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Caractéristiques physico-chimiques, genèse et conséquences tissulaires des dépôts cutanés calciques
Abstract
Bien que de nombreuses pathologies dermatologiques soient associées à des dépôts cutanés pathologiques, endogènes ou exogènes, ceux-ci restent mal décrits. Leur taille sub-micrométrique ainsi que leur diversité de composition chimique nécessitent l’utilisation de divers outils physico-chimiques pour en permettre une caractérisation complète. Notre objectif est d’apporter une caractérisation physico-chimique multi échelle du micromètre au nanomètre, mais aussi d’explorer la genèse et les conséquences tissulaires de ces dépôts en utilisant différentes techniques afin d’en extraire un message clinique. Après avoir présenté les connaissances actuelles sur ces dermatoses calcifiantes et décrit les principes de la microscopie électronique à balayage couplée à la spectroscopie de rayons X à dispersion d'énergie et des spectroscopies vibrationnelles, nous présentons l’application de ces outils à quatre dermatoses différentes : calciphylaxie, ulcères de jambe calcifiés, calcinosis cutis sur nécrolyse épidermique et sarcoïdose. L’ensemble de nos résultats montrent que les dépôts cutanés endogènes sont principalement composés de carbapatite, dont l’aspect ultra-structural correspond à des nano-sphérules phospho-calciques s’agrégeant pour former des plaques de dimension micronique. Ces dépôts présentent un tropisme vis-à-vis des fibres élastiques que des études complémentaires par microscopie multiphoton permettront d’explorer. Ces résultats originaux permettent de mieux comprendre la physio genèse des calcifications cutanées, mais également d’envisager des méthodes de diagnostic ainsi que des pistes thérapeutiques.
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Shampoo is a hair care product designed to clean the skin and hair of the scalp. Among the ingredients that go into the making of a shampoo are detergents, conditioners, thickeners, sequestering agents, pH adjusters, preservatives, and active ingredients such as anti-dandruff agents. The purpose of this study was to identify the composition of 140 shampoos available in pharmacies, in stores of a mass-market chain, or from mail-order retailers. Forty-one shampoos were advertised as "gentle", 12 as specially formulated for infants, 35 as anti-dandruff, and 52 without any particular claim. We analysed the cleansing base, preservatives, and anti-dandruff agents when relevant and identified the allergens regardless of whether or not they are listed under Regulation (EC) No. 1223/2009 as one of the 26 regulated substances. We discovered that unlike shampoos sold in stores of a mass-market chain and those available from mail-order retailers, those sold in pharmacies expose users to some of the 26 substances listed under Regulation (EC) No. 1223/2009. We also determined that baby shampoos sold in pharmacies are allergen-free. Regarding anti-dandruff formulations, the largest variety of active ingredients was found in shampoos sold in pharmacies. Overall, the most common active ingredients were olamines, zinc pyrithione, azoles, selenium disulphide, and plant extracts. Shampoos sold in pharmacies appear to contain fewer allergens listed under Regulation (EC) No. 1223/2009 compared to those sold elsewhere.
In recent years, tattoos have become more commonplace. However, this can result in various inflammatory processes, the management of which can be challenging in daily clinical practice. Tattoo-related inflammatory reactions can comprise different patterns, including acute and immediate reactions, foreign body granulomas, sarcoid granulomas, isomorphic lesions, allergic contact dermatitis and photosensitivity. We report three cases who were referred to the Dermatology Outpatient Clinic of the Hospital Universitario San Cecilio, Granada, Spain, in 2017 with various skin reactions in the red-ink areas of their tattoos. Screening was performed for infectious diseases like atypical mycobacterial infections and systemic processes such as sarcoidosis. A good therapeutic response was achieved in all cases. An adequate differential diagnosis is essential for the therapeutic management of this emerging health problem.
Keywords: Non-Therapeutic Body Modification; Tattooing, adverse effects; Inks; Foreign Body Reaction; Inflammation; Case Report; Spain.
Recent studies showed that critically ill patients might be at risk for hemodynamic impairment during Caspofungin (CAS) therapy. The aim of our present study was to examine the mechanisms behind CAS induced cardiac alterations. We revealed a dose dependent increase in [Ca ²⁺ ] i after CAS treatment. Ca ²⁺ ions were found to be released from intracellular caffeine sensitive stores most probably via activation of ryanodine receptors.
A drug-induced sarcoidosis-like reaction (DISR) is a systemic granulomatous reaction that is indistinguishable from sarcoidosis and occurs in temporal relationship with initiation of an offending drug. DISRs typically improve or resolve after the withdrawal of offending drug. Four common categories of drugs that have been associated with the development of a DISR are immune checkpoint inhibitors (ICIs), highly active anti-retroviral therapy (HAART), interferons (IFNs) and tumor necrosis factor alpha antagonists (TNF-alpha antagonists). Similar to sarcoidosis, DISRs do not necessarily require treatment, as they may cause no significant symptoms, quality of life impairment or organ dysfunction. When treatment of a DISR is required, standard anti-sarcoidosis regimens seem to be effective. As a DISR tends to improve or resolve when the offending drug is discontinued, this is another effective treatment for a DISR. However, the offending drug need not be discontinued if it is useful, and anti-granulomatous therapy can be added. In some situations, the development of a DISR may suggest a beneficial effect of the inducing drug. Understanding the mechanisms leading to DISRs may yield important insights into the immunopathogenesis of sarcoidosis.
Severe asthma constitutes illness in a relatively small proportion of all patients with asthma, but it is a major public health problem – with considerable effect on morbidity, mortality, as well as a high burden on health care resources. Regardless of effective treatments being widely available and the existence of treatment guidelines, a large population of severe asthma cases remain uncontrolled. Achieving and maintaining asthma control in this group of patients is, therefore, of utmost importance. The recognition of distinct inflammatory phenotypes within this population has driven the development of targeted biological therapies – particularly, selective targeted monoclonal antibodies (mAbs). It is noteworthy that in approximately 50% of these patients, there is strong evidence of the pathogenic role of T helper type-2 (Th2) cytokines, such as interleukin (IL)-4 and IL-13, orchestrating the eosinophilic and allergic inflammatory processes. Among the recently developed antiasthma biologic drugs, the mAb dupilumab is very promising given its ability to inhibit the biological effects of both IL-4 and IL-13. In this review, we focused on IL-4 and IL-13, as these interleukins are considered to play a key role in the pathophysiology of asthma, and on dupilumab, an anti-IL-4 receptor human mAb, as a forthcoming treatment for uncontrolled severe asthma in the near future.
The new rapid scan method, Flyscan mode, implemented on the DiffAbs beamline at Synchrotron SOLEIL, allows fast micro-X-ray fluorescence data acquisition. It paves the way for applications in the biomedical field where a large amount of data is needed to generate meaningful information for the clinician. This study presents a complete set of data acquired after injection of gold-cluster-enriched mesoporous silica nanospheres, used as potential theranostic vectors, into rats. While classical X-ray fluorescence investigations (using step-by-step acquisitions) are based on a limited number of samples (approximately one per day at the DiffAbs beamline), the Flyscan mode has enabled gathering information on the interaction of nanometer-scale vectors in different organs such as liver, spleen and kidney at the micrometer scale, for five rats, in only a single five-day synchrotron shift. Moreover, numerous X-ray absorption near-edge structure spectra, which are beam-time-consuming taking into account the low concentration of these theranostic vectors, were collected.
As asserted by numerous authors, Fourier Transform (FT)-Raman and FT-Infrared spectroscopies
constitute two useful tools for bio-medical diagnostics. We can distinguish two
different kinds of application, namely, tissue disorders analyzed using statistical methods,
and detection of ectopic calcifications through precise analysis of the shape and the position
of absorption bands. In this contribution, we present some new results regarding
these research themes, as well as recent experimental developments, such as the ability to
perform nanometer scale near-field infrared microscopy, which have already led to major
scientific breakthroughs.
Sarcoidosis is a multisystem inflammatory disease affecting different organs particularly lung, skin, eyes and joints. Characterized by noncaseating epithelioid granulomas, sarcoidosis is considered to be caused by a complex interplay between genetics and environmental agents while it still remains a disease of unknown etiology. 10 skin biopsies from patients with cutaneous sarcoidosis were included in the study. After polarized light examination (PLE) through optical microscopy, these skin biopsies have been investigated through μFourier transform (FTIR) infrared spectroscopy and Field Emission Scanning Electron Microscopy coupled with Energy Dispersive X-ray Spectroscopy (FE-SEM/EDX). Three biopsies showed a refractive material at PLE. FTIR and FE-SEM/EDX analyses indicate the presence of silica at the center of the granulomas in these three biopsies. Another striking result is related to the presence of calcite, a calcium carbonate at the periphery of the granulomas. To our best knowledge, this is the first time that the presence of this calcium carbonate has been reported. Such description at the submicrometer scale paves the way for a better understanding of the physicochemical processes related to sarcoidosis and will help clinicians to develop new diagnostic tools.
Among the different techniques specific to synchrotron radiation, the combination of X-ray absorption spectroscopy with X-ray scattering experiments is a powerful tool to characterize samples with a capability to gather structural and electronic information at the cellular level. In the present contribution, selected examples making use of such techniques point out as well the information that one can have access to. Via the presentation of the physicochemical data, this paper focuses on displaying the information that has a significant clinical character.
If imaging by physical methods is probably the best well-known link between physics and medicine, other ways such as X-ray fluorescence and diffraction techniques give significant information to clinicians. In this contribution, we would like to assess different results obtained through such techniques on three main problems in urology namely Randall's plaque, brushite kidney stones and phase conversion between weddellite and whewellite. Randall's plaque is a mineral deposit at the surface of the renal papilla which is responsible for the prevalence increase of kidney stones among young people. X-ray fluorescence suggests that an inflammation process is related to Randall's plaque. X-ray fluorescence shows that brushite stones, well known to be related to some pathologies or biochemical disorders, could also be related to unexpected conditions as suggested, for example, by the high content of Br found in several brushite stones. Such results deserve further investigations to explain the origin of that element in the stones. Regarding the phase conversion from weddellite to whewellite, X-ray fluorescence data suggest that trace elements initially present in the stone remain for the major part in situ during the conversion process, which may be clinically relevant to relate the crystalline phase and etiology. X-ray fluorescence and diffraction experiments can thus give significant clues to the clinicians. These examples as well as other investigations assessed in this contribution underline a typical scientific transfer between a physics laboratory and hospital.
Breast calcifications, defined as calcium deposits within breast tissue, can arise from a vast number of aetiologies. Diffuse or scattered distribution is typically seen in benign entities. Approximately 95% of all Ductal carcinoma-in-situ, which represents 25–30% of all reported breast cancers are diagnosed because of mammographically detected microcalcifications. In this investigation dedicated to breast calcifications, we assessed at the micrometer scale their chemical nature through last generation micro-Fourier transform Infrared microspectroscopy and their structural characteristics through last generation field emission scanning electron microscopy. Several striking results have been obtained. Heavily mineralized deposits seem to be the result of the agglomeration of micrometer scale spherules and for the first time, we show that micrometer scale spherules display very different internal structure. Moreover, while Ca phosphate apatite and calcium oxalate dihydrate are the two chemical phases usually reported, we underline the presence of a third chemical phase namely amorphous carbonated calcium phosphate. In the case of duct carcinoma in situ (DCIS), the chemical composition as well as the carbonate level are very inhomogeneous even inside micrometer scale breast calcifications. Moreover, for some samples related to DCIS, special features at the micrometer scale seem to be related to this pathology because they were not found for the other pathologies.
Crystal formation in kidney tissue is increasingly recognized as a major cause of severe or acute renal failure. Kidney biopsies are currently performed and analyzed using different staining procedures. Unfortunately, none of these techniques are able to distinguish the different Ca phosphates (e.g., amorphous or nanostructured Ca phosphate apatite, octacalcium phosphate, brushite…) or Ca oxalates (whewellite and weddellite). Moreover, the crystal’s morphology, a structural parameter proven as a major information to the clinician regarding kidney stones, is not taken into account. Such major limitations call for a different research approach, based on physicochemical techniques. Here we propose classical observations through field-emission scanning electron microscopy experiments combined with energy dispersive spectroscopy as well as measurements through Raman and μFourier transform Infra-Red Spectroscopy. If necessary, in the case of microcrystals, observations using cutting edge technology such as Synchrotron Radiation (SR) – FTIR or SR-UV visible spectroscopy can be subsequently performed on the same sample. Taken together this set of diagnostic tools will help clinicians gather information regarding the nature and the spatial distribution at the subcellular scale of different chemical phases present in kidney biopsies as well as on the crystal morphology and therefore obtain more precise diagnosis.
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https://laboutique.edpsciences.fr/editeur/12/GN-MEBA
Summary of the book in English then in French
English:
Scanning electron microscopy and associated microanalyses are involved in a wide variety of fields, both in academic and industrial environments. All the theoretical bases, the main technical characteristics, as well as practical supplements of use and maintenance related to these disciplines are developed in this book. The electron microscopes under high vacuum or controlled vacuum are exposed deeply, the micro-analyzes EDS and WDS of the last generations also. In addition to these structural pillars, other analytical or observation techniques, such as EBSD and 3D imaging, FIB, Monte Carlo simulations and in-situ tests, are discussed.
This unique volume is completely new volume of nearly 1000 pages, as regards to a previous edition of 1979, which is now out of print. It brings together the courses taught at the Saint Martin d'Hères summer school in 2006, organized by the National Group of Scanning Electron Microscopy and microAnalyses (GN-MEBA). This book is particularly recommended for experimenters but will also be of interest to materials scientists (hard or soft, conductors or non-conductors, laminates, etc.) wishing to invest themselves in all these imaging and analysis techniques, to fully exploit their potential strengths. It has been written by summer school teachers, all researchers or engineers and specialists in their field.
This work is part of a collection of GN-MEBA publications devoted to principles, experimental techniques and calculation and simulation methods in Scanning Electron Microscopy and Microanalyses.
Français
La microscopie électronique à balayage et les microanalyses associées sont impliquées dans des domaines extrêmement variés, aussi bien dans les milieux académiques que dans les milieux industriels. L’ensemble des bases théoriques, les principales caractéristiques techniques, ainsi que des compléments pratiques d'utilisation et d'entretien liés à ces disciplines sont développés dans cet ouvrage. Les microscopes électroniques sous haut vide ou vide contrôlé sont exposées profondément, les microanalyses EDS et WDS de dernières générations également. A coté de ces piliers structurants, d'autres techniques d'analyse ou d'observation sont abordées, telles l'analyse EBSD et l'imagerie 3D, le FIB, les simulations de Monte-Carlo et les essais in-situ, etc.
Ce volume en langue française, unique, est la version actualisée, et totalement refondue d'une précédente édition de 1979 aujourd'hui épuisée. Il regroupe, sur environ 1000 pages, les cours dispensés lors de l'école d'été de Saint Martin d'Hères en 2006, organisée par le Groupement National de Microscopie Electronique à Balayage et de microAnalyses (GN-MEBA). Ce livre est particulièrement recommandé aux expérimentateurs mais intéressera aussi les spécialistes en science des matériaux (durs ou mous, conducteurs ou non-conducteurs, stratifiés, etc.) désireux de s'investir dans toutes ces techniques d'imagerie et d'analyse, afin d'en exploiter pleinement les forts potentiels. Il a été écrit par les enseignants de l'école d'été, tous chercheurs ou ingénieurs et spécialistes dans leur domaine.
Cet ouvrage s'inscrit dans une collection de publications du GN-MEBA consacrée aux principes, aux techniques expérimentales et aux méthodes de calcul et de simulation en Microscopie Electronique à Balayage et en Microanalyses.
Recent advances in the characterization of microcrystals in tissue samples based on physico-chemical techniques are reviewed. It is a new opportunity for the physician to access early a diagnosis of rare but severe pathologies and to start a specific therapy able to delay or to stop an irreversible alteration of the organ, for example to avoid dialysis and transplantation when kidney is mainly affected. To date, more than 400 biopsies of kidneys containing crystals were performed and characterized using such techniques. The data collected on crystals, tissue alteration, clinical and biological investigations are of prime importance to help a better understanding of biochemical process involved in crystal formation. Such techniques may be applied to microcrystalline pathologies affecting other organs than kidney, namely prostate, pancreas, thyroid, breast… Multicentric and international collaborations were developed, thus offering new opportunities in studying pathophysiology of deposited microcrystals and their consequences. In fact, crystals may be the consequence of various pathologies, but they are also involved in the dysfunction of the tissue where they accumulate. Two techniques are mainly applied to such diagnosis: scanning electron microscopy and Fourier transform infrared spectroscopy, including synchrotron radiation infrared microspectroscopy.
Sarcoidosis is a disease with highly variable presentation and progression; although it is hypothesized that disease phenotype is related to genetic variation, how much of this variability is driven by genetic factors is not known. The HLA region is the most strongly and consistently associated genetic risk factor for sarcoidosis, supporting the notion that sarcoidosis is an exposure-mediated immunologic disease. Most of the genetic etiology of sarcoidosis remains unknown in terms of the specific variants that increase risk in various populations, their biologic functions, and how they interact with environmental exposures.
Long perceived as a form of exotic self-expression in some social fringe groups, tattoos have left their maverick image behind and become mainstream, particularly for young people. Historically, tattoo-related health and safety regulations have focused on rules of hygiene and prevention of infections. Meanwhile, the increasing popularity of tattooing has led to the development of many new colours, allowing tattoos to be more spectacular than ever before. However, little is known about the toxicological risks of the ingredients used. For risk assessment, safe intradermal application of these pigments needs data for toxicity and biokinetics and increased knowledge about the removal of tattoos. Other concerns are the potential for phototoxicity, substance migration, and the possible metabolic conversion of tattoo ink ingredients into toxic substances. Similar considerations apply to cleavage products that are formed during laser-assisted tattoo removal. In this Review, we summarise the issues of concern, putting them into context, and provide perspectives for the assessment of the acute and chronic health effects associated with tattooing.
Copyright © 2015 Elsevier Ltd. All rights reserved.
Tattoos fade with time. Part of this fading can be attributed to the photodegradation of pigments. When people get tired of their tattoos, removal by laser irradiation is the method of choice. In vivo laser irradiation of tattoos on mice has shown that the degradation of pigments can result in toxic compounds. Various in vitro studies on photodegradation by sunlight or laser have shown similar degradation products for both irradiations. Even visible light was shown to be able to decompose some pigments to toxic degradation products in vitro. Whereas the investigated phthalocyanins (C.I. 74160, 74260), quinacridones (C.I. 73915) or dioxazines (C.I. 51319) were fairly photostable in vitro, all azo pigments exposed to sunlight or laser were degraded into a variety of products, some of which were toxic or even carcinogenic, such as 2-amino-4-nitrotoluene, 3,3'-dichlorobenzidine and o-toluidine. Up to now, the absence of specific toxicological data is the reason why legal restrictions for tattoo inks are derived from those for cosmetics, toys and textiles. Photodegradation has not been considered. In light of the present analytical findings, even with their possible shortcomings, the evidence weighs heavily enough to consider banning azo pigments containing carcinogenic aromatic amines or allergens in their structure from use in tattoo inks. © 2015 S. Karger AG, Basel.
Significance
Interleukin 4 (IL-4) has been shown to be highly protective against delayed type hypersensitivity and organ-specific autoimmune and autoinflammatory reactions in mice and humans, but its mode of action has remained controversial and has failed to be explained solely by redirection of T H 1/T H 17 toward a T H 2-type immune response. Here we uncovered that IL-4 selectively suppresses IL-23 transcription and secretion by cells of the innate immune system. We further describe a previously unidentified therapeutic mode of action of IL-4 in T H 17-mediated inflammation, and a physiologically highly relevant approach to selectively target IL-23/T H 17-dependent inflammation while sparing IL-12 and T H 1 immune responses.
With an incidence of 1:7000 births, cystinuria, the most frequent cause of stone formation among genetic diseases, represents a major medical problem. Twenty-five cystine stones randomly selected from cystinuric patients were investigated. From a crystallographic point of view, cystine stones are composed of micrometre size crystallites, which are made up of an aggregation of nanocrystals. Through scanning electron microscopy, the morphology and size of the crystallites have been described, while the size of the nanocrystals was investigated by means of powder neutron diffraction. Powder neutron diffraction analysis and/or scanning electron microscopy examination of cystine stones provide evidence that usual alkalinization by sodium bicarbonate associated with high diuresis significantly reduces the size of both nanocrystals and crystallites, while for other treatments, including alkalinizing drugs and thiol derivatives, the data suggest mainly changes in the topology of crystallites. Alkalinization with sodium bicarbonate affects cystine kidney stones at the mesoscopic and nanoscopic scales, while other medical treatments only alter their surface. Such an approach may help to assess the interaction between drugs and cystine stones in cystinuric patients.
Sarcoidosis is a granulomatous disorder of unknown cause, affecting multiple organs, but mainly the lungs. The exact order of immunological events remains obscure. Reviewing current literature, combined with careful clinical observations, we propose a model for granuloma formation in pulmonary sarcoidosis. A tight collaboration between macrophages, dendritic cells, and lymphocyte subsets, initiates the first steps toward granuloma formation, orchestrated by cytokines and chemokines. In a substantial part of pulmonary sarcoidosis patients, granuloma formation becomes an on-going process, leading to debilitating disease, and sometimes death. The immunological response, determining granuloma sustainment is not well understood. An impaired immunosuppressive function of regulatory T cells has been suggested to contribute to the exaggerated response. Interestingly, therapeutical agents commonly used in sarcoidosis, such as glucocorticosteroids and anti-TNF agents, interfere with granuloma integrity and restore the immune homeostasis in autoimmune disorders. Increasing insight into their mechanisms of action may contribute to the search for new therapeutical targets in pulmonary sarcoidosis.
Kidney stones made of whewellite, i.e. calcium oxalate monohydrate, exhibit various morphological aspects. The crystalline structure of whewellite at the atomic scale was revisited through a single-crystal neutron study at room temperature using a four-circle automated diffractometer. The possible relationships between the various morphological types of whewellite stones and their structural characteristics were examined at the mesoscopic scale by the use of scanning electron microscopy and at the nanometric scale by powder neutron diffraction. All types of whewellite stones displayed a similar structure at the nanometric scale. However, significant differences were found at the mesoscopic scale. In particular, the crystallites in kidney stones resulting from a genetic hyperoxaluria exhibited a peculiar structure. There was a close relationship between stone morphology and crystallite organization at the mesoscopic level and the effectiveness of extracorporeal shockwave lithotripsy.
Use of deep ultraviolet (DUV, below 350 nm) fluorescence opens up new possibilities in biology because it does not need external specific probes or labeling but instead allows use of the intrinsic fluorescence that exists for many biomolecules when excited in this wavelength range. Indeed, observation of label free biomolecules or active drugs ensures that the label will not modify the biolocalization or any of its properties. In the past, it has not been easy to accomplish DUV fluorescence imaging due to limited sources and to microscope optics. Two worlds were coexisting: the spectrofluorometric measurements with full spectrum information with DUV excitation, which lacked high-resolution localization, and the microscopic world with very good spatial resolution but poor spectral resolution for which the wavelength range was limited to 350 nm. To combine the advantages of both worlds, we have developed a DUV fluorescence microscope for cell biology coupled to a synchrotron beamline, providing fine tunable excitation from 180 to 600 nm and full spectrum acquired on each point of the image, to study DUV excited fluorescence emitted from nanovolumes directly inside live cells or tissue biopsies.
This report reviews a case of dermatomyositis presenting with weakness and extensive calcification in an adult. While dermatomyositis is not uncommon in adults, it is uncommon for calcifications to be present. Children develop calcifications more frequently than adults. When present in adults, small calcifications on areas of frequent trauma such as elbows and fingers are more common. However, this patient presented with large calcified deposits in his abdomen and extremities. His treatment and course are described.
Background:
There is a documented association between drug exposure and sarcoidosis-like reactions. In this study, we used the largest pharmacovigilance database to describe drug-induced sarcoidosis.
Methods:
Data were collected from the World Health Organization (WHO) pharmacovigilance database (VigiBase). We excluded steroids and vaccines from the analysis. The primary endpoint was the lower endpoint of the 95% credibility interval for the information component (IC025 ).
Results:
A total of 127 reports had significant IC025 values for drug-induced sarcoidosis, and 110 were included in the final analysis, accounting for 2,425 adverse drug reactions. Overall, 2,074 (85.5%) reactions were considered "serious", and 86 (3.5%) were fatal. Most of the drugs that led to sarcoidosis adverse reactions were TNF-alpha antagonists, interferon or peg-interferon therapeutics, and immune checkpoint inhibitors. Other biologic drugs were less frequently associated with sarcoidosis adverse events. Cancer-targeted therapies such as BRAF or MEK inhibitors were associated with sarcoidosis reactions in 37 cases. Pulmonary hypertension drugs were also reported for drug-induced sarcoidosis. Among the 55 drugs considered as potential sarcoidosis inducers, 25 (45.4%) were never reported in Medline as drug-induced sarcoidosis.
Conclusions:
We provide a detailed list of suspected drugs associated with drug induced sarcoidosis that will improve the recognition of this drug-induced adverse event.
A 6-year-old girl presented with a history of blistering and scarring in trauma-prone areas. On examination, calcium deposits were seen on bilateral palms and soles within her non-healing wounds. Clinical, genetic and radiological evaluation confirmed the diagnosis of autosomal recessive dystrophic epidermolysis bullosa with dystrophic calcification. The patient was started on topical 10% sodium thiosulfate for her calcinosis cutis. Identification and management of dystrophic calcification are important as it impairs wound healing.
The mechanisms underlying abnormal granuloma formation in patients with sarcoidosis are complex and remain poorly understood. A novel in vitro human granuloma model was used to determine the molecular mechanisms of granuloma-genesis in patients with sarcoidosis in response to putative disease-causing mycobacterial antigens. Peripheral blood mononuclear cells (PBMCs) from patients with active sarcoidosis and from normal, disease-free controls were incubated for 7 days with purified protein derivative (PPD)-coated polystyrene beads. Molecular responses were analyzed, as reflected by differential expression (DE) of genes, extracellular cytokine patterns, and cell surface receptor expression. Unbiased systems biology approaches were used to identify signaling pathways engaged during granuloma formation. Model findings were compared to human lung and mediastinal lymph node gene expression profiles. Compared to identically treated PBMCs of controls (n = 5), PPD-treated sarcoidosis PBMCs (n = 6) were distinguished by the formation of cellular aggregates resembling granulomas. Pathway Analysis of DE gene patterns identified molecular pathways that are primarily regulated by IL-13, which promotes alternatively-activated (M2) macrophage polarization. M2 polarization was further demonstrated by immunohistochemistry performed on the in vitro sarcoidosis granuloma-like structures. IL-13-regulated gene pathways were confirmed in human sarcoidosis lung and mediastinal lymph node tissues. The in vitro human sarcoidosis granuloma model provides novel insights into early granuloma formation, particularly IL-13 regulation of molecular networks that regulate M2 macrophage polarization. M2 macrophages are predisposed to aggregation and multinucleated giant cell formation, which are characteristic features of sarcoidosis granulomas.
As a result of the increase in the practice of tattooing, the US Food and Drug Administration has identified a need for improved analytical methods to detect the pigments and potential impurities in the inks. Raman spectroscopy allows for nondestructive identification of compounds and is commonly used in art, archaeology, and forensics; however, the technique has only limitedly been applied to the identification of tattoo pigments. In this study, approximately 30 inorganic, organometallic, and organic pigments were evaluated with Raman spectroscopy by using 532, 633, and 780-nm lasers. Individual optimization of the instrumental parameters was performed for each pigment in order to enhance spectral quality. This research highlights the need for multiple laser interrogation, as the spectra of some pigments were difficult to obtain by using a particular wavelength due to interferences from absorption or fluorescence. However, by using these multiple wavelengths, all pigments could be identified by their unique spectral features. A spectral library of the pigments was created for each laser wavelength and then challenged with pigments from multiple manufacturers. All pigments were identified correctly, and the method is poised to be an effective, noninvasive means for qualitatively identifying tattoo pigments. Published 2017. This article is a U.S. Government work and is in the public domain in the USA.
Background/aims:
Sarcoidosis is, from historical data, suggested to be more prevalent among patients with tattoo reactions. We aimed to evaluate this association in a systematic study.
Methods:
This is a consecutive study of patients with tattoo complications, diagnosed in the "Tattoo Clinic" at Bispebjerg University Hospital in Copenhagen, Denmark, from 2008 to 2015, based on clinical assessment and histology. From the overall group of 494 tattoo complications in 406 patients, 92 reactions in 72 patients showed a papulo-nodular pattern studied for local and systemic sarcoidosis, since sarcoidosis is expected to be nodular.
Results:
Of the 92 reactions with a papulo-nodular pattern, 27 (29%) reactions in 19 patients were diagnosed as cutaneous or systemic sarcoidosis, supported by histology; 65 (71%) were diagnosed as non-sarcoidosis due to histology and no clinical sarcoid manifestations. "Rush phenomenon" with concomitant reaction in many other black tattoos, triggered by a recent tattoo with a papulo-nodular reaction, was observed in 70% in the sarcoidosis group and 28% in the non-sarcoidosis group, indicating a predisposing factor which may be autoimmune and linked with sarcoidosis. Agglomerates of black pigment forming foreign bodies may in the predisposed individual trigger widespread reaction in the skin and internal organs.
Conclusion:
Black tattoos with papulo-nodular reactions should be seen as markers of sarcoidosis. Papulo-nodular reactions may, as triggers, induce widespread reactions in other black tattoos - a "rush phenomenon" - depending on individual predisposition. Sarcoidosis is estimated to be 500-fold increased in papulo-nodular reactions compared to the prevalence in the general population, and the association with black tattoos is strong.
Accurate identification of risk factors for calcific uremic arteriolopathy (CUA) is necessary to develop preventive strategies for this morbid disease. We investigated whether baseline factors recorded at hemodialysis initiation would identify patients at risk for future CUA in a matched case-control study using data from a large dialysis organization. Hemodialysis patients with newly diagnosed CUA (n=1030) between January 1, 2010, and December 31, 2014, were matched by age, sex, and race in a 1:2 ratio to hemodialysis patients without CUA (n=2060). Mean ages for patients and controls were 54 and 55 years, respectively; 67% of participants were women and 49% were white. Median duration between hemodialysis initiation and subsequent CUA development was 925 days (interquartile range, 273-2185 days). In multivariable conditional logistic regression analyses, diabetes mellitus; higher body mass index; higher levels of serum calcium, phosphorous, and parathyroid hormone; and nutritional vitamin D, cinacalcet, and warfarin treatments were associated with increased odds of subsequent CUA development. Compared with patients with diabetes receiving no insulin injections, those receiving insulin injections had a dose-response increase in the odds of CUA involving lower abdomen and/or upper thigh areas (odds ratio, 1.49; 95% confidence interval, 1.03 to 2.51 for one or two injections per day; odds ratio, 1.88; 95% confidence interval, 1.30 to 3.43 for 3 injections per day; odds ratio, 3.74; 95% confidence interval, 2.28 to 6.25 for more than three injections per day), suggesting a dose-effect relationship between recurrent skin trauma and CUA risk. The presence of risk factors months to years before CUA development observed in this study will direct the design of preventive strategies and inform CUA pathobiology.
The skin is the second most common organ affected in sarcoidosis, which can affect patients of all ages and races, with African American women having the highest rates of sarcoidosis in the United States. The cutaneous manifestations are protean and can reflect involvement of sarcoidal granulomas within the lesion or represent reactive non-specific inflammation, as seen with erythema nodosum. Systemic work-up is necessary in any patient with cutaneous involvement of sarcoidal granulomas, and treatment depends on other organ involvement and severity of clinical disease. Skin-directed therapies are first line for mild disease, and immunomodulators or immunosuppressants may be necessary.
Granulomatous disorders are chronic cell-mediated immune responses histologically characterized by collections of macrophages, epithelioid cells, and multinucleated giant cells. This disease spectrum often has an infectious origin, but sometimes neither an infective agent nor an inciting antigenic stimulus can be identified.
The skin may be a preferential target for these disorders, especially in the areas that have been damaged by various forms of skin injury (eg, herpetic infections, trauma, thermal or solar burns, vaccinations, tattoos). These damaged skin sites frame the new concept of an immunocompromised cutaneous district (ICD), which defines a skin area with acquired immune dysregulation that can pave the way for the local onset of opportunistic disorders, such as infections, tumors, and granulomatous disorders. Sarcoidosis, granuloma annulare (GA), and forms of granulomatous vasculitis, such as Churg-Strauss syndrome (CSS) and Wegener’s granulomatosis (WG), are the most common granulomatous disorders that occur in an ICD and may share common pathogenic mechanisms.
Recent studies have found clinical and pathologic overlapping features across noninfectious granulomas. Although no unifying etiology exists, the development of granulomatous processes in the ICD has often been reported and the literature contains various hypotheses to explain it: (1) overactive immune response in a previously injured region with or without loss of immune tolerance; (2) overall reduced immune response; (3) retention of an exogeneous antigen or foreign body; (4) altered neural signaling; and (5) a combination of all the aforementioned processes. T helper cells, T regulatory cells, and macrophages, as well as a number of antigenic proteins, have been identified as potential contributing factors. In addition, a genetic predisposition and an intact systemic immune system are both instrumental for the persistence of local granuloma formation in the ICD.
Hypercalcemia in sarcoidosis is due to three mechanistic reasons: (1) systemic conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D by the enzyme 1-α hydroxylase produced by activated monocyte/macrophage system, (2) production of parathormone-related peptide (PTHrP) by the sarcoid granuloma, (3) tissue-level conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D by 1-αhydroxylase produced by local monocyte/macrophage system in the sarcoid granuloma. We report two cases of one proposed mechanism of hypercalcaemia in sarcoidosis (mechanism 3). Both individuals presented with sarcoidosis and 25-hydroxyvitamin D deficiency and developed symptomatic hypercalcaemia with vitamin D replacement. Given their low serum parathormone and parathormone-related peptide levels, low serum 25-hydroxy vitamin D and normal serum 1,25-dihydroxyvitamin D, the systemic 25-hydroxy vitamin D deficiency may not have reflected an increased activity of vitamin D at the local granulomatous tissue level.
Wolfgang Steinicke celebrates the centenary of a famous publication.
Ectopic calcification is defined as inappropriate biomineralization occurring in soft tissues. 1 Ectopic calcifications are typically composed of calcium phosphate salts, including hydroxyapatite, but can also consist of calcium oxalates and octacalcium phosphate as seen in kidney stones. 2 In uremic patients, a systemic mineral imbalance is associated with widespread ectopic calcification, referred to as metastatic calcification. 3 In the absence of a systemic mineral imbalance, ectopic calcification is typically termed dystrophic calcification. Often, these sites show evidence of tissue alteration and/or necrosis. Dystrophic mineralization is commonly observed in soft tissues as a result of injury, disease, and aging. Although most soft tissues can undergo calcification, skin, kidney, tendons, and cardiovascular tissues appear particularly prone to developing this pathology. 4 In addition, a number of prosthetic devices are prone to ectopic calcification, as discussed below. Recent insights into the mechanisms regulating ectopic calcification have come from studies of cardiovascular calcification, including that by Kim et al 5 in this issue of the Journal, and thus will be the major focus of this article. The reader is referred to other reviews for information about additional tissue-specific ectopic calcifications. 2,6,7
From an experimental point of view and more particularly in heterogeneous catalysis, the LIII white line is at the center of electronic charge transfer either between either the nanometer scale metallic particle and the support or between the two metals which are present inside the cluster. In this work, we show that a strong correlation exists between the intensity of the white line and the size of the cluster. Thus, at least two physical phenomenon can affect the intensity of the white line: the size of the cluster, which can be considered as an intrinsic effect (density of state of nanometer scale platinum cluster are far from the bulk one), and a possible charge transfer between the cluster and the support, which can be considered as an extrinsic one. If the first results obtained with the FeFF program are encouraging, it is clear that to go further in the analysis, the detailed geometric configurations present in the cluster surface have to be integrated very precisely in order to obtain quantitative effects that would be more clearly related to the characteristics of the density of states.
We consider the analysis of the K edge of 3d or 4d transition metals when nanometer-scale metallic clusters
are considered. From a practical point of view, numerical simulation of the XANES part of the K absorption
spectrum of most elements of the periodic table can be performed through full multiple scattering calculations.
Then, on the basis of a linear combination of the XANES spectra of reference compounds, the presence of
the different phases present inside the materials can be quantified. Here, we show that for nanometer scale
metallic clusters, it is not sufficient to consider only the electronic state of the metal of interest to perform a
linear combination analysis. In the case of these peculiar materials, special attention has to be paid to different
structural parameters, for example, the size and morphology of the cluster, the interatomic distance (taking
into account contraction/dilatation processes), and the presence of heterometallic bonds (in the case of bimetallic
clusters). Moreover, this approach is not specific to the metallic state. As a conclusion, the quantitative
measurement of the structural parameters coming from EXAFS analysis constitutes an invaluable starting
point for the FEFF-PCA simulation. The fact that major results coming from the emergence of dynamical
studies, namely, Quick-EXAFS or energy dispersive EXAFS, are now obtained will lead to significant
breakthroughs in the understanding of the genesis/reactivity of nanometer-scale entities.
Background:
Calciphylaxis is a rare, life-threatening syndrome marked by vascular calcification and cutaneous necrosis. The role of radiographic imaging in assisting in diagnosis has not been established.
Objective:
To investigate the potential role of plain radiographic imaging in the diagnosis of calciphylaxis.
Methods:
We searched for cases of patients at our tertiary referral center with a diagnosis of calciphylaxis between Jan 1, 1996, and Dec 31, 2010. Two control patients receiving dialysis but without calciphylaxis were age- and sex-matched to each study patient. Plain radiographs were obtained from the date closest to diagnosis in patients with calciphylaxis and from matched controls at approximately the same dates. Two radiologists, masked as to cases and controls, read each image together. Size of calcified vessels, pattern and extent of calcifications, presence of net-like or other calcifications, and bone density/mineralization were recorded and analyzed.
Results:
Twenty-nine patients with calciphylaxis (mean age, 57 years; 21 [72%] women) were identified. Mean age at diagnosis was 57 years (range, 36-75 years). Compared with those of controls, plain radiographs of patients with calciphylaxis had more vascular calcifications, more small-vessel calcifications, and a netlike pattern of calcifications. A netlike pattern of calcifications had considerable strength of association with calciphylaxis (odds ratio, 9.4) and a specificity of nearly 90%. These findings were preserved even if only one image was used per patient.
