universitaire Ziekenhuizen Leuven between 2008 and 2016 was performed. Patients were divided into four groups based on their baseline body mass index, and we also examined weight evolution for patients presenting with new-onset heart failure versus those suffering from chronic heart failure. Body mass index was assessed at baseline, 6, 12, 18, and 24 months. To indicate the functional capacity, we analyzed the results of routine 6-Minute Walk Test performed at 6, 12, and 18 months., Results: During the first 6 months after surgery, the underweight patients evolved to normal weight and the body mass index of the obese patients reduced significantly. Afterward, all patients gained weight. The weight loss of the obese was not maintained over time. The weight of patients with normal weight and overweight evolved to overweight and obesity, respectively. No body mass index changes were demonstrated for patients presenting with new-onset heart failure, and the body mass index of patients suffering from chronic HF significantly increased. There was a significant improvement in functional capacity at 6 months, but this level remained unchanged at 12 and 18 months after surgery., Conclusion: Although the initial 6 months evolve beneficial, all patients gain weight in the second year and do not further improve their exercise capacity.

Objectives: We sought to determine the indications, type, and outcomes of reoperations on the aortic root after repair of tetralogy of Fallot (TOF)., Methods: Eleven centers belonging to the European Congenital Heart Surgeons Association contributed to the data collection process. We included 36 patients who underwent surgical procedures on the aortic root, including surgery on the aortic valve and ascending aorta, between January 1975 and December 2017. Original diagnoses included TOF-pulmonary stenosis (n = 18) and TOF-pulmonary atresia (n = 18). The main indications for reoperation were aortic insufficiency (n = 19, 53%), aortic insufficiency and dilatation of the ascending aorta (n = 10, 28%), aortic root dilatation (n = 4, 11%), and ascending aorta dilatation (n = 3, 8%)., Results: The median age at reoperation was 30.4 years (interquartile range 20.3-45.3 years), and mechanical aortic valve replacement was the most common procedure performed. Five patients died early after reoperation (14%), and larger ascending aorta diameters were associated with early mortality (P = .04). The median age at the last follow-up was 41.4 years (interquartile range 24.5-51.6 years). Late death occurred in five patients (5/31, 16%). Most survivors (15/26, 58%) were asymptomatic at the last clinical examination (New York Heart Association, NYHA class I). The remaining patients were NYHA class II (n = 7) and III (n = 3). The most common symptoms were fatigue (n = 5), dyspnea (n = 4), and exercise intolerance (n = 3)., Conclusions: Reoperations on the aortic root are infrequent but may become necessary late after TOF repair. The main indications for reoperation are aortic insufficiency, either isolated or associated with a dilatation of the ascending aorta. The surgical risk at reoperation was high and the presence of ascending aorta dilation is related to higher mortality., (© 2019 Wiley Periodicals, Inc.)

REM sleep without atonia (RSWA) is the polysomnographic finding of persistent muscle tone during REM sleep, resulting in paroxysmal phasic or tonic EMG activity. RSWA is essential for the diagnosis of REM sleep behavior disorder (RBD), but can also occur without dream-enacting behavior. Loss of atonia during REM sleep is considered as a biomarker for synucleinopathies. We will give an overview of the pathophysiology of RSWA and will highlight the diagnostic methods for RSWA. We will describe the different etiologies of RSWA and finally we will focus on the role of RSWA as biomarker for Lewy body disease. RSWA severity in isolated RBD patients is a potential predictor for early conversion to Parkinson's disease (PD) or dementia with Lewy bodies. In PD patients, RSWA severity is associated with more severe motor symptoms and disease progression. Future studies are needed to delineate the importance of isolated RSWA as prodromal marker of Lewy body disease., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Rosettes are a specific form of a white shiny structure seen with polarized dermoscopy. The precise morphological correlate and optical explication are not known., Objective: To estimate the frequency of rosettes in ex vivo dermoscopy and to find explication and morphologic correlate of this dermoscopic feature., Methods: A series of 6108 consecutive skin biopsies were examined with ex vivo dermoscopy and when rosettes were present serial transverse sections with polarization were examined., Results: In this series of 6108 consecutive skin biopsies, rosettes were found on ex vivo dermoscopy in 63 cases. When multiple we observed that they are always oriented at the same angle. Transverse sections with polarization of these lesions proved that smaller rosettes are mainly caused by polarizing horny material in adnexal openings, and larger rosettes by concentric perifollicular fibrosis., Conclusions: Rosettes are an optical effect of crossed polarization by concentric fibrosis or horny material and hence are not lesion-specific., (© 2015 European Academy of Dermatology and Venereology.)

