RESUMO
Primary antiphospholipid syndrome is characterized by thrombosis and autoantibodies directed against phospholipids or associated proteins. The genetic etiology of PAPS remains unknown. We enrolled 21 patients with thromboembolic events associated to lupus anticoagulant, anticardiolipin and anti ß2 glycoprotein1 autoantibodies. We performed whole exome sequencing and a systematic variant-based analysis in genes associated with thrombosis, in candidate genes previously associated with APS or inborn errors of immunity. Data were compared to public databases and to a control cohort of 873 non-autoimmune patients. Variants were identified following a state-of-the-art pipeline. Enrichment analysis was performed by comparing with the control cohort. We found an absence of significant HLA bias and genetic heterogeneity in these patients, including when testing combinations of rare variants in genes encoding for proteins involved in thrombosis and of variants in genes linked with inborn errors of immunity. These results provide evidence of genetic heterogeneity in PAPS, even in a homogenous series of triple positive patients. At the individual scale, a combination of variants may participate to the breakdown of B cell tolerance and to the vessel damage.
Assuntos
Síndrome Antifosfolipídica , Trombose , Humanos , Exoma , Síndrome Antifosfolipídica/complicações , Inibidor de Coagulação do Lúpus , Autoanticorpos , Trombose/complicaçõesRESUMO
We report a case of spinal cord toxoplasmosis occurring as a primary infection in a 31-year-old immunocompetent man. Exhaustive immunologic and genetic investigations did not identify any immunodeficiency. The causative agent was a typical type 2 strain. In cases of spinal cord lesions, toxoplasmosis should be considered, even in an immunocompetent patient.
Assuntos
Carne/parasitologia , Repetições de Microssatélites/genética , Toxoplasma/genética , Toxoplasmose Cerebral/diagnóstico , Adulto , Animais , Genótipo , Humanos , Masculino , Sus scrofa/parasitologia , Toxoplasma/classificação , Toxoplasmose Cerebral/parasitologiaRESUMO
BACKGROUND: Stratum Corneum (SC) is the most superficial layer of the epidermis. It plays the main barrier role against water loss and the aggression of external chemical and biological substances. Thermal treatment in warm purified water followed by trypsin incubation of excised human skin is a well-established in vitro method for SC removal. Different protocols can be found in literature, but little is described about the effect of temperature and trypsin during isolation process on its barrier function. METHODS: In this study, we have examined the epidermis and SC matrix structural change upon isolation by means of confocal Raman spectroscopy. RESULTS: Several spectral features, i.e. in-depth and planar lateral packing, conformational order and secondary structure have been investigated to reveal modifications in the structural properties of the lipids and proteins in the SC. Thermal treatment at 60°C leads to a losing in compactness and a steeper concentration of the lipid and protein descriptors while the trypsinization step modifies the organization of the proteins and of the lipid barrier, leading to a domain organization. CONCLUSIONS: The present study improves the knowledge of the effects on the barrier function of SC removal protocol.
Assuntos
Epiderme/fisiologia , Metabolismo dos Lipídeos/fisiologia , Absorção Cutânea/fisiologia , Análise Espectral Raman/métodos , Tripsina/metabolismo , Feminino , Humanos , Masculino , Microscopia Confocal/métodos , Pessoa de Meia-Idade , TemperaturaRESUMO
BACKGROUND/PURPOSE: The Stratum Corneum (SC) barrier function mainly depends on the SC structure at the tissue level, its composition, and the organization of intercellular lipidic cement at the molecular level. The goal of this study was to assess the age-dependent changes of the SC barrier function and the associated physiological parameters. METHODS: This study was conducted on 40 French women divided into four groups of age. Measurements were done on three sites: cheek, protected, and exposed arm sites. SC composition (water, lipid/protein ratio, cholesterol, and ceramides) was measured using Raman confocal microspectroscopy, skin surface hydration using skin conductance, and barrier function through transepidermal water loss (TEWL) measurements. RESULTS: Transepidermal water loss decreases slightly with age, which is partially explained by the age-dependent increase in SC thickness. This decrease is faster for the face compared to both arm sites. The lipid to protein ratio and lipid compactness decrease significantly with age only for the arm sites. Water concentration profiles only decrease very close to the skin surface. At all ages tested, the SC on the cheek showed significantly higher TEWL, water and lipid content and less thickness compared to the arm sites. Comparison of the exposed to unexposed arm site showed difference only for the lipid compactness at the older group studied. CONCLUSION: Skin aging, body site and environmental exposure can affect the SC barrier function, its structure, and its lipid content. The thickening of the SC with age compensates for the decrease of the quantity and ordering of the lipidic cement.
