The HSPB1-p62/SQSTM1 functional complex regulates the unconventional secretion and transcellular spreading of the HD-associated mutant huntingtin protein.

Conformational diseases, such as Alzheimer, Parkinson and Huntington diseases, are part of a common class of neurological disorders characterized by the aggregation and progressive accumulation of proteins bearing aberrant conformations. Huntington disease (HD) has autosomal dominant inheritance and is caused by mutations leading to an abnormal expansion in the polyglutamine (polyQ) tract of the huntingtin (HTT) protein, leading to the formation of HTT inclusion bodies in neurons of affected patients. Interestingly, recent experimental evidence is challenging the conventional view by which the disease pathogenesis is solely a consequence of the intracellular accumulation of mutant protein aggregates. These studies reveal that transcellular transfer of mutated huntingtin protein is able to seed oligomers involving even the wild-type (WT) forms of the protein. To date, there is still no successful strategy to treat HD. Here, we describe a novel functional role for the HSPB1-p62/SQSTM1 complex, which acts as a cargo loading platform, allowing the unconventional secretion of mutant HTT by extracellular vesicles. HSPB1 interacts preferentially with polyQ-expanded HTT compared with the WT protein and affects its aggregation. Furthermore, HSPB1 levels correlate with the rate of mutant HTT secretion, which is controlled by the activity of the PI3K/AKT/mTOR signalling pathway. Finally, we show that these HTT-containing vesicular structures are biologically active and able to be internalized by recipient cells, therefore providing an additional mechanism to explain the prion-like spreading properties of mutant HTT. These findings might also have implications for the turn-over of other disease-associated, aggregation-prone proteins.

Prospective multicentre study on barbed reposition pharyngoplasty standing alone or as a part of multilevel surgery for sleep apnoea.

OBJECTIVES: The aim of this study was to demonstrate in a prospective multicentre study that Barbed Reposition Pharyngoplasty (BRP) procedure is safe and effective in management of obstructive sleep apnoea/hypopnea syndrome (OSAHS) patients. DESIGN: Prospective study. SETTING: Multicentre study. PARTICIPANTS: Patients suffering from obstructive sleep apnoea. MAIN OUTCOMES MEASURES: Values of postoperative apnoea-hypopnea index (AHI), oxygen desaturation index (ODI), epworth sleepiness scale (ESS). RESULTS: 111 Barbed Reposition Pharyngoplasty procedures standing alone or as a part of multilevel surgery for OSAHS, performed between January and September 2016, were analysed in 15 different centres. The average hospitalisation period was 2.5 ± 0.5 days. The mean patient age was 46.3 ± 10.5 years. The average body mass index at the time of the procedure was 27.9 ± 3.2, and the majority of the patients were men (83%). The mean preoperative and postoperative apnoea/hypopnea index was 33.4 ± 19.5 and 13.5 ± 10.3, respectively (P < .001). The mean preoperative and postoperative ESS score was 10.2 ± 4.5 and 6.1 ± 3.6, respectively (P < .001). The mean preoperative and postoperative ODI were 29.6 ± 20.7 and 12.7 ± 10.8, respectively (P < .001). CONCLUSIONS: Patients undergoing BRP standing alone or as part of a multilevel approach for the treatment of OSAHS have a reasonable expectation for success with minimal morbidity.

Claimed effects, outcome variables and methods of measurement for health claims proposed under European Community Regulation 1924/2006 in the framework of protection against oxidative damage and cardiovascular health.

