Assuntos
Complemento C3/análise , Toxidermias/etiologia , Toxidermias/imunologia , Medicamentos de Ervas Chinesas/efeitos adversos , Dermatopatias Vesiculobolhosas/induzido quimicamente , Dermatopatias Vesiculobolhosas/imunologia , Idoso , Toxidermias/patologia , Feminino , Imunofluorescência , Humanos , Dermatopatias Vesiculobolhosas/patologiaRESUMO
BACKGROUND: Tumour necrosis factor (TNF)-α antagonist therapy is currently used for moderate and severe psoriasis. However, this treatment has several drawbacks, including interindividual variability in clinical response and secondary loss of effectiveness. OBJECTIVES: To evaluate quantitatively the TNF-α-neutralizing activity of the plasma of patients with psoriasis during TNF-α antagonist therapy and to determine poor responders objectively. METHODS: We used a human interleukin-8 reporter monocyte cell line, THP-G8, that harbours a stable luciferase orange (SLO) gene under the control of the interleukin-8 promoter. After confirming its dose-dependent response to exogenous TNF-α, we examined the suppressive activity of TNF-α antagonists and of the patients' plasma during TNF-α antagonist therapy on TNF-α-induced SLO luciferase activity (TNF-SLO-LA). RESULTS: Pretreatment of TNF-α with TNF-α antagonists or with the plasma of patients with psoriasis who achieved 75% improvement in Psoriasis Area and Severity Index (PASI 75) dose dependently suppressed TNF-SLO-LA. There was a significant correlation between change in PASI and percentage suppression (inhibitory rate of a 1 : 2 dilution of patient plasma on TNF-SLO-LA). A percentage suppression of 50·3% has a positive predictive value of 87% of achieving PASI 75, with a sensitivity of 93% and a specificity of 80%. CONCLUSIONS: Therapeutic monitoring of patients with psoriasis during TNF-α antagonist therapy using THP-G8 can provide a useful tool to determine objectively the efficacy of the administered TNF-α antagonists.
Assuntos
Fármacos Dermatológicos/uso terapêutico , Monitoramento de Medicamentos/métodos , Interleucina-8/metabolismo , Psoríase/tratamento farmacológico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adalimumab/imunologia , Adalimumab/uso terapêutico , Adulto , Idoso , Anticorpos/metabolismo , Linhagem Celular , Feminino , Humanos , Infliximab/imunologia , Infliximab/uso terapêutico , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Resultado do Tratamento , Fator de Necrose Tumoral alfa/imunologia , Adulto JovemAssuntos
COVID-19 , Dermatoses da Mão/etiologia , Desinfecção das Mãos , Ceratodermia Palmar e Plantar/etiologia , Adulto , COVID-19/prevenção & controle , Feminino , Dermatoses da Mão/patologia , Dermatoses da Mão/terapia , Humanos , Ceratodermia Palmar e Plantar/patologia , Ceratodermia Palmar e Plantar/terapia , SARS-CoV-2 , Água/efeitos adversosAssuntos
Urticária , Colinérgicos , Humanos , Dor/etiologia , Prurido/etiologia , Urticária/diagnóstico , Escala Visual AnalógicaRESUMO
BACKGROUND: Current treatment with biologics has produced dramatic therapeutic effects in patients with psoriasis, although these agents occasionally decrease in efficacy. One of the main factors responsible for this attenuation is attributed to the development of antidrug antibodies (ADAs). OBJECTIVES: To analyse the relationship between serum drug concentrations, the presence of ADAs and treatment efficacy of adalimumab and infliximab, and to determine the optimal use of these biologics. METHODS: This was a 1-year prospective study in the dermatology departments of Kobe University Hospital and collaborating hospitals. All patients starting a regimen of adalimumab and infliximab for psoriasis were included. We measured the serum concentration of the drugs and titres of antibodies to adalimumab and infliximab, as well as the Psoriasis