Assuntos
Envelhecimento/fisiologia , Água Corporal/metabolismo , Epiderme/fisiologia , Metabolismo dos Lipídeos/fisiologia , Absorção Cutânea/fisiologia , Perda Insensível de Água/fisiologia , Adolescente , Adulto , Idoso , Feminino , Humanos , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Skin dryness is an omnipresent symptom in various types of skin disorders. Thereby, a large panel of skin care products is developed for therapeutic purposes. However, there is still a lack of non-invasive methods to determine the mechanisms of action of moisturizers at the molecular level. METHODS: In the present study, confocal Raman spectroscopy coupled to classical least square analyses and ATR-FTIR were used to investigate the effect of different molecules on the stratum corneum (SC) hydration degree and barrier state. First, hygroscopic property was determined by analyzing samples at 90% RH; secondly, the water barrier function was evaluated after the dehydration process (4% RH). The molecules penetration kinetics across SC were also studied for 2 h. RESULTS: Using the present approach, glycerin and propylene glycol were found to be humectants; lanoline showed occlusive action, lactic acid has both humectant and barrier enhancer properties, and ethylhexyl palmitate and caprylic/capric acid triglyceride seemed to be emollients. These observations are in accordance with literature. CONCLUSION: The present method non-invasively characterizes the mechanism of action of tested molecules. This may improve knowledge of new molecules' structure-activity relationship and help make an effective therapeutic concept dealing with the various skin dysfunctions.
Assuntos
Água Corporal/metabolismo , Interpretação Estatística de Dados , Emolientes/farmacologia , Epiderme/metabolismo , Absorção Cutânea/fisiologia , Análise Espectral Raman/métodos , Adulto , Algoritmos , Simulação por Computador , Diagnóstico por Computador/métodos , Epiderme/efeitos dos fármacos , Feminino , Humanos , Técnicas In Vitro , Análise dos Mínimos Quadrados , Pessoa de Meia-Idade , Modelos Estatísticos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Absorção Cutânea/efeitos dos fármacos , Higiene da PeleRESUMO
INTRODUCTION: Alveolar echinococcosis is an endemic parasitic disease prevalent in certain cold regions of the Northern Hemisphere, including Eastern France, Switzerland, Germany, Canada, and the United States. Widely underdiagnosed, it is associated with infection by Echinococcus multilocularis, a small tapeworm belonging to the cestode class, capable of causing multi-systemic involvement, particularly in elderly or immunocompromised patients. CASE REPORT: We present the case of an 82-year-old patient, immunocompromised due to prolonged corticosteroid therapy and treatment with dupilumab. She was referred to our department for a diagnostic assessment of atypical hepatic and pulmonary lesions, initially suspected of tuberculosis or an IgG4-related disease. The hypothesis of alveolar echinococcosis caused by E. multilocularis was eventually considered based on a set of arguments, further confirmed by molecular diagnosis. We discuss the role of dupilumab in the systemic evolution and atypical presentation of the disease, through the induction of a specific immunosuppression. CONCLUSION: Alveolar echinococcosis should be systematically considered in case of systemic disease with prominent hepatic and pulmonary involvement, especially in immunocompromised patients.
Assuntos
Anticorpos Monoclonais Humanizados , Equinococose , Echinococcus multilocularis , Hospedeiro Imunocomprometido , Humanos , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Feminino , Equinococose/diagnóstico , Equinococose/tratamento farmacológico , Idoso de 80 Anos ou mais , Equinococose Hepática/diagnóstico , Equinococose Hepática/tratamento farmacológico , AnimaisRESUMO
Epstein-Barr virus (EBV), discovered in 1964, is a double-stranded DNA virus belonging to the Herpesviridae family. EBV has a lymphoid tropism with transforming capacities using different oncogenic viral proteins. This virus has two replication cycles: a lytic cycle mainly occuring during primary infection and a latent cycle allowing viral persistence into host memory B cells. More than 90% of adults are seropositive for EBV worldwide, with a past history of asymptomatic or mild primary infection. EBV infection can sometimes cause life-threatening complications such as hemophagocytic lymphohistiocytosis, and lead to the development of lymphoproliferative disorders or cancers. Risk factors associated with these phenotypes have been recently described through the study of monogenic primary immune deficiencies with EBV susceptibility. We here review the virological and immunological aspects of EBV infection and EBV-related complications with an overview of current available treatments.
Assuntos
Infecções por Vírus Epstein-Barr , Síndromes de Imunodeficiência , Linfo-Histiocitose Hemofagocítica , Transtornos Linfoproliferativos , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/diagnóstico , Infecções por Vírus Epstein-Barr/epidemiologia , Herpesvirus Humano 4 , Humanos , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/epidemiologiaRESUMO
BACKGROUND: FTIR spectroscopy is classically used to study the supramolecular organization of the stratum corneum lipids. Exposure to UV(A) is responsible for a small decrease in packing observed on cutaneous lipid films. METHODS: Lipid films and human skin biopsies were either exposed to UV(A) irradiation of 120 J/cm(2), UV(B) irradiation of 0.15 J/cm(2) or put in contact with ethanol. Using FTIR in vitro and IR microspectroscopy ex vivo provided information on: i) the precise localisation of the stratum corneum in the skin, ii) its thickness, and iii) the organization of its constituted lipids. RESULTS: Different action modes were observed for UV irradiation and the contact with ethanol with a certain destabilisation of the lipidic layer. Ethanol was also found to be responsible for the creation of pores. The destabilisation of the lipid cement was mainly observed ex vivo. CONCLUSION: The barrier function of the skin is affected by the action of physical and chemical external agents at the molecular level. The increased laxity of the lipid packing could enable the percutaneous penetration velocity of actives.
Assuntos
Epiderme/química , Lipídeos/química , Adulto , Fenômenos Biofísicos , Ceramidas/química , Epiderme/efeitos da radiação , Etanol , Feminino , Humanos , Ligação de Hidrogênio , Técnicas In Vitro , Lipídeos/efeitos da radiação , Substâncias Macromoleculares/química , Micelas , Modelos Moleculares , Espectroscopia de Infravermelho com Transformada de Fourier , Raios UltravioletaRESUMO
INTRODUCTION: First described in 1959, Hughes-Stovin syndrome is a very rare disorder combining vascular aneurysms, especially from pulmonary arteries, and thrombosis. The disease affects mostly the young male and is sometime associated with Behçet' disease. CASE REPORT: Here, we report the case of a 19-year-old man with hemoptysis and dyspnea revealing recurrent pulmonary embolisms despite efficient anticoagulant therapy. The patient subsequently developed fever and an inflammatory syndrome. Physical examination showed ulcers of the tongue. Angio-CT revealed recent pulmonary embolism, femoral vein thrombosis, and a unique threatening aneurysm of a left pulmonary artery segment. The aneurysm was embolized and simultaneously a vena cava filter was inserted. CONCLUSION: Hughes-Stovin syndrome requires immediate therapeutic decision, with an important risk of the anticoagulation. High dose steroids and in most cases, intensive immunosuppressive therapies are required such as cyclophosphamide.
Assuntos
Aneurisma/diagnóstico , Artéria Pulmonar/patologia , Trombose Venosa/diagnóstico , Aneurisma/complicações , Síndrome de Behçet/complicações , Síndrome de Behçet/diagnóstico , Síndrome de Behçet/patologia , Dispneia/diagnóstico , Dispneia/etiologia , Hemoptise/diagnóstico , Hemoptise/etiologia , Humanos , Masculino , Recidiva , Síndrome , Trombose Venosa/complicações , Adulto JovemRESUMO
An investigation of the effects of UV(A) irradiation on the stratum corneum lipids was carried out in vitro on films. The modifications of their conformational order were studied by FTIR and the formation of new entities was detected by mass spectroscopy. The results show not only differences in behaviour of the three lipid classes (fatty acids (FA), ceramides (CER), and cholesterol), but also variation within a class, depending on the molecules structure. Upon UV(A) irradiation, beta scission occurs on all the components, saturated and unsaturated. Moreover, unsaturated FA or CER having a double bond on their FA moiety may become saturated or may be transformed into their free radical form. Unsaturated FA are more sensitive to UV(A) and lead more easily to oxygenated components than unsaturated CER. The chemical effects are irradiation dose dependent but do not deeply influence the supramolecular organisation of these lipids. The global conformation of the lipids stays in an orthorhombic state, a decrease of the packing density however is observed.
Assuntos
Ceramidas/efeitos da radiação , Colesterol/efeitos da radiação , Ácidos Graxos/efeitos da radiação , Espectrometria de Massas/métodos , Fotoquímica , Pele/efeitos da radiação , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Ceramidas/química , Ceramidas/metabolismo , Colesterol/química , Colesterol/metabolismo , Ácidos Graxos/química , Ácidos Graxos/metabolismo , Radicais Livres/química , Radicais Livres/metabolismo , Pele/química , Pele/metabolismo , Raios UltravioletaRESUMO
INTRODUCTION: Sinusoidal obstruction syndrome is a rare complication of autologous hematopoietic stem cell transplantation. This syndrome is mainly described following conditioning regiment with busulfan, cyclophosphamide and/or total body irradiation. CASE REPORTS: We report for the first time two cases of sinusoidal obstruction syndrome occurring lately after BeAM conditioning regiment (bendamustine, etoposide, aracytine, melphalan) for autologous stem cell transplantation in patients treated for malignant lymphoma. CONCLUSION: Our observations highlight the difficulty to diagnose this complication with often non-specific clinical presentation and possible delayed occurrence after to transplantation, but also the therapeutic challenges, defibrotide being the only agent currently efficient. Physiopathology and potential responsibility of bendamustine in the sinusoidal obstruction syndrome occurrence will be discussed.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cloridrato de Bendamustina/efeitos adversos , Transplante de Células-Tronco Hematopoéticas , Hepatopatia Veno-Oclusiva/induzido quimicamente , Condicionamento Pré-Transplante/efeitos adversos , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cloridrato de Bendamustina/administração & dosagem , Carmustina/efeitos adversos , Carmustina/uso terapêutico , Citarabina/efeitos adversos , Citarabina/uso terapêutico , Etoposídeo/efeitos adversos , Etoposídeo/uso terapêutico , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Hepatopatia Veno-Oclusiva/patologia , Humanos , Melfalan/efeitos adversos , Melfalan/uso terapêutico , Pessoa de Meia-Idade , Condicionamento Pré-Transplante/métodos , Transplante AutólogoRESUMO
Lymphopenia is frequent in systemic lupus erythematosus (SLE) and profound (<500/mm3) in 10% of cases. T lymphocytes, especially CD4+, are more affected than B cells. The pathophysiological mechanisms are complex, involving lymphocytotoxic antibodies, excess of apoptosis, increased susceptibility of T cells to complement mediated cytolysis, as well as lymphopoiesis impairment and lymphocyte sequestration. Lymphopenia in SLE is independent from other cytopenia and immunosuppressive drug regiments, and associated with disease activity, risk of flare and damage scores. Infectious risk is mostly bacterial, and lymphopenia <1 G/L is an independent risk factor for severe bacterial infections occurrence. The T cellular deficiency is associated with less control of viral replication, but severe and symptomatic infections are scarce. Although exceptional in SLE, pneumocystis is more severe than in HIV+ patients, and risk of progressive multifocal leukoencephalopathy seems increased compared to other rheumatic diseases. To date, there are no specific recommendations for management of SLE with lymphopenia. Infectious prophylaxis should remain exceptional and discussed on a case by case basis. Further studies are needed to assess the clinical characteristics and outcomes of patients with SLE and profound lymphopenia (<500/mm3), which are probably a subset of SLE with primary immunodeficiency and require specific management.
Assuntos
Lúpus Eritematoso Sistêmico/complicações , Linfopenia/etiologia , Apoptose/imunologia , Linfócitos B/fisiologia , Humanos , Imunossupressores/efeitos adversos , Imunossupressores/classificação , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Linfopenia/sangue , Linfopenia/induzido quimicamente , Linfopenia/terapia , Linfopoese/efeitos dos fármacos , Linfopoese/fisiologia , Infecções Oportunistas/imunologia , Linfócitos T/fisiologiaRESUMO
Many evidences highlight that immunodeficiency and autoimmunity are two sides of a same coin. Primary immune deficiencies (PIDs), which are rare mono- or multigenic defects of innate or adaptative immunity, frequently associate with autoimmunity. Analyses of single-gene defects in immune pathways of families with PIDs, by new tools of molecular biology (next genome sequencing technologies), allowed a better understanding of the ways that could both drive immune defect with immune deficiency and autoimmunity. Moreover, genes implicated in rare single-gene defects are now known to be also involved in polygenic conventional autoimmune diseases. Here, we describe the main autoimmune symptoms occurring in PIDs and the underlying mechanisms that lead to autoimmunity in immunodeficiency. We review the links between autoimmunity and immunodeficiency and purpose some principles of care for patients with PIDs and autoimmunity.
