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Background The Ehlers-Danlos syndromes (EDS) are rare connective tissue disorders consisting of 13 subtypes with overlapping features including joint hypermobility, skin and generalized connective tissue fragility. Classical EDS (cEDS) is principally caused by heterozygous COL5A1 or COL5A2 variants and rarely by the COL1A1 p.(Arg312Cys) substitution. Current major criteria are (1) skin hyperextensibility plus atrophic scars and (2) generalized joint hypermobility (gJHM). Minor criteria include additional mucocutaneous signs, epicanthal folds, gJHM complications, and an affected first-degree relative. Minimal criteria prompting molecular testing are major criterion 1 plus either major criterion 2 or 3 minor criteria. In addition to these features, the clinical picture also involves multiple organ systems, but large-scale cohort studies are still missing. This study aimed to investigate the multisystemic involvement and natural history of cEDS through a cross-sectional study on a cohort of 75 molecularly confirmed patients evaluated from 2010 to 2019 in a tertiary referral center. The diagnostic criteria, additional mucocutaneous, osteoarticular, musculoskeletal, cardiovascular, gastrointestinal, uro-gynecological, neuropsychiatric, and atopic issues, and facial/ocular features were ascertained, and feature rates compared by sex and age. Results Our study confirms that cEDS is mainly characterized by cutaneous and articular involvement, though none of their hallmarks was represented in all cases and suggests a milder multisystemic involvement and a more favorable natural history compared to other EDS subtypes. Abnormal scarring was the most frequent and characteristic sign, skin hyperextensibility and gJHM were less common, all without any sex and age bias; joint instability complications were more recurrent in adults. Some orthopedic features showed a high prevalence, whereas the other issues related to the investigated organ systems were less recurrent with few exceptions and age-related differences. Conclusions Our findings define the diagnostic relevance of cutaneous and articular features and additional clinical signs associated to cEDS. Furthermore, our data suggest an update of the current EDS nosology concerning scarring that should be considered separately from skin hyperextensibility and that the clinical diagnosis of cEDS may be enhanced by the accurate evaluation of orthopedic manifestations at all ages, faciocutaneous indicators in children, and some acquired traits related to joint instability complications, premature skin aging, and patterning of abnormal scarring in older individuals.

Joint hypermobility syndrome/Ehlers-Danlos syndrome hypermobility type (JHS/EDS-HT), is likely the most common systemic heritable connective tissue disorder, and is mostly recognized by generalized joint hypermobility, joint instability complications, minor skin changes and a wide range of satellite features. JHS/EDS-HT is considered an autosomal dominant trait but is still without a defined molecular basis. The absence of (a) causative gene(s) for JHS/EDS-HT is likely attributable to marked genetic heterogeneity and/or interaction of multiple loci. In order to help in deciphering such a complex molecular background, we carried out a comprehensive immunofluorescence analysis and gene expression profiling in cultured skin fibroblasts from five women affected with JHS/EDS-HT. Protein study revealed disarray of several matrix structural components such as fibrillins, tenascins, elastin, collagens, fibronectin, and their integrin receptors. Transcriptome analysis indicated perturbation of different signaling cascades that are required for homeostatic regulation either during development or in adult tissues as well as altered expression of several genes involved in maintenance of extracellular matrix architecture and homeostasis (e.g., SPON2, TGM2, MMP16, GPC4, SULF1), cell-cell adhesion (e.g., CDH2, CHD10, PCDH9, CLDN11, FLG, DSP), immune/inflammatory/pain responses (e.g., CFD, AQP9, COLEC12, KCNQ5, PRLR), and essential for redox balance (e.g., ADH1C, AKR1C2, AKR1C3, MAOB, GSTM5). Our findings provide a picture of the gene expression profile and dysregulated pathways in JHS/EDS-HT skin fibroblasts that correlate well with the systemic phenotype of the patients.