BACKGROUND AND AIMS: The high number of negative opinions from the European Food Safety Authority (EFSA) to the requests for authorization of health claims is largely due to the design of human intervention studies, including the inappropriate choice of outcome variables (OVs) and of their methods of measurement (MMs). The present manuscript reports the results of an investigation aimed to collect, collate and critically analyse the information in relation to claimed effects, OVs and MMs, in the context of protection against oxidative damage and cardiovascular health compliant with Regulation 1924/2006. METHODS AND RESULTS: Claimed effects, OVs and the related MMs were collected from EFSA Guidance documents and applications for authorization of health claims under Articles 13.5 and 14. The OVs and their MMs were evaluated only if the claimed effect was sufficiently defined and was considered beneficial by EFSA. The collection, collation and critical analysis of the relevant scientific literature consisted in the definition of the keywords, the PubMed search strategies and the creation of databases of references. The critical analysis of the OVs and their MMs was performed on the basis of the literature review and was aimed at defining the appropriateness of OVs and MMs in the context of the specific claimed effects. CONCLUSIONS: The information provided in this document could serve to EFSA for the development of further guidance on the scientific requirements for health claims, as well as to the stakeholders for the proper design of human intervention studies aimed to substantiate such health claims.

An update on juvenile dermatomyositis.

Juvenile dermatomyositis (JDM) is a rare, severe, autoimmune disease characterized by a small-vessel vasculopathy that primarily affects skin and muscle, but also lung, joints, gut and heart. Nowadays prompt recognition of this entity and aggressive treatment, when needed, improves outcomes and has decreased mortality that, before corticosteroid became a mainstay in therapy, could reach 40%.

Psoriasis and seborrheic dermatitis in infancy and childhood.

Psoriasis is a common inflammatory dermatosis that may be seen in infants, children, and adolescents. The clinical presentation and course may be quite variable, and while patients with mild disease are often easily managed, those with recalcitrant or more severe disease often present a therapeutic dilemma given the number of therapies available and the relative lack of data on the efficacy and safety of use of these therapies in children. Diagnosis in children can be more difficult, but family history may be helpful. Moreover, sometimes clinical pattern of pediatric psoriasis is very different from its adult counterpart or it could manifests in association with atopic dermatitis, and for these reason it is possibly misdiagnosed and under recognized. We therefore focus on diagnostic patterns and effective treatments of this challenging disease.

Depigmentation therapy in vitiligo universalis with cryotherapy and 4-hydroxyanisole.

Vitiligo is a disease characterized by the loss of melanocytes, resulting in progressive depigmentation of skin, and areas of normally pigmented skin can be of cosmetic concern. Several options have been tried to remove the pigment and make the skin a more even colour. We present an easy and effective therapeutic procedure based on single-session cryotherapy followed by topical 4-hydroxyanisole (4-HA).

Vitiligo management: combination of surgical treatment and phototherapy under reflectance confocal microscopy monitoring.

OBJECTIVE: Vitiligo is a chronic acquired pigmentary skin disorder characterized by well-defined asymptomatic white macule as a result of loss of functional melanocytes in the epidermis. The psychological burden experienced by patients is of great interest and consequently research of the best medical approach is constantly developing. This review focuses on surgical approach and the combination of surgery and phototherapy. In addition, reflectance confocal microscopy (RCM) could be useful to discriminate between stable or active vitiligo and to evaluate efficacy of therapy. MATERIALS AND METHODS: We searched PubMed with the following keywords: (vitiligo[Title/Abstract]) AND therapy[Title/Abstract]) AND surgery[Title/Abstract]) AND phototherapy[Title/Abstract]) AND reflectance confocal microscopy[Title/Abstract]). RESULTS: To date, surgery is an effective therapeutic approach in stable vitiligo. Phototherapy, which is the most effective medical option, can improve the results obtained with surgery if performed in combination. Preliminary data show that RCM help physician in evaluating stability of vitiligo and is also useful to monitor clinical response. CONCLUSIONS: Vitiligo is a psychosocially debilitating disease requiring a multidisciplinary approach. Even if a standard management could not be stated, combination of surgery and phototherapy in stable vitiligo could lead to great improvement than monotherapy. RCM is a modern tool which should be used in order to perform surgery and phototherapy properly and to subsequently evaluate efficacy on a microscopic level.

Microarchitectural and physical changes during fetal growth in human vertebral bone.