Objective: To analyse overall cost involved with destination therapy (DT) in comparison to transplantation (HTX) and bridging to transplantation., Methods: Three groups of patients at one hospital were considered for this cost analysis: (1) patients included in the BENEMACS study starting May 2009 (n = 6); (2) all patients from May 2009 till May 2010 undergoing heart transplantation (n = 19); or (iii) undergoing Heartmate II implantation as a bridge to transplant (n = 13). Patients undergoing bridging were more sick (lower Intermacs class). DT patients were older (64±8 years). Cost was derived from actual hospital invoices, device, organ procurement and medical cost, and follow-up care during 1 year from implantation. Costs are presented in euro, by their mean values and standard deviation., Results: One-year survivals were 83, 84, and 77%, respectively, for DT, HTX, and bridging. Costs for initial and re-hospitalizations were not different between groups. Costs for medical follow-up and medication were significantly higher for transplanted patients. The 1-year total cost was €85 531±19 823 for HTX, €125 108±32 399 for bridging, and €137 068±29 007 for DT. As 42% of the transplanted patients were bridged, the cost of the medical pathway HTX was €138 076±19 823. Assuming a 5-year survival and a similar yearly follow-up cost, the average cost per year is €42 153 for HTX, €53 637 for transplantation including the bridging cost, and €47 487 for DT., Conclusion: Direct transplantation without bridging is the most cost-efficient treatment. The cost per patient per year for DT is similar to HTX considering its bridging activity.

Background: Bleeding complications are frequent adverse events in patients supported with axial continuous-flow pumps. Previous retrospective studies demonstrated that bleeding events in patients with the HeartMate II (Thoratec Corp, Pleasanton, CA) were attributed to acquired von Willebrand syndrome. We sought to analyze the von Willebrand factor (VWF) profile in patients receiving a HeartMate II or a CircuLite (Saddle Brook, NJ,) device (Synergy Pocket Micro-pump) prospectively., Methods: Prospectively analyzed were 34 patients supported with left ventricular assist device (LVAD; 26 with HeartMate II and 8 with CircuLite). The control group comprised 20 patients who underwent heart transplantation (HTx). Blood samples were taken pre-operatively and at 14 days and 3, 6, 9, and 12 months post-operatively., Results: Patients with LVADs had a high incidence of bleeding complications. From the immediate post-operative phase throughout the entire observation, the VWF ristocetin cofactor activity (Rco)/antigen (Ag) ratio of patients with HeartMate II and CircuLite devices was consistently lower compared with HTx patients. No correlation was found between the individual VWF:Rco/Ag ratio and bleeding events or transfusion requirements. The VWF:Rco/Ag ratio normalized immediately in patients who received HTx., Conclusions: Acquired von Willebrand syndrome was confirmed to occur immediately after the implantation of both types of LVAD and persisted up to 12 months. A lower VWF:Rco/Ag ratio was associated with larger transfusion requirements. Acquired von Willebrand syndrome resolves after LVAD explantation., (Copyright © 2013 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

The overall aim of the study was to develop a composite and comparative view of what factors enhance the learning experiences of student nurses whilst they are in clinical practice. The study involved students undertaking general nurse training programmes in nine Western European countries. The study focused on: (1) student nurse experiences of clinical learning environments, (2) the supervision provided by qualified nurses in clinical placements, and (3) the level of interaction between student and nurse teachers. The study utilised a validated theoretical model: the Clinical Learning Environment, Supervision and Nurse Teacher (CLES+T) evaluation scale. The evaluation scale has a number of sub-dimensions: Pedagogical atmosphere on the ward; Supervisory Relationships; the Leadership Style of Ward Managers; Premises of Nursing; and the Role of the Nurse Teacher. Data (N=1903) was collected from Cyprus, Belgium, England, Finland, Ireland, Italy, Netherlands, Spain and Sweden using web-based questionnaire 2007-2008. The findings revealed that respondents were generally satisfied with their clinical placements. There was clear support for the mentorship approach; 57% of respondents had a successful mentorship experience although some 18% of respondents experienced unsuccessful supervision. The most satisfied students studied at a university college, and had at least a seven week clinical placement supported by individualised mentorship relationships. Learning to become a nurse is a multidimensional process that requires both significant time being spent working with patients and a supportive supervisory relationship., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

A young immunocompetent patient is presented with a very rare presentation of a common viral illness: herpes zoster of the left hemilarynx with sensorial and motoric neuropathy of three ipsilateral lower cranial nerves: IX, X and XI. The mucosal lesions were discovered during upper gastrointestinal endoscopy. PCR of erosional exsudate confirmed the clinical diagnosis. Antiviral therapy and corticosteroids possibly contributed to the prosperous evolution with complete healing.