Area and Severity Index scores at weeks 0, 4, 12, 24 and 48 during the first year of treatment. RESULTS: We observed a 50% positive rate of ADAs to adalimumab, and a 41% positive rate of ADAs to infliximab. The titres of ADAs showed a wide range from low to high titres. In the high-titre groups, the patients exhibited a decreased clinical response, and demonstrated a negative correlation between titre and clinical response. However, an equivalent therapeutic effect was observed between the low-titre group and the group with no antibodies detected for adalimumab. For infliximab, the patients with ADAs showed decreased clinical response. An apparent negative correlation between antibody production and reduced clinical response was observed. CONCLUSIONS: Two biologics, adalimumab and infliximab, showed different therapeutic behaviour. The measurement of ADAs and drug concentrations has important implications for treatment with biologics.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Anticorpos Neutralizantes/fisiologia , Fármacos Dermatológicos/uso terapêutico , Psoríase/tratamento farmacológico , Adalimumab , Anticorpos Monoclonais/sangue , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais Humanizados/sangue , Anticorpos Monoclonais Humanizados/imunologia , Formação de Anticorpos/efeitos dos fármacos , Fatores Biológicos/uso terapêutico , Fármacos Dermatológicos/sangue , Fármacos Dermatológicos/imunologia , Feminino , Humanos , Infliximab , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Psoríase/imunologia , Resultado do TratamentoAssuntos
Neoplasias Cutâneas/patologia , Xeroderma Pigmentoso/genética , Xeroderma Pigmentoso/patologia , Transportadores de Cassetes de Ligação de ATP/genética , Criança , Reparo do DNA/genética , Neoplasias Faciais/genética , Neoplasias Faciais/patologia , Feminino , Heterozigoto , Humanos , Melanose/genética , Melanose/patologia , Mutação de Sentido Incorreto/genética , Neoplasias Cutâneas/genéticaRESUMO
BACKGROUND: Solar urticaria (SU) is a photodermatosis that is thought to be caused through the effects of mast cell mediators released because of an altered chromophore, possibly a photoallergen recognized by IgE. Phototherapy for SU to induce a tolerant state appears to be most effective, but is often time consuming and provides only short-lived remission. Ultraviolet (UV) A rush hardening has been successful and less time consuming in serum factor-negative patients with SU. However, the mechanism of action and long-lasting effects of UVA rush hardening therapy remain unclear. OBJECTIVES: We aimed to evaluate whether UVA rush hardening exhibits long-lasting therapeutic effects in serum factor-positive patients with SU and to examine the action mechanism of tolerance. METHODS: Two serum factor-positive patients with SU were exposed to multiple UVA irradiations at 1-h intervals per day for 2 or 3 days. Intradermal injection of their in vitro-irradiated autologous serum or compound 48/80 and a prick test for histamine were performed before and after UVA rush hardening. RESULTS: The two serum factor-positive patients with SU benefited greatly from UVA rush hardening, as documented by a marked increase in minimal wealing dose, and remained symptom free without using sunscreen in their daily life. Intradermal injection of in vitro-irradiated autologous serum induced wealing before hardening, but not in tolerized skin after hardening. The responses to compound 48/80 and histamine were unaltered. CONCLUSIONS: UVA rush hardening is an effective and long-lasting treatment even in serum factor-positive patients with SU. The mechanism of tolerance may involve continued blockade of photoallergen binding to IgE on mast cells, rather than depletion of mast cell mediators or histamine tachyphylaxis.
Assuntos
Transtornos de Fotossensibilidade/radioterapia , Luz Solar/efeitos adversos , Terapia Ultravioleta/métodos , Urticária/radioterapia , Adulto , Eritema/etiologia , Eritema/radioterapia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Urticária/etiologiaAssuntos
Doenças da Medula Óssea/microbiologia , Infecções por Bactérias Gram-Positivas/complicações , Granuloma/microbiologia , Doenças Linfáticas/microbiologia , Propionibacterium acnes/isolamento & purificação , Sarcoidose Pulmonar/microbiologia , Dermatopatias/microbiologia , Adulto , Humanos , Linfonodos/microbiologia , MasculinoRESUMO
BACKGROUND: Mondor's disease (MD) is considered an inflammatory condition of superficial vasculitis that develops mainly in the anterolateral thoracoabdominal wall. The pathogenesis of the disease has been controversial, however, because of the lack of histopathologic methods for differentiating between the small vein and the lymphatic vessel. AIM: To objectively examine the origin of vascular lesions in MD, we investigated the endothelial cells of their blood and lymphatic vessels. METHODS: Immunohistochemical examinations were carried out on specimens involving vascular lesions from 16 patients with MD, using antibodies against von Willebrand factor and human lymphatic vessel endothelial hyaluronan receptor-1, which specifically discriminate between lymphatic and blood vessels. RESULTS: The histopathologic findings clearly showed thrombophlebitis in 14 patients, a lesion originating in the lymphatic vessel in one patient, and sclerosis that consisted of the artery together with veins in another. CONCLUSION: This study suggests that almost all cases of MD are due to thrombophlebitis, with a small minority due to lymphangitis or other conditions. We believe this study will contribute to the better recognition of the factual changes in the condition designated MD.
Assuntos
Endotélio Linfático/metabolismo , Endotélio Linfático/patologia , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Vasculite/patologia , Proteínas de Transporte Vesicular/metabolismo , Fator de von Willebrand/metabolismo , Parede Abdominal/patologia , Adulto , Idoso , Diagnóstico Diferencial , Feminino , Humanos , Linfangite/complicações , Linfangite/diagnóstico , Vasos Linfáticos/metabolismo , Vasos Linfáticos/patologia , Masculino , Pessoa de Meia-Idade , Tromboflebite/complicações , Tromboflebite/diagnóstico , Vasculite/etiologia , Vasculite/metabolismo , Veias/metabolismo , Veias/patologiaRESUMO
AIMS: Although interleukin 8 (IL-8) is not produced in the normal cornea, it has been detected there in several pathological conditions. In this study, the direct effects of IL-8 overexpression on the cornea was examined. METHODS: The corneal surface of severe combined immunodeficiency mice was infected by the adenovirus vector encoding human IL-8 (IL-8/Ad5) and clinical and pathological changes were observed at various time points. RESULTS: Clinically, marked angiogenesis and ulcer formation in the cornea were observed by 12 hours and 24 hours, respectively. Histologically, prominent angiogenesis was observed in the corneal stroma at 12 hours. Cleft formation between the corneal epithelium and stroma, and neutrophil infiltration into the corneal stroma were seen at 16 hours. By 24 hours after the infection with IL-8/Ad5, a shallow ulcer was formed in the cornea. In contrast, infection with the control adenovirus carrying the beta galactosidase gene (LacZ) showed neither corneal ulceration nor neutrophil infiltration. Immunohistochemical analysis showed that infection with IL-8/Ad5 resulted in the production of IL-8 by corneal and conjunctival stromal cells. CONCLUSION: Our results indicate that IL-8 overexpression in corneal tissue causes ulcer formation in the cornea through chemoattraction of neutrophils, suggesting the aetiological role of IL-8 in some types of corneal ulcers.
Assuntos
Córnea/metabolismo , Úlcera da Córnea/etiologia , Interleucina-8/metabolismo , Adenoviridae/genética , Animais , Córnea/patologia , Úlcera da Córnea/patologia , Vetores Genéticos/administração & dosagem , Imuno-Histoquímica , Interleucina-8/genética , Camundongos , Camundongos SCID , Soluções Oftálmicas , Transdução Genética/métodosRESUMO
O6-Alkylguanine-DNA alkyltransferase (AGT) activity was assayed in the extracts of 47 cell strains originating from mouse skin tumors induced by UV irradiation. They were also examined for the sensitivity to 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride by colony formation. The AGT activity (fmol/mg protein) of the tumor cell strains varied widely and the mean +/- SE was 72.5 +/- 9.37, while the AGT activity of the nontumor cell strains was 134 +/- 17. Among 47 strains, 6 strains showed extremely low or no AGT activity, about 5 fmol/mg protein or less, and were hypersensitive to 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride. Long-term culture of the tumor cells did not change the AGT activity except in some strains which might have had coexisting normal cells in the population in early passages. All strains showed similar UV sensitivity regardless of AGT activity. This is the first report which demonstrates that about 13% of newly induced tumor cell strains are deficient in AGT activity similar to Mer-/Mex- phenotype that was found in approximately 20% of the established human tumor cell strains.
Assuntos
Proteínas de Bactérias/metabolismo , Proteínas de Escherichia coli , Proteínas de Neoplasias/metabolismo , Neoplasias Induzidas por Radiação/enzimologia , Neoplasias Cutâneas/enzimologia , Animais , Ensaios de Seleção de Medicamentos Antitumorais , Camundongos , Camundongos Pelados , Neoplasias Induzidas por Radiação/tratamento farmacológico , Nimustina/farmacologia , O(6)-Metilguanina-DNA Metiltransferase , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/etiologia , Organismos Livres de Patógenos Específicos , Fatores de Tempo , Fatores de Transcrição , Células Tumorais Cultivadas/enzimologiaRESUMO
A shuttle vector plasmid, pYZ289, was constructed from the pZ189 plasmid and polyoma virus DNA. The plasmid contains a supF gene as a marker of mutation and can replicate in both Escherichia coli and mouse cells. The pYZ289 plasmids treated with N-methyl-N-nitrosourea were passed through mouse cells originating from skin tumors, which are either proficient (HL18) or deficient (HL8) in O6-methylguanine-DNA methyltransferase activity, and mutations in the supF gene were analyzed. In the repair-deficient HL8 cells, N-methyl-N-nitrosourea-treated pYZ289 showed lower plasmid survival and higher mutation frequency than in the repair-proficient HL18 cells. DNA sequence analysis in the mutated supF gene revealed that most mutations occurred in G:C base pairs (86% for HL8, 76% for HL18), and the frequency of G:C----A:T transition was higher in HL8 cells (69%) than in HL18 cells (31%). G:C----T:A transversions occurred more frequently in HL18 cells (31%) than in HL8 cells (12%). Mutations occurred frequently at the base pair positions of 123 and 159 of supF gene in HL18 cells and at 169 in HL8 cells. Analysis of the bases neighboring the mutations appeared to be related to the mutability of the base pairs with the sequence of 5'-purine-G-G-3' being the most frequently mutated. These results show that the new pYZ289 plasmid is useful for the analysis of mutations and that a deficiency in O6-methylguanine-DNA methyltransferase enhances the N-methyl-N-nitrosourea-induced mutation with significant specificity.
Assuntos
Metilnitrosoureia/toxicidade , Metiltransferases/deficiência , Mutação/genética , Plasmídeos/genética , Transfecção , Animais , Sequência de Bases , Linhagem Celular Transformada , Relação Dose-Resposta a Droga , Genes Virais/genética , Camundongos , Camundongos Pelados , Dados de Sequência Molecular , O(6)-Metilguanina-DNA Metiltransferase , Organismos Livres de Patógenos EspecíficosRESUMO
Mutations in the p53 gene were identified in five of eight non-melanoma skin tumors in the sun-exposed areas of xeroderma pigmentosum patients by the polymerase chain reaction and single strand conformation polymorphism analysis followed by sequencing of the DNA. All mutations occurred at the dipyrimidine sites, indicating that they were caused by UV irradiation. Two tumors had multiple mutations, and four tumors had nonsense mutations. Since xeroderma pigmentosum patients are extremely sensitive to UV, the solar UV should have caused the mutations in the p53 gene and the mutations must have played a significant role in UV tumorigenesis.