The ossification process in human vertebra during the early stage of its formation was studied by X-ray diffraction (XRD) and X-ray microtomography (microCT) at the European Synchrotron Radiation Facility (ESRF), Grenoble, France. Twenty-two samples taken from vertebral ossification centers of human fetal bone (gestational age ranging between 16 and 26 weeks) were investigated. The analysis of three-dimensional images at high spatial resolution (approximately 10 and approximately 2 microm) allows a detailed quantitative description of bone microarchitecture. A denser trabecular network was found in fetal bone compared with that of adult bone. The images evidenced a global isotropic structure clearly composed of two regions: a central region (trabecular bone) and a peripheral region (immature bone). XRD experiments evidenced hydroxyapatite-like crystalline structure in the mineral phase at any fetal age after 16 weeks. Interestingly, the analysis of XRD patterns highlighted the evolution of crystalline structure of mineralized bone as a function of age involving the growth of the hydroxyapatite crystallites.

Synchrotron radiation microtomography allows the analysis of three-dimensional microarchitecture and degree of mineralization of human iliac crest biopsy specimens: effects of etidronate treatment.

Quantitative microcomputed tomography using synchrotron radiation (SR microCT) was used to assess the effects of a sequential etidronate therapy on both three-dimensional (3D) microarchitecture and degree of mineralization of bone (DMB) in postmenopausal osteoporosis. Thirty-two iliac crest biopsy specimens were taken from 14 patients with osteoporosis (aged 64 +/- 1.8 years) before (baseline) and after 1 year of etidronate treatment, and after 2 years of treatment for four of the patients. The samples were imaged at high spatial resolution (voxel size = 10 microm) using the microtomography system developed at the European Synchrotron Radiation Facility (ESRF), Grenoble, France. Three-dimensional microarchitecture parameters were calculated and compared with those obtained from conventional histomorphometry. In addition, the DMB was evaluated also in 3D. No significant statistical changes regarding bone mass and structural parameters were observed in histomorphometry or 3D analyses. The distribution of the DMB in cortical and trabecular bone showed a trend to a shift toward highest mineralization values after 1 year of etidronate treatment (3.88% and 1.24% in cortical and trabecular bone, respectively). This trend was more evident after 2 years. The study also showed that SR microCT is an accurate technique and the only one for quantifying both the mineralization and the microarchitecture of bone samples at the same time in 3D.

UVB radiation preferentially induces recruitment of memory CD4+ T cells in normal human skin: long-term effect after a single exposure.

Acute, low-doses of ultraviolet (UV)-B radiation affect the immune competent cells of the skin immune system. In this study, we examined the time-dependent changes of the cutaneous T cell population in normal human volunteers following a single local exposure to UV. Solar-simulated UV radiation caused an initial decrease in intraepidermal T cell numbers, even leading to T cell depletion at day 4, whereupon a considerable infiltration of T cells in the epidermis occurred that peaked at day 14. In the dermis the number of T cells was markedly increased at days 2 (peak) and 4 after irradiation, and subsequently declined to the nonirradiated control values at day 10. Double-staining with several T cell markers showed that the T cells, infiltrating the (epi)dermis upon UV exposure, were almost exclusively CD4+ CD45RO+ T cells, expressing an alpha/beta type T cell receptor, but lacking the activation markers HLA-DR, VLA-1, and IL-2R. Application of UVB radiation resulted in similar dynamics of T cells, indicating that the UVB wavelengths within the solar-simulated UV radiation were responsible for the selective influx of CD4+ T cells. In conjunction with UVB-induced alterations in the type and function of antigen-presenting cells (i.e., Langerhans cells and macrophages), the changes of the cutaneous T cell population may also contribute to UVB-induced immunosuppression at skin level in man.

Ultrasonic characterization of human cancellous bone using transmission and backscatter measurements: relationships to density and microstructure.

