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Infecciones por Mycobacterium no Tuberculosas , Infecciones por Mycobacterium , Mycobacterium chelonae , Enfermedades Cutáneas Bacterianas , Humanos , Levofloxacino/uso terapéutico , Fluoroquinolonas/uso terapéutico , Enfermedades Cutáneas Bacterianas/diagnóstico , Enfermedades Cutáneas Bacterianas/tratamiento farmacológico , Enfermedades Cutáneas Bacterianas/microbiología , Infecciones por Mycobacterium no Tuberculosas/diagnóstico , Infecciones por Mycobacterium no Tuberculosas/tratamiento farmacológico , Antibacterianos/uso terapéuticoRESUMEN
Multiple primary malignant neoplasm (MPMN) is a rare disease with two or more malignant neoplasms in one patient. In less than 0.1% of cancer patients, four or more occur. MPMN is frequently associated with hereditary cancer syndrome, although in rare cases, it is not. A female patient developed 17 MPMNs. Although they were successfully treated with surgery, radiation, and adjuvant chemotherapy, the patient died from the recurrence of ovarian cancer. To explore genetic susceptibility to MPMN, immunohistochemical analysis, microsatellite instability analysis, germ line exome sequencing, and unscheduled DNA synthesis assays were performed. However, the results of immunohistochemical analysis and microsatellite instability indicated that there were no known hereditary cancer syndromes, and exome sequencing with 88 representative genes associated with hereditary cancer syndrome revealed no variants. An unscheduled DNA synthesis assay to rule out xeroderma pigmentosum was also performed, but the result was negative. While the presence of multiple neoplasms is rare, the present case represents 17 primary neoplasms with no associations with hereditary cancer syndrome. Although the cause of MPMN was not detected in this patient, careful follow-up and deliberate cancer screening enabled successful disease management over 17 years from the appearance of the first neoplasm.
Asunto(s)
Conducto Auditivo Externo , Neoplasias Primarias Múltiples , Colon , Esófago , Femenino , Humanos , Boca , Recurrencia Local de Neoplasia , OvarioAsunto(s)
Amiloidosis Familiar , Amiloidosis , Síndrome de Sjögren , Enfermedades Cutáneas Genéticas , Amiloide , Amiloidosis/complicaciones , Amiloidosis/diagnóstico , Humanos , Síndrome de Sjögren/complicaciones , Síndrome de Sjögren/diagnóstico , Enfermedades Cutáneas Genéticas/complicaciones , Enfermedades Cutáneas Genéticas/diagnósticoRESUMEN
Endothelial dysfunction is a hallmark of vasculopathy associated with systemic sclerosis (SSc). Reactive hyperemia peripheral arterial tonometry is a rapid and non-invasive technique to assess peripheral microvascular endothelial function by measuring changes in digital pulse volume during reactive hyperemia. Low scores of the reactive hyperemia index (RHI) imply an impaired vasodilatory response and, accordingly, impaired endothelial and vascular health. To investigate the clinical significance of the RHI in SSc patients, RHI values were measured in 43 SSc patients and 10 healthy controls. In diffuse cutaneous SSc (dcSSc) patients, RHI values were significantly decreased compared with healthy controls, and inversely correlated with disease duration. In total SSc patients, there was a significant inverse correlation between RHI values and skin score, and interstitial lung disease was associated with the decrease in RHI values. Among vascular symptoms, the current and past history of digital ulcers was seen more frequently in patients with decreased RHI values than in those with normal RHI values. Although no SSc patients had pulmonary arterial hypertension, an inverse correlation was evident between RHI values and mean pulmonary arterial pressure measured by right heart catheterization. These results indicate that the decrease in RHI values is associated with skin fibrosis, interstitial lung disease, digital ulcers and pulmonary vascular involvement leading to pulmonary arterial hypertension, supporting the canonical idea that endothelial dysfunction is a critical event underlying the development of tissue fibrosis and vascular complications in SSc.