Reflectance confocal microscopy (RCM) is a novel noninvasive technique for “in vivo” examination of the skin. In a confocal microscope, near‐ infrared light from a diode laser is focused on a microscopic skin target. As this light passes between cellular structures having different refraction indexes, it is naturally reflected, and this reflected light is then captured and recomposed into a two‐dimensional gray scale image by computer software. Focusing the microscope (adjusting the focal point on the z‐axis) allows images to be obtained of different levels within the skin. Commercially available microscope systems of this type can create images with enough detail for use in histological analysis. The first investigations using these microscopes served to identify the appearance of the various cell populations living in the different layers of normal skin. Today, the main interest has become focused on the use of these microscopes as a diagnostic tool: a means of investigating benign and malignant tumors of melanocytes and keratinocytes, and, more importantly, the findings of this field of study can be used to develop a diagnostic algorithm which would be not only highly sensitive but specific as well. The aim of the paper is to provide an updated literature review and an in‐depth critique of the state‐of‐the‐art of RCM for skin cancer imaging with a critical discussion of the possibilities and limitations for clinical use.

Background Orf virus (ORFV) is the pathogen responsible for Orf, a zoonotic viral infection that can be spread to humans from sheep and goats. Here, we present a case of human Orf complicated by an immune-related reaction, to raise awareness of this under-recognized disease avoiding unnecessary investigations and overtreatment. Case report A 51-year-old woman with no previous medical history presented with a one-week history of three asymptomatic swelling nodules with a grey necrotic center and red outer halo on her index finger. At physical examination there was also a pruritic papulovesicular eruption on her hands and feet. She reported a recent contact with a goat which had a similar nodular lesion in its mouth. A biopsy of the lesions was performed and a diagnosis of Orf complicated by widespread erythema multiforme was made based on the clinical and histopathological features. The lesions spontaneously resolved within the next 2 weeks. Conclusions Orf is not very prevalent in our region, so we performed a biopsy of the lesion to guide us toward a diagnosis. However, we should remember that the diagnosis of ecthyma relies on clinical evaluation and epidemiological criteria.

Background Spondylodysplastic EDS (spEDS) is a rare connective tissue disorder that groups the phenotypes caused by biallelic B4GALT7 , B3GALT6, and SLC39A13 mutations. In the 2017 EDS nosology, minimal criteria (general and gene-specific) for a clinical suspicion of spEDS have been proposed, but molecular analysis is required to reach a definite diagnosis. The majority of spEDS patients presented with short stature, skin hyperextensibility, facial dysmorphisms, peculiar radiological findings, muscle hypotonia and joint laxity and/or its complications. To date only 7 patients with β4GALT7-deficiency (spEDS- B4GALT7 ) have been described and their clinical data suggested that, in addition to short stature and muscle hypotonia, radioulnar synostosis, hypermetropia, and delayed cognitive development might be a hallmark of this specific type of spEDS. Additional 22 patients affected with an overlapping phenotype, i.e., Larsen of Reunion Island syndrome, all carrying a homozygous B4GALT7 mutation, are also recognized. Results Herein, we report on a 30-year-old Moroccan woman who fitted the minimal criteria to suspect spEDS, but lacked radioulnar synostosis and intellectual disability and presented with neurosensorial hearing loss and limb edema of lymphatic origin. Sanger sequencing of B4GALT7 was performed since the evaluation of the spEDS gene-specific minor criteria suggested this specific subtype. Mutational screening revealed the homozygous c.829G>T, p.Glu277* pathogenetic variant leading to aberrant splicing. Conclusions Our findings expand both the clinical and mutational spectrum of this ultrarare connective tissue disorder. The comparison of the patient’s features with those of the other spEDS and Larsen of Reunion Island syndrome patients reported up to now offers future perspectives for spEDS nosology and clinical research in this field.

We tested the hypothesis that increasing the exercise dose or changing the exercise mode would augment hypotensive effects when traditional aerobic exercise training failed to produce it in postmenopausal women. Sixty-five postmenopausal women with essential hypertension were randomly allocated into the continuous aerobic training (CAT) and non-exercising control (CON) groups. CAT group cycled at moderate intensity 3 times a week for 12 weeks. Individuals who failed to decrease systolic blood pressure (BP) were classified as non-responders (n = 34) and performed an additional 12 weeks of exercise training with either increasing the exercise dose or changing the exercise mode. The 3 follow-up groups were continuous aerobic training 3 times a week, continuous aerobic training 4 times a week, and high-intensity interval training. After the first 12 weeks of exercise training, systolic BP decreased by 1.5 mmHg (NS) with a wide range of inter-individual responses (-23 to 23 mmHg). Sixty-seven percent of women who were initially classified as non-responders participated in the second training period. Sixty percent of women who participated in continuous exercise training 3 or 4 times a week at greater exercise intensities reduced systolic BP. All (100%) of the women who performed high-intensity interval training experienced significant reductions in systolic BP. Traditional aerobic exercise was not sufficient to decrease BP significantly in the majority of postmenopausal women. However, those women who were not sensitive to recommended exercise may reduce BP if they were exposed to continuous aerobic exercise at higher intensities and/or volumes or a different mode of exercise.