The present study was designed to evaluate the relationships between ultrasonic backscatter, density, and microarchitecture of cancellous bone. The slopes of the frequency-dependent attenuation coefficient (nBUA), ultrasound bone velocity (UBV), the frequency-averaged backscatter coefficient (BUB) were measured in 25 cylindrical cancellous bone cores. Bone mineral density (BMD) was determined using X-ray quantitative computed tomography. Microarchitecture was investigated with synchrotron radiation microtomography with an isotropic spatial resolution of 10 microm. Several microstructural parameters reflecting morphology, connectivity, and anisotropy of the specimens were derived from the reconstructed three-dimensional (3D) microarchitecture. The association of the ultrasonic variables with density and microarchitecture was assessed using simple and multivariate linear regression techniques. For all ultrasonic variables, a strong association was found with density (r = 0.84-0.90). We also found that, with the exception of connectivity, all microstructural parameters correlated significantly with density, with r values of 0.54-0.92. For most microstructural parameters there was a highly significant correlation with ultrasonic parameters (r = 0.33-0.91). However, the additional variance explained by microstructural parameters compared with the variance explained by BMD alone was small (Delta r(2) = 6% at best). In particular, no significant independent association was found between microstructure and backscatter coefficient (a microstructure-related ultrasonic parameter) after adjustment for density. The source for the unaccounted variance of quantitative ultrasound (QUS) parameters remains unknown.

Exposure to UVB induces accumulation of LFA-1+ T cells and enhanced expression of the chemokine psoriasin in normal human skin.

Normal human skin shows preferential (epi)dermal infiltration of CD4+ T cells upon acute UV exposure. To study the mechanism behind this feature we locally exposed healthy volunteers to doses of UV commonly encountered by the population. Expression of integrins on T cells and expression of adhesion molecules on dermal endothelial cells were quantitatively assessed by immunohistochemistry in situ. We also investigated the effects of ultraviolet-B (UVB) exposure on psoriasin and IL-16, two specific chemoattractant factors for CD4+ T cells, at messenger RNA (mRNA) level by semiquantitative reverse transcriptase-polymerase chain reaction and at protein level by immunohistochemistry. We found, at day 2 after exposure to four minimal erythema doses of UVB, predominant accumulation of LFA-1+/CLA-/VLA-4- T cells in the dermis. Concomitantly the expression of ICAM-1, but not that of E-selectin and VCAM-1, was upregulated on dermal endothelial cells. The increase in the number of dermal T cells was not due to proliferation because only 2% of the UVB-induced dermal T cells expressed the marker of proliferation Ki-67. Whereas exposure to 35 J/cm2 of ultraviolet-A (UVA), like UVB, induced a loss of intraepidermal T cells at day 2 after exposure, UVA induced neither any influx of T cells into the dermis nor any adhesion molecule upregulation on endothelial cells. In response to UVB exposure, the expression of psoriasin mRNA, but not of IL-16 mRNA, was upregulated; the expression of psoriasin protein was also found to be upregulated. These results suggest that LFA-1/ICAM-1 pathway and psoriasin are both involved in the accumulation of CD4+ T cells into UVB-irradiated skin, possibly via a recruitment mechanism.

Solar-simulated ultraviolet irradiation induces selective influx of CD4+ T lymphocytes in normal human skin.

The proportion and composition of the human cutaneous CD3+ T lymphocyte population was determined in situ following a single exposure to physiological, erythema-inducing doses of simulated solar radiation, mainly consisting of UV radiation. Biopsies were taken 1, 2 and 7 days after local irradiation of normal volunteers with 1, 2 and 4 MED by a xenonarc lamp and immunohistochemistry was performed on cryostat sections. Ultraviolet radiation caused an initial decrease of intraepidermal CD3+ T-cell numbers or even could lead to T-cell depletion 24 and 48 h postirradiation, and this was followed by an infiltration of T cells in the epidermis as determined 1 week after UV exposure. The number of dermal CD3+ T cells was increased 24 h after irradiation, reached a maximum at 48 h and subsequently declined at day 7, though remained significantly higher than the unirradiated control. Double staining demonstrated that the CD3+ T cells, which immigrated into the (epi)dermis upon UV exposure, coexpressed CD4 but not CD8. Therefore the CD4/CD8 ratio in skin was markedly increased during the first week upon UV exposure. Our time course study shows that UV radiation affects the T-cell population within human skin by depleting the majority of epidermal T cells and initiating a selective influx of CD4+ T cells.