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Hiperemia/diagnóstico , Enfermedades Pulmonares Intersticiales/epidemiología , Hipertensión Arterial Pulmonar/epidemiología , Esclerodermia Difusa/complicaciones , Úlcera Cutánea/epidemiología , Anciano , Endotelio Vascular/fisiopatología , Femenino , Fibrosis , Humanos , Hiperemia/fisiopatología , Enfermedades Pulmonares Intersticiales/etiología , Enfermedades Pulmonares Intersticiales/fisiopatología , Masculino , Persona de Mediana Edad , Hipertensión Arterial Pulmonar/etiología , Hipertensión Arterial Pulmonar/fisiopatología , Arteria Pulmonar/fisiopatología , Pulso Arterial/métodos , Estudios Retrospectivos , Medición de Riesgo/métodos , Esclerodermia Difusa/patología , Esclerodermia Difusa/fisiopatología , Piel/irrigación sanguínea , Piel/patología , Piel/fisiopatología , Úlcera Cutánea/etiología , Úlcera Cutánea/fisiopatología , Vasodilatación/fisiologíaRESUMEN
Generalized pustular psoriasis (GPP) is a systemic inflammatory disease that presents with erythema and sterile pustules, pathologically characterized by Kogoj's spongiform pustules. GPP is sometimes accompanied by mucosal involvement, and the most common lesion is on the tongue. IL36RN mutation was found to contribute to the pathogenesis of GPP especially in patients who develop GPP without a past medical history of psoriasis vulgaris. The association of IL36RN mutation with mucosal involvement in GPP is controversial. We herein report a 60-year-old male GPP patient with no past history of plaque psoriasis presenting with not only severe skin lesions and arthritis but also severe mucosal involvements of pharyngeal and gastrointestinal lesions, which led to gastrointestinal bleeding. Our case did not have any mutation in the IL36RN gene. We should be aware that severe GPP can cause gastrointestinal bleeding. The relevancy of IL36RN mutation with mucosal involvement in GPP remains to be elucidated.
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Fármacos Dermatológicos/uso terapéutico , Úlcera Duodenal/etiología , Enfermedades del Esófago/etiología , Melena/etiología , Psoriasis/complicaciones , Anticuerpos Monoclonales Humanizados/uso terapéutico , Biopsia , Úlcera Duodenal/diagnóstico por imagen , Úlcera Duodenal/patología , Endoscopía del Sistema Digestivo , Transfusión de Eritrocitos , Enfermedades del Esófago/diagnóstico por imagen , Enfermedades del Esófago/patología , Mucosa Esofágica/diagnóstico por imagen , Mucosa Esofágica/patología , Humanos , Interleucinas/genética , Mucosa Intestinal/diagnóstico por imagen , Mucosa Intestinal/patología , Masculino , Melena/diagnóstico por imagen , Melena/patología , Melena/terapia , Persona de Mediana Edad , Mutación , Psoriasis/tratamiento farmacológico , Psoriasis/genética , Psoriasis/patología , Piel/patología , Resultado del TratamientoRESUMEN
There have been no established parameters to predict responsiveness to i.v. cyclophosphamide (IVCY) pulse therapy in combination with corticosteroids in patients with interstitial lung disease (ILD) related to systemic sclerosis (SSc). This retrospective study was conducted to determine predictive factors for efficacy of IVCY at the time of before and during the treatment. Thirty-two Japanese SSc patients, ever treated for ILD with IVCY in combination with prednisolone, were analyzed retrospectively. We performed detailed time-course analyses of parameters derived from blood samples and pulmonary function tests. With the exclusion of eight unclassified patients, 24 patients were classified into 14 good responders (GR) or 10 poor responders (PR) on the basis of changes in percent predicted diffusing capacity for carbon monoxide (DLco). Pretreatment percent predicted DLco was significantly reduced in PR compared with GR. In addition, serum parameters such as Krebs von den Lungen-6 (KL-6), surfactant protein D (SP-D) and C-reactive protein were significantly higher in PR than in GR. Furthermore, our time-course analyses revealed a transient increase in serum KL-6 levels with a peak at 3 months after the first infusion of cyclophosphamide, which showed no relation to therapeutic efficacy. Moreover, continuously high serum KL-6 levels (>2000 U/mL) and rapid decrease in SP-D levels (<200 ng/mL) during IVCY were remarkably characteristic of PR and GR, respectively. ILD severity/activity before treatment and variability of serum KL-6 and SP-D levels during treatment may be useful to predict therapeutic effects of IVCY on SSc-ILD.
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Ciclofosfamida/uso terapéutico , Inmunosupresores/uso terapéutico , Enfermedades Pulmonares Intersticiales/tratamiento farmacológico , Esclerodermia Sistémica/complicaciones , Adulto , Anciano , Biomarcadores/sangre , Ciclofosfamida/administración & dosificación , Femenino , Humanos , Inmunosupresores/administración & dosificación , Infusiones Intravenosas , Japón , Estudios Longitudinales , Enfermedades Pulmonares Intersticiales/sangre , Enfermedades Pulmonares Intersticiales/diagnóstico , Enfermedades Pulmonares Intersticiales/etiología , Masculino , Persona de Mediana Edad , Pronóstico , Capacidad de Difusión Pulmonar , Quimioterapia por Pulso , Estudios Retrospectivos , