RESUMO
BACKGROUND: Trappin-2/pre-elafin is an endogenous inhibitor of human neutrophil elastase involved in inflammation, innate immunity and vascular remodelling, which consist of the complex pathological process of systemic sclerosis (SSc). OBJECTIVES: To clarify the potential role of trappin-2 in SSc. METHODS: Serum trappin-2 levels were determined by enzyme-linked immunosorbent assay in 51 SSc and 18 healthy subjects. Trappin-2 expression was evaluated in SSc lesional skin and cultured endothelial cells treated with FLI1 siRNA by immunohistochemistry, reverse transcription-real-time PCR and/or immunoblotting. Friend leukaemia virus integration 1 (Fli1) binding to the PI3 promoter was assessed by chromatin immunoprecipitation. RESULTS: Since serum trappin-2 levels inversely correlated with estimated glomerular filtration rate in SSc patients with renal dysfunction, SSc patients with normal renal function were analysed. Although serum trappin-2 levels were comparable between diffuse cutaneous SSc, limited cutaneous SSc and control subjects, the prevalence of digital ulcers or elevated right ventricular systolic pressure (RVSP) was significantly higher in SSc patients with elevated serum trappin-2 levels than in those with normal levels. Furthermore, serum trappin-2 levels were significantly increased in SSc patients with digital ulcers or elevated RVSP compared to those without. Moreover, serum trappin-2 levels positively correlated with RVSP values in SSc patients. Importantly, trappin-2 expression was enhanced in small vessels of SSc lesional skin. In cultured endothelial cells, trappin-2 expression was elevated by gene silencing of FLI1 at mRNA and protein levels and Fli1 occupied the PI3 promoter. CONCLUSIONS: Endothelial trappin-2 up-regulation partially due to Fli1 deficiency can be associated with the development of SSc vasculopathy.
Assuntos
Elafina/sangue , Escleroderma Sistêmico/sangue , Úlcera Cutânea/etiologia , Disfunção Ventricular Direita/etiologia , Idoso , Pressão Sanguínea , Vasos Sanguíneos/metabolismo , Estudos de Casos e Controles , Células Cultivadas , Células Endoteliais , Feminino , Inativação Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Proteína Proto-Oncogênica c-fli-1/genética , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/genética , Pele/irrigação sanguínea , Úlcera Cutânea/sangue , Sístole , Regulação para Cima , Disfunção Ventricular Direita/sangueRESUMO
BACKGROUND: Interleukin (IL)-25 is a member of the IL-17 family, which can promote and augment T-helper (Th) type 2 responses. The expression of IL-25 and its cognate receptor, IL-25 receptor (IL-25R), is upregulated and correlated with disease activity in Th2-associated diseases. OBJECTIVES: To examine the expression and function of IL-25 in cutaneous T-cell lymphoma (CTCL). METHODS: Expression and location of IL-25 in lesional skin was investigated with immunohistochemistry. The effect of various cytokines on IL-25 production from normal human epidermal keratinocytes was assessed by quantitative reverse-transcription real-time polymerase chain reaction. Serum IL-25 levels were measured by enzyme-linked immunosorbent assay. The direct effect of IL-25 on tumour cells was also examined using CTCL cell lines and peripheral blood mononuclear cells in patients with Sézary syndrome. RESULTS: IL-25 expression was increased in epidermal keratinocytes in lesional skin of CTCL. Th2 cytokines, IL-4 and IL-13, and periostin induced IL-25 expression by normal human epidermal keratinocytes. Serum IL-25 levels were increased in patients with advanced CTCL and correlated with serum lactate dehydrogenase levels. MyLa cells expressed IL-25R and its expression was augmented by stimulation with IL-25. IL-25 enhanced IL-13 production from MyLa cells via phosphorylation of signal transducer and activator of transcription 6. Peripheral blood mononuclear cells from one patient with Sézary syndrome expressed IL-25R and showed increase of IL-13 production by IL-25. CONCLUSIONS: Th2 cytokines highly expressed in CTCL lesional skin induce IL-25 production by epidermal keratinocytes, which may, in turn, lead to formation of a Th2-dominant microenvironment through the direct induction of IL-13 by tumour cells.