Assuntos
Doenças Autoimunes/complicações , Síndromes de Imunodeficiência/etiologia , Imunidade Adaptativa/genética , Adulto , Doenças Autoimunes/epidemiologia , Doenças Autoimunes/terapia , Autoimunidade/genética , Autoimunidade/fisiologia , Humanos , Síndromes de Imunodeficiência/epidemiologia , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/terapiaRESUMO
Raman spectroscopy is a rapid, non-destructive and non-invasive method that is a promising tool for real-time analytical control of drug concentrations. This study evaluated a handheld Raman device to discriminate and quantify two isomeric drugs used to treat cancer. Doxorubicin (DOXO) and epirubicin (EPIR) samples were analyzed at therapeutic concentrations from 0.1 to 2mg/mL (n=90) and 0.08-2mg/mL (n=90) by non-invasive measurements using a portable Raman spectrometer. The discrimination of these two molecules was demonstrated for all concentrations (n=180) by qualitative analysis using partial least square discriminant analysis (PLS-DA) with 100% classification accuracy, sensitivity and specificity and 0% error rate. For each molecule, quantitative analyses were performed using PLS regression. The validity of the model was evaluated using root mean square error of cross validation (RMSECV) and prediction (RMSEP) that furnished 0.05 and 0.02mg/mL for DOXO and 0.17 and 0.16mg/mL for EPIR after pretreatment optimization. Based on the accuracy profile, the linearity range was from 1.256 to 2.000mg/mL for DOXO (R2=0.9988) and from 0.553 to 2.000mg/Ml for EPIR (R2=0.9240) and repeatability (CV% max of 1.8% for DOXO and 3.2% for EPIR) and intermediate precision (CV% max of 2.8% for DOXO and 4.5% for EPIR) were both acceptable. Despite the narrow validated concentration range for quantitative analysis, this study shows the potential of a handheld Raman spectrometer coupled to chemometric approaches for real-time quantification of cytotoxic drugs, as well for discriminating between two drugs with similar UV absorption profiles. Finally, the use of a handheld spectrometer with the possibility of a direct measurement of substances in containers is a potentially valuable tool for combining patient safety with security of healthcare workers.
Assuntos
Antineoplásicos/análise , Doxorrubicina/análise , Antineoplásicos/química , Doxorrubicina/química , Isomerismo , Soluções , Análise Espectral RamanAssuntos
Doenças Autoimunes/terapia , Autoimunidade/fisiologia , Medicina de Precisão , Doenças Autoimunes/genética , Predisposição Genética para Doença , Genômica/história , Genômica/métodos , Genômica/tendências , História do Século XIX , História do Século XX , História do Século XXI , Humanos , Invenções/história , Invenções/tendências , Metabolômica/história , Metabolômica/métodos , Metabolômica/tendências , Terapia de Alvo Molecular/história , Terapia de Alvo Molecular/métodos , Terapia de Alvo Molecular/tendências , Medicina de Precisão/efeitos adversos , Medicina de Precisão/história , Medicina de Precisão/métodos , Medicina de Precisão/tendênciasRESUMO
A specific reverse-phase high-performance liquid chromatographic (HPLC) technique is described for the analysis of bile acids and their conjugates in human serum. Precise quantitation is obtained using UV detection. 13C-NMR spectrometry suggests a structural explanation for the different HPLC retention times of chenodeoxycholic acid, its epimer (ursodeoxycholic acid), and their methyl esters.
Assuntos
Ácido Quenodesoxicólico/análise , Ácido Desoxicólico/análogos & derivados , Ácido Ursodesoxicólico/análise , Fenômenos Químicos , Química , Ácido Quenodesoxicólico/sangue , Cromatografia Líquida de Alta Pressão/métodos , Humanos , Ligação de Hidrogênio , Espectroscopia de Ressonância Magnética/métodos , Conformação Molecular , Ácido Ursodesoxicólico/sangueRESUMO
Detection and determination of bile acids and their glycine- and taurine-conjugated derivatives are realized by reversed-phase liquid chromatography either directly or after ion-pair formation. Operating conditions and the relation between capacity factors and structure are investigated. The determination of bile acids extracted from biological samples is possible by these techniques.