Inspiratory muscle strength training improves lung function in patients with the hypermobile Ehlers-Danlos syndrome: A randomized controlled trial.

As exertional inspiratory dyspnea is a common disabling complaint in hypermobile Ehlers-Danlos syndrome (hEDS) often also known as joint hypermobility syndrome (JHS), we investigated inspiratory muscle (IM) strength in patients with hEDS, and we assessed the effects of IM training (IMT) on IM strength, lung function, and exercise capacity. A prospective evaluation of IM strength followed by a randomized controlled trial of IMT was performed in women with hEDS. Sniff nasal inspiratory pressure (SNIP) was used to routinely measure IM strength and IMT was carried out using a pressure threshold device. IM strength (main outcome), cardiopulmonary function, exercise capacity, and emotional distress of both the treated and control groups were evaluated at the start and at the end of the 6-week training period. IM strength was reduced (<80% of predicted) in 77% of patients (80/104). Lung function was normal, although 24% of patients had a higher forced expiratory vital capacity (FVC) than normal and 12% of patients had a higher total lung capacity (TLC) than normal. Both the IMT and control groups (n = 20) had similar baseline characteristics. Significant changes were noted only in the IMT group after IMT. At the end of the program, IMT improved SNIP (20%) (before: 41 ± 17 cm H2 O [28, 53] vs. after: 49 ± 18 cm H2 O [34;65]), six-minute walking distance (6MWD) (60 m) (455 ± 107 m [379,532] vs. 515 ± 127 m [408, 621]), and forced expiratory volume in one second (FEV1) (285 mL) (94 ± 14% pred [84,104] vs. 103 ± 11% pred [94, 112]). IM strength is significantly reduced in patients with hEDS. IMT improved IM strength, lung function, and exercise capacity. Our findings suggest that IMT should be added to usual care.

Hedgehog- and mTOR-targeted therapies for advanced basal cell carcinomas.

Basal cell carcinomas (BCCs) are the most frequent human cancer. Over 90% of all BCCs have a mutation in PTCH1 or smoothened, two conducting proteins of the Hedgehog pathway. They rarely progress deeply and metastasize; however, if they do, these advanced basal cell carcinoma become amenable to treatment by inhibiting the Hedgehog and the P13K-mTOR pathways. Such innovative drugs include vismodegib, cyclopamine, itraconazole, everolimus and a few other agents that are in early clinical development.

Protomyofibroblast Pathway in Early Thermal Burn Healing.

Wound healing following partial thickness thermal burns is commonly hampered by the risk of hypertrophic scarring. Skin myofibroblast (MF) density is commonly increased in postburn healing. The transition between fibroblast-like cells and α-smooth muscle actin (SMA)+ MF possibly begins with CD14+ monocytes, evolving to CD14+ CD34+ fibrocytes, followed by ß-SMA+ protomyofibroblast (PMF) maturation. Skin biopsies from 25 burn patients were collected about 1 and 4 weeks after injury. Immunohistochemistry was performed using monoclonal antibodies to α-SMA, ß-SMA, factor XIIIa, lysozyme, Mac 387, CD14, CD117 and Ulex europaeus agglutinin-1 (UEA-1). The set of Mac 387+ and CD14+ monocytes was accompanied by both CD34+ fibrocytes and factor XIIIa+ dendrocytes. By contrast, ß-SMA+ PMF were rare. Of note, α-SMA+ MF were more abundant at week 4 than at week 1 (p < 0.01). The UEA-1+ endothelial cells showed marked variations in their dermal distribution, irrespective of the densities in the other scrutinized cells. In conclusion, healing of partial thickness thermal burns involves a diversity of cell types including PMF. In the present samples, the PMF density remained low. © 2015 S. Karger AG, Basel.

Dermal ultrastructure in collagen VI myopathy.

The COL VI mutations are responsible for a spectrum of myopathies. The authors report cutaneous ultrastructural alterations in a patient with COL6A2 myopathy. The changes include variations in size of collagen fibrils, flower-like sections of collagen fibrils, as well as thickening of vessel and nerve basement membranes. Electron microscopy of a skin biopsy contributes to the diagnosis of COL VI myopathies.

Cyanoacrylate skin surface stripping and the 3S-Biokit advent in tropical dermatology: a look from Liège.

In the dermatopathology field, some simple available laboratory tests require minimum equipment for establishing a diagnosis. Among them, the cyanoacrylate skin surface stripping (CSSS), formerly named skin surface biopsy or follicular biopsy, represents a convenient low cost procedure. It is a minimally invasive method collecting a continuous sheet of stratum corneum and horny follicular casts. In the vast majority of cases, it is painless and is unassociated with adverse events. CSSS can be performed in subjects of any age. The method has a number of applications in diagnostic dermatopathology and cosmetology, as well as in experimental dermatology settings. A series of derived analytic procedures include xerosis grading, comedometry, corneofungimetry, corneodynamics of stratum corneum renewal, corneomelametry, corneosurfametry, and corneoxenometry.

Comprehensive clinical and molecular analysis of 12 families with type 1 recessive cutis laxa.

Autosomal recessive cutis laxa type I (ARCL type I) is characterized by generalized cutis laxa with pulmonary emphysema and/or vascular complications. Rarely, mutations can be identified in FBLN4 or FBLN5. Recently, LTBP4 mutations have been implicated in a similar phenotype. Studying FBLN4, FBLN5, and LTBP4 in 12 families with ARCL type I, we found bi-allelic FBLN5 mutations in two probands, whereas nine probands harbored biallelic mutations in LTBP4. FBLN5 and LTBP4 mutations cause a very similar phenotype associated with severe pulmonary emphysema, in the absence of vascular tortuosity or aneurysms. Gastrointestinal and genitourinary tract involvement seems to be more severe in patients with LTBP4 mutations. Functional studies showed that most premature termination mutations in LTBP4 result in severely reduced mRNA and protein levels. This correlated with increased transforming growth factor-beta (TGFß) activity. However, one mutation, c.4127dupC, escaped nonsense-mediated decay. The corresponding mutant protein (p.Arg1377Alafs(*) 27) showed reduced colocalization with fibronectin, leading to an abnormal morphology of microfibrils in fibroblast cultures, while retaining normal TGFß activity. We conclude that LTBP4 mutations cause disease through both loss of function and gain of function mechanisms.

Ustekinumab biotherapy and real-time psoriasis capacitance mapping: a pilot study.

In recent years, the treatment of moderate to severe psoriasis has benefited from the development of targeted biologicals. Assessing this new class of drugs calls for precise modalities of severity/improvement ratings of the disease. Bioengineering-driven dermometrology aims at improving objective and quantitative assessments of disease severity and treatment efficacy. Skin capacitance mapping/imaging is one of those emerging methods. Among its clinical applications, psoriasis capacitance mapping (PCM) was introduced in order to assess both skin scaliness and water trapping inside the stratum corneum (inflammatory serum deposits) on lesional skin. PCM was used for assessing the therapeutic effects of ustekinumab on target lesions of 5 psoriatic patients. The reduction in the inflammatory dampness of the stratum corneum was conveniently seen after a 1-month ustekinumab treatment. The present pilot study suggests that PCM could be used as a fast and convenient method for assessing the anti-inflammatory efficacy of ustekinumab and other biotherapies.

Challenging regional psoriasis and ustekinumab biotherapy: impact of the patterns of disease.

In some patients, psoriasis appears refractory to many treatments, particularly when the disease is confined to some specific body regions. In this respect, palmoplantar psoriasis and palmoplantar pustulosis are possibly related conditions in their immunopathomechanisms involving Il-12, IL-23, and Th17. Nail psoriasis and scalp psoriasis are two other particular psoriasis manifestations. Accordingly, ustekinumab was tested in a few of these patients. The present paper is limited to peer-reviewed case reports. Data were not supported by bioinstrumental assessments and controlled trials. Overall, they are indicative of potential efficacy. The cost-effectiveness and the risk-benefit assessments merit further investigations.

Dermal ultrastructure in low Beighton score members of 17 families with hypermobile-type Ehlers-Danlos syndrome.

The distinction between the Ehlers-Danlos syndrome hypermobile type (EDSH) and the benign joint hypermobility syndrome (BJHS) is unclear. The aim of the present study was to compare skin ultrastructural abnormalities of EDSH and BJHS among different families. Skin of 23 EDSH, 27 BJHS, and 41 asymptomatic subjects from 17 families was examined using transmission electron microscopy. Similar ultrastructural abnormalities were found irrespective of the Beighton score. Flower-like collagen fibrils represented the key change and elastic fibers were altered as well. Beighton score is a clinical parameter rating joint mobility that appeared unrelated to quantitative and qualitative collagen ultrastructural alterations in the skin. Some EDSH family members fit with BJHS diagnosis. BJHS possibly represents a mild variant of EDSH.

Ustekinumab in psoriasis immunopathology with emphasis on the Th17-IL23 axis: a primer.

Psoriasis is a chronic relapsing immunoinflammatory dermatosis that is commonly associated with systemic comorbidities. The pathogenic importance of interleukin (IL)-12 and IL-23 is beyond doubt, as well as the involvement of T helper cells (Th)1 and Th17 cells. There is upregulation of the p40 subunit shared by IL-12 and IL-23 and of the IL-23 p19 subunit, but not an increased expression of the IL-12 p35 subunit. This indicates that IL-23 appears more involved than IL-12 in the pathogenesis of psoriatic plaques. Ustekinumab is a fully human monoclonal antibody of the immunoglobulin (Ig) G1 class targeting the p40 subunit common to both IL-12 and IL-23, thus inhibiting both IL-12 and IL-23 receptor-mediated signalling. Ustekinumab is part of the recent biologic therapies active in psoriasis, autoimmune arthritides, and inflammatory bowel diseases.

Bioimpact of EGFR antagonists on the pilosebaceous follicles.

Cancer patients under targeted chemotherapy to the epidermal growth factor receptor (EGFR) frequently suffer from unusual skin adverse events. In the past, these changes were globally qualified as a rash. Our aim was to assess objectively by non invasive bioinstrumentation some early structural and functional skin changes associated with EGFR inhibitor treatment. A series of 27 cancer patients aged 58-66 years were assessed using two ultraviolet light emitting CCD cameras, Visioscan(®) and Visiopor(®). Assessments were performed on the foreheads at inclusion and therefore at weekly intervals for 2 months at most. No topical treatment was applied during the assessment period. The Visioscan(®) camera revealed specular light reflectance at the site of follicular plugging. The interfollicular stratum corneum showed occasional focal hyperkeratosis. These features increased in severity with the EGFR inhibitor treatment, indicating follicular involvement as an early adverse event of the therapy. The follicular fluorescence revealed by the Visiopor(®) camera remained unchanged over the treatment period. The present findings suggest an EGFR inhibitor-induced kerosis (follicular hyperkeratosis) possibly responsible for acneiform reactions.

Patterns of aluminum hydroxychloride deposition onto the skin.

BACKGROUND: Aluminum hydroxychloride (AlCl(3) ) is an antiperspirant. AIM: To revisit the AlCl(3) deposition in vivo and in vitro on glass slides and stratum corneum (SC) harvested by cyanoacrylate skin surface strippings (CSSS). METHODS: Transepidermal water loss (TEWL) was assessed following application of 5% AlCl(3) on the forearms. The AlCl(3) -coated skin, glass slides and CSSS were observed using two ultraviolet light-emitting CCD cameras in order to record changes in specular reflectance related to AlCl(3) deposition. In addition, the corneoxenometry bioassay was performed in order to predict AlCl(3) irritation. RESULTS: AlCl(3) deposited on glass slides looked as linear threads and rings of similar sizes. AlCl(3) deposits on skin were almost restricted inside the microrelief lines and as annular deposits at their crossings where acrosyringia are opening. After daily AlCl(3) applications, deposits extended on the CSSS plateaus. At rest in absence of sweating, TEWL was decreased following AlCl(3) applications. During physical exercise, the TEWL increase was limited on the AlCl(3) areas. CSSS appeared unreactive to AlCl(3) at the corneoxenometry bioassay. CONCLUSION: The similar aspect of AlCl(3) deposits on human SC and on glass slides suggested a physical property of AlCl(3) . Repetitive applications of AlCl(3) increased both the deposit area and the barrier function.

Field melanin mapping of the hairless scalp.

BACKGROUND: Mottled subclinical melanoderma (MSM) is frequently seen on facial skin using the ultraviolet light enhanced visualization (ULEV) method. The corresponding aspect on the hairless scalp remains unknown. OBJECTIVE: To explore the field distribution of melanin on the scalp of fair-skinned Caucasian subjects. METHOD: The scalp was examined in 43 men with androgenic alopecia. The Visioscan(®) camera provided the ULEV pictures. Another optical (Visioface(®) Quick) device was used under white light illumination followed by colour contrast enhancement. This was reached after specific computer filtration of the cyan hue wavelengths. RESULTS: Under white light illumination, the scalp looked normal. MSM patterns were disclosed by both optical procedures as evenly scattered discrete patchy fields of hypermelanosis. The smaller rounded spots were restricted to the lips of the hair infundibula. Larger irregularly shaped spots predominated in the interfollicular areas. A few hypomelanotic spots were scattered over the scalp. CONCLUSION: The present observations based on dual optical methods possibly provide information about a patterned pathobiology of melanocytes on the scalp. The spotty MSM pattern looked similar to the reported aspects on the face. It somewhat resembled the widespread PUVA-induced lentiginosis.

Recent trends in specular light reflectance beyond clinical fluorescence diagnosis.

Under specific light illumination, particularly ultraviolet (UV) and near-UV light stimulation, the skin produces both specular light reflectance and, possibly, specific fluorescent emission. These properties offer diagnostic clues and disclose some peculiar functions of the skin. A series of superficial infections (erythrasma, some tinea capitis types, tinea/pityriasis versicolor, dermatophytoses, etc.) and pilosebaceous follicles enriched in Propionibacterium spp show fluorescence. This latter characteristic is downgraded or lost while on some anti-acne treatments. A quenching effect of fluorescence is observed following the application of sunscreens. The (pre)neoplastic areas prepared for methylaminolevulinate photodynamic therapy (MAL-PDT) show reddish fluorescence following drug metabolisation producing porphyrins by the abnormal activated cells. Of note, when using a recording sensitive CCD camera instead of casual visual observation, skin fluorescence may be superimposed on the specular reflectance of the incident light. With the current technology, these situations are not distinguished with confidence. Any harsh and scaly lesion appears brighter following yellowish specular light reflectance. Stratum corneum samplings collected on clear self-adhesive discs or cyanoacrylate skin surface strippings are conveniently examined ex vivo, taking advantage of the same optical properties.

Photoaging under recreational sunbeds.

BACKGROUND: Artificial sources of restricted light wavelength, particularly tanning beds, are progressively gaining importance in photoaging. OBJECTIVE: To assess the kinetics and the long-term evolution of skin pigmentation and tensile functions in sunbed worshippers over a period of 8 years. METHODS: Photoaging was explored in women who were both sunshine and sunbed worshippers. A series of 65 phototype III women aged 31-46 years completed a 100-month survey. Quarterly assessments were performed on the forearms to measure (a) the skin color individual typology angle (ITA°), (b) the extent in mottled subclinical melanoderma (MSM) using the ultraviolet light-enhanced visualization method and (c) the rheological properties of skin. RESULTS: A progressive increase in both skin extensibility and hysteresis was observed, contrasting with a decrease in biologic elasticity. These rheological changes were correlated with the ITA° changes, but not with the MSM extent. The kinetics of evolution of each test variable were distinct over time. DISCUSSION: This work is the first attempt at evaluating the kinetics of changes in physical parameters during a long period of frequent exposures to tanning sunbeds and sunshine for lifestyle purposes. The alterations were quite important in the color, MSM and rheological functions of the skin.

Facing up to the imperceptible perspiration. Modulatory influences by diabetic neuropathy, physical exercise and antiperspirant.

BACKGROUND: Sweating is variably altered by physical exercise, diabetic neuropathy and antiperspirants. METHODS: Skin temperature, skin surface water loss (SSWL), the Corneometer(®) average capacitance (CMAC) and skin capacitance mapping (SCM) were measured before and after moderate physical exercise in 20 healthy subjects. The effect of 5% aluminium chloride hexahydrate (ACH) in a water solution was similarly tested. The same assessments were performed in 20 diabetic patients at rest. RESULTS: Diabetic neuropathy appeared at rest as an increased (compensatory) SCM on the forearms without obvious modification on the hypohidrotic legs. On ACH sites after exercise, SCM revealed both a lowered number of active sweat glands and a lighter stratum corneum (SC) (dryness). In addition, CMAC and SSWL were decreased on ACH sites at rest and at completion of exercise. CONCLUSION: In diabetic neuropathy, the compensatory hyperhidrosis is more easily disclosed than the hypohidrosis. ACH affects both sweat excretion and the SC hydration.

The skin landscape following nonoptical capacitance imaging.