Assuntos
Interleucina-17/fisiologia , Linfoma Cutâneo de Células T/imunologia , Células Th2/imunologia , Microambiente Tumoral/imunologia , Linhagem Celular , Progressão da Doença , Feminino , Humanos , Interleucina-13/biossíntese , Interleucina-17/metabolismo , Queratinócitos/imunologia , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Fosforilação/imunologia , Receptores de Interleucina/imunologia , Fator de Transcrição STAT6/metabolismo , Regulação para Cima/imunologiaRESUMO
BACKGROUND: Advanced-stage mycosis fungoides (MF)/Sézary syndrome (SS) patients are weighted by an unfavorable prognosis and share an unmet clinical need of effective treatments. International guidelines are available detailing treatment options for the different stages but without recommending treatments in any particular order due to lack of comparative trials. The aims of this second CLIC study were to retrospectively analyze the pattern of care worldwide for advanced-stage MF/SS patients, the distribution of treatments according to geographical areas (USA versus non-USA), and whether the heterogeneity of approaches has potential impact on survival. PATIENTS AND METHODS: This study included 853 patients from 21 specialist centers (14 European, 4 USA, 1 each Australian, Brazilian, and Japanese). RESULTS: Heterogeneity of treatment approaches was found, with up to 24 different modalities or combinations used as first-line and 36% of patients receiving four or more treatments. Stage IIB disease was most frequently treated by total-skin-electron-beam radiotherapy, bexarotene and gemcitabine; erythrodermic and SS patients by extracorporeal photochemotherapy, and stage IVA2 by polychemotherapy. Significant differences were found between USA and non-USA centers, with bexarotene, photopheresis and histone deacetylase inhibitors most frequently prescribed for first-line treatment in USA while phototherapy, interferon, chlorambucil and gemcitabine in non-USA centers. These differences did not significantly impact on survival. However, when considering death and therapy change as competing risk events and the impact of first treatment line on both events, both monochemotherapy (SHR = 2.07) and polychemotherapy (SHR = 1.69) showed elevated relative risks. CONCLUSION: This large multicenter retrospective study shows that there exist a large treatment heterogeneity in advanced MF/SS and differences between USA and non-USA centers but these were not related to survival, while our data reveal that chemotherapy as first treatment is associated with a higher risk of death and/or change of therapy and thus other therapeutic options should be preferable as first treatment approach.
Assuntos
Micose Fungoide/terapia , Síndrome de Sézary/terapia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Austrália/epidemiologia , Brasil/epidemiologia , Criança , Europa (Continente)/epidemiologia , Feminino , Humanos , Japão/epidemiologia , Masculino , Oncologia/métodos , Oncologia/estatística & dados numéricos , Pessoa de Meia-Idade , Micose Fungoide/mortalidade , Micose Fungoide/patologia , Estadiamento de Neoplasias , Estudos Retrospectivos , Síndrome de Sézary/mortalidade , Síndrome de Sézary/patologia , Estados Unidos/epidemiologia , Adulto JovemRESUMO
OBJECTIVE: Evaluating bacterial load in pressure ulcers (PUs) is key to combat infection; therefore, using technologies to measure bacterial count can be particularly useful. A rapid bacteria counting system was recently developed and introduced to the wound care field. However, its reliability was not established. This cross-sectional study aimed to evaluate the inter-rater and intra-rater reliability of bacterial count using this rapid counting system. METHOD: We took bacterial swabs from patients with category I or greater PUs to assess inter- and intra-rater reliability. An assessor swabbed the longest axis of the PU once and bacterial counts were measured using a rapid bacteria counting system. To confirm the inter-rater and intra-rater reliability, intraclass correlation coefficients (ICCs) were calculated. RESULTS: We took 63 and 57 pairs of bacterial counts from 13 patients with 16 category I or greater PUs to assess inter- and intra-rater reliability, respectively. Overall ICCs [95% confidence intervals (CI)] for the bacterial counts were 0.83 [0.73-0.90, p<0.001, inter-rater reliability, n=63], and 0.89 [0.82-0.94, p< 0.001, intra-rater reliability, n=57]. CONCLUSION: A high level of reliability for counting bacterial numbers in PU sites was confirmed. The results should encourage clinicians and researchers to use this type of device for the real-time assessment of wound bacterial bioburden at the patient's bedside.
Assuntos
Carga Bacteriana , Úlcera por Pressão/microbiologia , Infecção dos Ferimentos/diagnóstico , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Variações Dependentes do Observador , Reprodutibilidade dos TestesRESUMO
BACKGROUND: Endothelial protein C receptor (EPCR), expressed predominantly on endothelial cells, plays a critical role in the regulation of the coagulation system and also mediates various cytoprotective effects by binding and activating protein C. So far, the role of EPCR has not been studied in systemic sclerosis (SSc). OBJECTIVES: To investigate the potential contribution of EPCR to the development of SSc. METHODS: EPCR expression was examined in skin samples and cultivated dermal microvascular endothelial cells by immunostaining, immunoblotting and/or quantitative reverse-transcription polymerase chain reaction. Fli1, binding to the PROCR promoter, was assessed by chromatin immunoprecipitation. Serum EPCR levels were determined by enzyme-linked immunosorbent assay in 65 patients with SSc and 20 healthy subjects. RESULTS: EPCR expression was decreased in dermal small vessels of SSc lesional skin compared with those of healthy control skin. Transcription factor Fli1, deficiency of which is implicated in SSc vasculopathy, occupied the PROCR promoter, and EPCR expression was suppressed in Fli1 small interfering RNA-treated endothelial cells and dermal small vessels of Fli1(+/-) mice. In patients with SSc, decreased serum EPCR levels were associated with diffuse skin involvement, interstitial lung disease and digital ulcers. Furthermore, serum EPCR levels inversely correlated with plasma levels of plasmin-α2-plasmin inhibitor complex (PIC). Importantly, bosentan significantly reversed circulating EPCR and PIC levels in patients with SSc, and the expression of Fli1 and EPCR in dermal small vessels was elevated in patients treated with bosentan compared with untreated patients. CONCLUSIONS: Endothelial EPCR downregulation due to Fli1 deficiency may contribute to hypercoagulation status leading to tissue fibrosis and impaired peripheral circulation in SSc.
Assuntos
Antígenos CD/fisiologia , Proteína Proto-Oncogênica c-fli-1/deficiência , Receptores de Superfície Celular/fisiologia , Escleroderma Sistêmico/etiologia , Adulto , Idoso , Análise de Variância , Animais , Bleomicina/farmacologia , Bosentana , Estudos de Casos e Controles , Células Cultivadas , Regulação para Baixo/fisiologia , Células Endoteliais/metabolismo , Receptor de Proteína C Endotelial , Antagonistas dos Receptores de Endotelina/farmacologia , Endotélio Vascular/metabolismo , Ensaio de Imunoadsorção Enzimática , Feminino , Fibrinolisina/efeitos dos fármacos , Humanos , Masculino , Camundongos , Microvasos/metabolismo , Pessoa de Meia-Idade , Escleroderma Sistêmico/sangue , Sulfonamidas/farmacologia , Trombofilia/etiologia , alfa 2-Antiplasmina/efeitos dos fármacosRESUMO
BACKGROUND: Interleukin (IL)-33 is a recently identified cytokine, which is a member of the IL-1 family and binds to a heterodimeric receptor comprising ST2 (suppression of tumorigenicity 2) and IL-1 receptor accessory protein. Serum levels of IL-33 have been reported to be upregulated in various T helper (Th)1/Th17-mediated diseases, such as rheumatoid arthritis and inflammatory bowel disease. IL-33 expression is increased in lesional skin in patients with psoriasis, but serum levels in patients with psoriasis have not yet been studied. AIM: To study serum IL-33 levels in patients with psoriasis, a Th1/Th17-mediated skin disease, before and after anti-tumour necrosis factor (TNF)-α therapy. METHODS: Serum IL-33 levels were measured in patients with psoriasis vulgaris (PV), psoriatic arthritis (PsA) or pustular psoriasis (PP), and compared with those of healthy controls. Associations between serum IL-33 levels and serum TNF-α, IL-6, vascular endothelial growth factor and C-reactive protein levels were also studied. In addition, the effect of IL-33 stimulation on IL-6, IL-8, TNF-α and VEGF secretion by human keratinocyte was analysed. RESULTS: Serum IL-33 levels in patients with PV, PsA and PP were significantly higher than those in healthy controls. Serum IL-33 levels correlated with serum TNF-α levels in patients with psoriasis, and decreased after anti-TNF-α therapy. IL-33 stimulated IL-6 and IL-8 secretion by human keratinocytes. CONCLUSIONS: These results suggest that serum IL-33 levels generally reflect increased inflammation in patients with psoriasis.