Limitations:
This was a retrospective study.
Conclusion:
A netlike pattern of calcifications on plain radiographs was more common in patients with calciphylaxis and may aid in diagnosis.
Crystal-induced kidney disease is a frequent occurrence in human pathology. It is becoming more and more apparent that knowledge of kidney stone composition and structure appears to be the key for establishing the etiology of stone disease. A number of analytical methods may be applied to stone analysis, but only a few of them are able to quickly and easily provide extensive information on both stone structure and composition relevant for clinical diagnosis. More than 12,000 calculi were analyzed using a combination of microscopic examination, sequential infrared (IR) analysis by Fourier transform infrared spectroscopy (FTIR) of each part of stone, and quantification of all components present. We also investigated 50 biopsies using FTIR microscopy. Our results confirm that IR spectroscopy is a reliable and accurate technique for both molecular and crystalline identification. Some limitations of standard procedures, because of very small samples or due to absorption band overlap, can be solved using FTIR micromethod or a particular method like IR microscopy. In such cases, the spectrum identification must be conducted in different manners. Until now, spectral identification procedures based on computerized spectra libraries must be used with caution because of false results, mainly for mixtures of mineral compounds. Trained eyes always provide the best results for reading spectra from common stones. In routine practice, accurate identification of all components present in calculi is necessary for understanding urolithiasis mechanisms, but only semiquantitative assessment is sufficient to guide physicians toward establishing correct etiology. © 1997 John Wiley & Sons, Inc. Biospectroscopy 3: 347–369, 1997
the ultimate goal is to use techniques usually dedicated to fundamental physics and those related to largescale facilities for characterizing pathological calcifications at the subcellular scale to (1) establish a possible link between the chemical characteristics of the calcification and the abnormality, (2) allow for an early diagnosis, and (3) revisit results provided early by more classical techniques.
We would like to describe some basic aspects of pathological calcifications from a medical and chemical viewpoint. This brief description (additional information can be obtained in excellent reviews dedicated to biomineralization processes) is a prerequisite to appreciate the complexity of such objects and the need for intimate collaboration between physicist, chemist,and clinician scientific communities.
We will review some physicochemical aspects related to solubility, nucleation and crystal growth, especially of calcium salts encountered in pathological calcifications, and the role of proteins in these processes.
Despite advances in molecular biology and a repertoire of other therapeutic options, chronic venous leg ulcers remain a significant problem within our society. There are various reasons, both local and systemic, which contribute to the non healing nature of such wounds. Among them, dystrophic calcification (DC) or calcified deposits within the ulcer bed, although rare, is an overlooked and a seldom reported cause. In the presence of DC, wound healing cannot proceed through a timely and orderly manner resulting in a non healing ulcer. In this article, we discuss the aetiology, pathophysiology and the management options of this rarely reported condition. We also report their clinical prognosis using a series of patients with venous ulcers complicated by DC leading to difficulties in healing.
Any nonliving material introduced into the skin and resistant to degradation may trigger an inflammatory response.
The origin and way of introduction goes from traumatic (accidental or self-induced) to cosmetic and surgical procedures to topical application of drugs and products.
The increased use of exogenous injectable aesthetic microimplants (soft-tissue fillers) is paralleled by an increase in adverse cutaneous reactions.
The most common clinical presentation of granulomatous reactions includes papules, nodules and stiff infiltration of the skin with or without ulceration.
Histopathology is a good means to identify the type of exogenous agent, particularly of filler particles.
Sarcoidosis is a multisystemic, granulomatous disease with protean manifestations and variable prognosis. Because the skin can be the only organ in which the disease is recognized, dermatologists may be responsible for the care of sarcoidosis patients. Therefore, dermatologists should be cognizant of the disease's extracutaneous manifestations to assure appropriate evaluation and treatment. Part II of this review describes the diagnostic approach and management of the extracutaneous manifestations of sarcoidosis.
The introduction in the dermis of exogenous pigments and dyes to obtain a permanent design (tattooing) represents a unique in-vivo situation, where a large amount of metallic salts and organic dyes remain in the skin for the lifetime of the bearer. The potential local and systemic carcinogenic effects of tattoos and tattoo inks remain unclear. Several studies have shed light on the presence of potential carcinogenic or procarcinogenic products in tattoo inks. We extensively reviewed the literature and found 50 cases of skin cancer on tattoos: 23 cases of squamous-cell carcinoma and keratoacanthoma, 16 cases of melanoma, and 11 cases of basal-cell carcinoma. The number of skin cancers arising in tattoos is seemingly low, and this association has to be considered thus far as coincidental.
In this article an attempt is made to review critically the papers concerning novel membrane characterization methods. In particular, our focus on Raman spectroscopy, electron spin resonance (ESR) and atomic force microscopy. For each method the general principle is briefly outlined, followed by discussions on characterization of polymeric materials, in general, and synthetic polymeric membranes, in particular. After highlighting several examples, discussions are made on advantages for each method in order to identify specific area of applications. In general, Raman Spectroscopy is most adequate to obtain information on crystalline structure of the macromolecules and, change of polymeric structure in membrane, ESR on the mobility of molecules in membrane polymer matrixes and membrane pores, and Atomic Force Microscope for three-dimensional display of membrane surfaces.
A user friendly program for X-ray fluorescence analysis has been developed at the European Synchrotron Radiation Facility. The program allows interactive as well as batch processing of large data sets and it is particularly well suited for X-ray imaging. Its implementation of a complete description of the M shell is particularly helpful for analysis of data collected at low energies. The code is platform independent (Linux, Windows, MacOS X, Solaris …) and it is freely available for non-commercial use. Description of the algorithms used and practical examples are presented.