Skin capacitance is an electrical property measurable at the level of the stratum corneum. Values are related to the moisture content of the tissue. Using the silicon image sensor technology, it has recently become possible to measure capacitance at 50 microm intervals on the skin surface. The resulting nonoptical picture corresponds to skin capacitance imaging. This novel tool for dermatologists highlights with precision the hollow skin surface patterns, including dermatoglyphics, the patterns of the shallow skin lines, and wrinkles. The topographic heterogeneity in skin surface hydration is made visible. In addition, the sweat gland and follicular openings are disclosed. Skin disorders induced by surfactants or presenting as hyperkeratotic areas, including some neoplasms, may show typical aspects. It is concluded that skin capacitance imaging brings added value to the clinical assessment performed by dermatologists.

Functionally active macrophage-derived myeloperoxidase in the skin of drug-induced toxic epidermal necrolysis.

BACKGROUND: Drug-induced toxic epidermal necrolysis (TEN) probably results from a complex and specific immune cell reaction involving lymphocytes and macrophages. OBJECTIVE: To assess the functional role of macrophages in TEN. METHODS: Immunohistochemistry was performed on biopsies from early blisters developed in 9 TEN patients. The amount of extracellular myeloperoxidase (MPO) was measured by ELISA in TEN blister fluid and serum. Controls were blister fluids taken from 9 second-degree burns. In addition, 3-chlorotyrosine (a specific marker of MPO activity) was searched for using liquid mass chromatography both in TEN and burn blister fluids. RESULTS: Immunohistochemistry revealed numerous CD68+ macrophages in 8/9 TEN patients; 5-20% of these cells and rare CD15+ neutrophils exhibited MPO immunoreactivity, while keratinocytes were negative. The amount of MPO was significantly higher in TEN blister fluid than in TEN serum, suggesting macrophage production of MPO in the skin. In addition, MPO was significantly more abundant in TEN blister fluid than in burn blister fluid. 3-Chlorotyrosine was detected in 7/9 TEN blister fluids, but in only 2/9 burn blister fluids. DISCUSSION: MPO produced by macrophages was functionally active in most TEN patients, leading to the production of hypochlorous acid, a potent oxidative compound that alters keratinocytes.

Angiogenic fast-growing melanomas and their micrometastases.

Malignant melanoma (MM), particularly its fast-growing type, is prone to interstitial, intravascular and extravascular migratory metastases. There is no information linking their growth fraction, the configuration of the MM advancing edge, the extent in vascularity and the propensity to metastatic progression. The objective of this study was to determine the growth fraction, the size of vascularity and the contours of the progression border of 32 fast-growing MM with regard to the presence or absence of a micrometastatic spread inside the skin and overt metastases in the sentinel lymph nodes. In vivo high resolution colorimetry was performed as a clinical estimate of MM vascularity. Euclidean geometry and fractal analysis were used on immunohistochemical sections. The relative microvasculature profile area beneath MM, and the fractal dimension D of the MM frontline were assessed. The MIB/Ki-67 index was determined in MM cells. Value a* of colorimetry was similarly increased in the presence or absence of micro-metastases. No difference in growth fraction was revealed between these neoplasms. Correlations were found between vascularity and angiotropism, and between the micrometastatic process and the sentinel lymph node involvement. By contrast, no correlation was shown between vascularity and the fractal D dimension of the MM advancing edge. In sum, this study establishes a link between the extent of MM growth fraction, vascularity and the presence of dermal and nodal micrometastases in fast-growing MM.

Updating corneofungimetry: a bioassay exploring dermatomycoses and antifungal susceptibility.

Superficial dermatomycoses are frequent conditions in humans and animals. Specific treatment modalities have been designed using a variety of different antifungal compounds. The need for antifungal susceptibility testing (AST) has been growing steadily over the last two decades due to the extending number of newer antifungal agents. Objective inter- and intraindividual comparisons of their respective efficacies are nearly impossible to perform in vivo. Currently, a series of standardized AST methods and interpretative guidelines have been designed. However, their clinical relevance for dermatomycoses is not consistent. The corneofungimetry bioassay was designed to test comparatively a series of antifungals on pathogenic fungi growing on sheets of human stratum corneum. Computerized morphometric assessments bring numerical values allowing statistical comparisons. Variants of corneofungimetry address more specific aspects related to fungal cell adhesion, fungitoxicity and lipid-dependent fungi.