Assuntos
Interleucina-33/metabolismo , Psoríase/metabolismo , Adulto , Análise de Variância , Proteína C-Reativa/metabolismo , Estudos de Casos e Controles , Citocinas/metabolismo , Feminino , Humanos , Interleucinas/metabolismo , Queratinócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Psoríase/sangue , Fator de Necrose Tumoral alfa/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
OBJECTIVE: To verify the reliability and validity of FLIR ONE, a device connected to a smartphone, for the assessment of inflammation based on relative temperature increase compared with the thermography routinely used in pressure ulcer (PU) and diabetic foot assessment. METHOD: Participants in this pilot cross-sectional observational study were recruited from the patients in the PU team rounds and the diabetic foot outpatient clinic at the university hospital in January 2015. Cohen's kappa coefficient with its 95% confidence intervals was used to evaluate the criterion-related validity and inter- and intra-rater reliability for the thermal imaging assessment. For assessing criterion-related validity, a hand-held high-end infrared thermography device was used to provide reference data. Comparison of thermal images between the smartphone-connected device and the hand-held device was performed with both a 'predetermined range' and an 'automatically-set range.' For assessing inter-rater reliability, two assessors evaluated the thermal images taken by the mobile thermography. For assessing intra-rater reliability, one assessor evaluated the thermal images twice. The thermal images were shown to the assessors at random. RESULTS: Among 16 thermal images obtained from eight patients, kappa coefficients for each value were as follows: for the predetermined range and automatically-set range, respectively, the criterion-related validity was 1.00 (95% confidence interval 1.00-1.00) and 1.00 (95% confidence interval 1.00-1.00); the inter-rater reliability was 1.00 (95% confidence interval 1.00-1.00) and 1.00 (95% confidence interval 1.00-1.00); and the intra-rater reliability was 1.00 (95% confidence interval 1.00-1.00) and 1.00 (95% confidence interval 1.00-1.00). CONCLUSION: This pilot study suggests that FLIR ONE can work as an alternative device for assessing subclinical inflammation in PUs and the diabetic foot in clinical settings. Our results may facilitate clinicians in accepting the routine use of thermal imaging assessment at the patients' bedside.
Assuntos
Pé Diabético/diagnóstico , Úlcera por Pressão/diagnóstico , Smartphone , Termografia/instrumentação , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Feminino , Humanos , Inflamação , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Reprodutibilidade dos Testes , Região Sacrococcígea , Termografia/métodosAssuntos
Linfoma Extranodal de Células T-NK/metabolismo , Receptores CCR3/metabolismo , Receptores CXCR3/metabolismo , Neoplasias Cutâneas/metabolismo , Idoso de 80 Anos ou mais , Humanos , Perna (Membro)/patologia , Linfoma Extranodal de Células T-NK/patologia , Masculino , Pele/patologia , Neoplasias Cutâneas/patologiaRESUMO
BACKGROUND: Patients with human immunodeficiency virus (HIV) infection exhibit various skin diseases. HIV-associated eosinophilic folliculitis (EF) and pruritic papular eruption (PPE) are frequently seen. OBJECTIVE: To understand the mechanisms underlying HIV-associated EF and PPE. METHODS: In order to know frequencies of EF and PPE among patients with HIV infection, we first collected HIV(+) patients who visited dermatology clinic in National Center for Global Health and Medicine during February 2007. We next collected 25 serum samples from HIV(+) patients with skin diseases from May 2008 to May 2010. Eight of 25 patients had EF (EF group), four had PPE (PPE group) and others had non-itchy skin problems such as condyloma acuminatum (no itch group). RESULTS: We first confirmed high frequencies of EF (10.7%) and PPE (5.3%) among 75 HIV(+) patients who visited our clinic during one month. We then measured serum levels of CCL11, CCL17, CCL26 and CCL27. Serum CCL17 levels in EF were significantly higher than those of PPE and no itch group. Serum CCL26 and CCL27 levels in EF were higher than those of no itch group. The number of CD4(+) cells in EF was significantly lower than that in no itch group. CONCLUSION: High serum levels of CCL17, CCL26 and CCL27, and low CD4(+) cell counts may account for the development of HIV-associated EF.
Assuntos
Quimiocinas/sangue , Eosinofilia/sangue , Foliculite/sangue , Infecções por HIV/complicações , Dermatopatias Vesiculobolhosas/sangue , Contagem de Linfócito CD4 , Ensaio de Imunoadsorção Enzimática , Eosinofilia/complicações , Foliculite/complicações , Humanos , Dermatopatias Vesiculobolhosas/complicaçõesRESUMO
BACKGROUND: CC chemokine ligand (CCL) 18 is expressed by monocytes and dendritic cells (DCs), and has potent chemotactic activity for T cells, B cells and DCs. CCL18 expression is up-regulated in lesional skin of atopic dermatitis and bullous pemphigoid, suggesting its important roles in the development of these skin diseases. OBJECTIVE: To investigate roles of CCL18 in cutaneous T-cell lymphoma (CTCL). METHODS: The CCL18 messenger RNA (mRNA) expression in CTCL skin (n = 21) and in normal skin (n = 7) was examined by quantitative RT-PCR. CCL18 expression was also examined by immunohistochemistry. Serum CCL18 levels were measured in 38 patients with CTCL and 20 healthy controls by enzyme-linked immunosorbent assay. We also analysed correlation between serum CCL18 levels and other clinical and laboratory data. RESULTS: The CTCL lesional skin contained higher levels of CCL18 mRNA than normal skin. CCL18 was expressed by dermal macrophages and DCs in CTCL skin. Serum CCL18 levels in patients with CTCL were significantly higher than those of healthy controls and correlated with types of skin lesions. They also significantly correlated with modified severity-weighted assessment scores, serum sIL-2R, LDH, IL-4, IL-10, IL-31, CCL17 and CCL26 levels. Patients with high serum levels of CCL18 showed significantly poor prognosis compared with those with low CCL18 levels. CONCLUSION: CCL18 mRNA is up-regulated in CTCL lesional skin, and serum CCL18 levels are significantly increased and correlated with the severity of CTCL. These results suggest that CCL18 may be associated with the development of CTCL.