Skin pigmentation is accomplished by production of melanin in specialized membrane-bound organelles termed melanosomes and by transfer of these organelles from melanocytes to surrounding keratinocytes. The mechanism by which these cells transfer melanin is yet unknown. A central role has been established for the protease-activated receptor-2 of the keratinocyte which effectuates melanin transfer via phagocytosis. What exactly is being phagocytosed - naked melanin, melanosomes or melanocytic cell parts - remains to be defined. Analogy of melanocytes to neuronal cells and cells of the haemopoietic lineage suggests exocytosis of melanosomes and subsequent phagocytosis of naked melanin. Otherwise, microscopy studies demonstrate cytophagocytosis of melanocytic dendrites. Other plausible mechanisms are transfer via melanosome-containing vesicles shed by the melanocyte or transfer via fusion of keratinocyte and melanocyte plasma membranes with formation of tunnelling nanotubes. Molecules involved in transfer are being identified. Transfer is influenced by the interactions of lectins and glycoproteins and, probably, by the action of E-cadherin, SNAREs, Rab and Rho GTPases. Further clues as to what mechanism and molecular machinery will arise with the identification of the function of specific genes which are mutated in diseases that affect transfer.

Many approaches have been tried to establish assays for melanosome transfer to keratinocytes. In this report, we describe and summarize various novel attempts to label melanosomes in search of a reliable, specific, reproducible and quantitative assay system. We tried to fluorescently label melanosomes by transfection of GFP-labeled melanosomal proteins and by incubation of melanocytes with fluorescent melanin intermediates or homologues. In most cases a weak cytoplasmic fluorescence was perceived, which was probably because of incorrect sorting or deficient incorporation of the fluorescent protein and different localization. We were able to label melanosomes via incorporation of 14C-thiouracil into melanin. Consequently, we tried to develop an assay to separate keratinocytes with transferred radioactivity from melanocytes after co-culture. Differential trypsinization and different magnetic bead separation techniques were tested with unsatisfactory results. An attempt was also made to incorporate fluorescent thiouracil, since this would allow cells to be separated by FACS. In conclusion, different methods to measure pigment transfer between donor melanocytes and acceptor keratinocytes were thoroughly examined. This information could give other researchers a head start in the search for a melanosome transfer assay with said qualities to better understand pigment transfer.

Malignant transformation of melanocytes frequently coincides with alterations in epithelial cadherin (E-cadherin) expression, switching on of neural cadherin (N-cadherin), and, when progressed to a metastatic stage, loss of membranous placental cadherin (P-cadherin). In vitro studies of melanoma cell lines have shown invasion suppressor and promoter roles for E-cadherin and N-cadherin, respectively. In the present study, we investigated the effect of P-cadherin on aggregation and invasion using melanoma cells retrovirally transduced with human P-cadherin. De novo expression of P-cadherin in P-cadherin-negative cell lines (BLM and HMB2) promoted cell-cell contacts and Ca2+-dependent cell-cell aggregation in two- and three-dimensional cultures, whereas it counteracted invasion. These effects were not observed following P-cadherin transduction of endogenously P-cadherin-positive MeWo cells. In addition, P-cadherin-transduced BLM cells coaggregated with keratinocytes and showed markedly reduced invasion in a reconstructed skin model. The proadhesive and anti-invasive effects of P-cadherin were abolished on targeted mutation of its intracellular juxtamembrane domain or its extracellular domain. For the latter mutation, we mimicked a known missense mutation in P-cadherin (R503H), which is associated with congenital hypotrichosis with juvenile macular dystrophy.

Patients with the autosomal recessive Griscelli-Pruniéras syndrome type II are immunologically impaired and have an unusual silvery-grey hypopigmented colour of scalp hair, eyelashes and eyebrows but no noteworthy pigmentary abnormalities of the skin. In most Griscelli patients, the RAB27A gene, which encodes a small GTPase that is associated with the melanosome membrane in melanocytes, is mutated. Here we discuss a genomic RAB27A deletion found in a 21-month-old Moroccan Griscelli patient. Additionally, we provide evidence that the loss of functional Rab27a in melanocytes of this Griscelli patient is partially compensated by the up-regulation of Rab27b, a homologue of Rab27a. By real-time quantitative PCR and western blot analysis, we found that Rab27b mRNA and protein, expressed at low levels in normal human melanocytes, is significantly up-regulated in melanocytes derived from this patient. Our immunofluorescence and yeast two-hybrid screening studies reveal that Rab27b can form a tripartite complex on the melanosome membrane with Melanophilin, a Rab27a effector, and protein products of Myosin Va transcripts that contain exon F. Our data suggest that up-regulated Rab27b in melanocytes of the Griscelli patient can partially take over the function of Rab27a, which could explain the fact that this patient had an evenly pigmented skin and was able to tan.