Recent studies have begun to identify the molecular determinants of inter-individual variability of cardiorespiratory fitness (CRF) in response to exercise training programs. However, we still have an incomplete picture of the molecular mechanisms underlying trainability in response to exercise training. We investigated baseline serum and skeletal muscle metabolomics profile and its associations with maximal power output (MPO) gains in response to 8-week of continuous endurance training (ET) and high-intensity interval training (HIIT) programs matched for total units of exercise performed (the TIMES study). Eighty healthy sedentary young adult males were randomized to one of three groups and 70 were defined as completers (> 90% of sessions): ET (n = 30), HIIT (n = 30) and control (CO, n = 10). For the CO, participants were asked to not exercise for 8 weeks. Serum and skeletal muscle samples were analyzed by 1H-NMR spectroscopy. The targeted screens yielded 43 serum and 70 muscle reproducible metabolites (intraclass > 0.75; coefficient of variation < 25%). Associations of baseline metabolites with MPO trainability were explored within each training program via three analytical strategies: (1) correlations with gains in MPO; (2) differences between high and low responders to ET and HIIT; and (3) metabolites contributions to the most significant pathways related to gains in MPO. The significance level was set at P < 0.01 or false discovery rate of 0.1. The exercise programs generated similar gains in MPO (ET = 21.4 ± 8.0%; HIIT = 24.3 ± 8.5%). MPO associated baseline metabolites supported by all three levels of evidence were: serum glycerol, muscle alanine, proline, threonine, creatinine, AMP and pyruvate for ET, and serum lysine, phenylalanine, creatine, and muscle glycolate for HIIT. The most common pathways suggested by the metabolite profiles were aminoacyl-tRNA biosynthesis, and carbohydrate and amino acid metabolism. We suggest that MPO gains in both programs are potentially associated with metabolites indicative of baseline amino acid and translation processes with additional evidence for carbohydrate metabolism in ET.

The term linkeropathies (LKs) refers to a group of rare heritable connective tissue disorders, characterized by a variable degree of short stature, skeletal dysplasia, joint laxity, cutaneous anomalies, dysmorphism, heart malformation, and developmental delay. The LK genes encode for enzymes that add glycosaminoglycan chains onto proteoglycans via a common tetrasaccharide linker region. Biallelic variants in XYLT1 and XYLT2, encoding xylosyltransferases, are associated with Desbuquois dysplasia type 2 and spondylo-ocular syndrome, respectively. Defects in B4GALT7 and B3GALT6, encoding galactosyltransferases, lead to spondylodysplastic Ehlers-Danlos syndrome (spEDS). Mutations in B3GAT3, encoding a glucuronyltransferase, were described in 25 patients from 12 families with variable phenotypes resembling Larsen, Antley-Bixler, Shprintzen-Goldberg, and Geroderma osteodysplastica syndromes. Herein, we report on a 13-year-old girl with a clinical presentation suggestive of spEDS, according to the 2017 EDS nosology, in whom compound heterozygosity for two B3GAT3 likely pathogenic variants was identified. We review the spectrum of B3GAT3-related disorders and provide a comparison of all LK patients reported up to now, highlighting that LKs are a phenotypic continuum bridging EDS and skeletal disorders, hence offering future nosologic perspectives.

Sun exposure is the main risk factor for cutaneous malignant melanoma (CMM). However, the UV-related pathogenetic mechanisms leading to CMM are far to be fully elucidated. In this paper we will focus on what we still don't fully know about the relationship between UVR and CMM. In particular, we will discuss: the action spectrum of human CMM, how different modalities of exposure (continuous/ intermittent; erythemal/ suberythemal) relate to different CMM variants, the preferential UVR induced DNA mutations observed in different CMM variants, the role of UV-related and UV-unrelated genetic damages in the same melanoma cells. Moreover, we will debate the importance of UVA induced oxidative and anaerobic damages to DNA and other cell structures and the role of melanins, of modulation of innate and acquired immunity, of vitamin D and of chronic exposure to phototoxic drugs and other xenobiotics. A better understanding of these issues will help developing more effective preventative strategies and new therapeutic approaches.