Assuntos
Quimiocinas CC/genética , Regulação Neoplásica da Expressão Gênica , Linfoma Cutâneo de Células T/genética , Neoplasias Cutâneas/genética , Adulto , Idoso , Biópsia por Agulha , Estudos de Casos e Controles , Quimiocinas CC/metabolismo , Progressão da Doença , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Imuno-Histoquímica , Linfoma Cutâneo de Células T/patologia , Linfoma Cutâneo de Células T/fisiopatologia , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/patologia , Prognóstico , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real/métodos , Valores de Referência , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/fisiopatologia , Estatísticas não Paramétricas , Regulação para CimaRESUMO
BACKGROUND: CD26 is a multifunctional type II transmembrane glycoprotein, which also exists as a secreted isoform, soluble CD26 (sCD26). The CD26 expression on circulating T cells is decreased in some skin diseases such as cutaneous T-cell lymphoma (CTCL) and psoriasis. It remains to be determined whether sCD26 can be used as a marker of skin diseases or not. OBJECTIVE: To investigate utility of sCD26 as a diagnostic marker of skin diseases in combination with thymus and activation-regulated chemokine (TARC). METHODS: Serum sCD26 levels were measured using enzyme-linked immunosorbent assay in 130 participants including 32 patients with atopic dermatitis (AD); 45 patients with CTCL; 26 patients with psoriasis; and 27 healthy controls. RESULTS: Serum sCD26 levels in patients with CTCL and psoriasis (162.1 ± 80.2 ng/mL and 125.4 ± 82.1 ng/mL respectively) were significantly lower than those of healthy controls (392.6 ± 198.7 ng/mL; P < 0.01 and 0.01 respectively). In patients with CTCL, serum sCD26 levels of patients with advanced stage were 135.0 ± 51.5 ng/mL and they were significantly lower than those with early stage (193.1 ± 96.0 ng/mL; P < 0.05). When we used serum sCD26 and TARC levels for diagnostic criteria, sensitivity, specificity, positive predictive value and negative predictive value for AD, CTCL and psoriasis were 65.2-73.7%, 81.4-97.6%, 65.2-94.4%, and 81.4-88.9% respectively. CONCLUSION: Serum sCD26 levels, combined with serum TARC levels, are helpful in diagnosis of AD, CTCL and psoriasis.
Assuntos
Quimiocina CCL17/sangue , Dermatite Atópica/sangue , Dipeptidil Peptidase 4/sangue , Linfoma Cutâneo de Células T/sangue , Psoríase/sangue , Adulto , Biomarcadores/sangue , Estudos de Casos e Controles , Quimiocina CCL17/metabolismo , Dermatite Atópica/diagnóstico , Dermatite Atópica/fisiopatologia , Dipeptidil Peptidase 4/metabolismo , Progressão da Doença , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Linfoma Cutâneo de Células T/diagnóstico , Linfoma Cutâneo de Células T/fisiopatologia , Masculino , Pessoa de Meia-Idade , Psoríase/diagnóstico , Psoríase/fisiopatologia , Valores de Referência , Medição de Risco , Sensibilidade e Especificidade , Índice de Gravidade de Doença , SolubilidadeRESUMO
BACKGROUND: B-cell-activating factor belonging to the tumour necrosis factor family (BAFF) is known for its role in the survival and maturation of B cells. It has been recently suggested that BAFF also plays important roles in T-cell activation in T-cell mediated diseases such as psoriasis. OBJECTIVES: To investigate the role of BAFF in cutaneous T-cell lymphoma (CTCL). METHODS: BAFF messenger RNA (mRNA) expression in skin samples (24 CTCL cases and seven healthy controls) and in skin-derived fibroblasts (five CTCL cases and five healthy controls) was examined by quantitative reverse transcription-polymerase chain reaction. We also performed immunohistochemical staining for BAFF and its receptors. Serum BAFF levels were measured in patients with CTCL (n=46), atopic dermatitis (n=36) or psoriasis (n=27) and 27 healthy controls by enzyme-linked immunosorbent assay. RESULTS: Lesional skin of CTCL contained higher levels of BAFF mRNA than normal skin and the expression levels correlated with disease activity. BAFF mRNA expression levels were elevated in fibroblasts from CTCL skin. Tumour cells in the lesional skin of CTCL expressed BAFF and its receptors, while fibroblasts expressed only BAFF. Serum BAFF levels of CTCL patients were significantly higher than those of healthy controls and correlated with types of skin lesions and clinical stages. They also significantly correlated with serum soluble interleukin-2 receptor and lactate dehydrogenase levels. CONCLUSIONS: BAFF expression in CTCL skin and serum BAFF levels are significantly increased and correlate with the severity of CTCL. These results suggest that BAFF may have important roles in the development of CTCL.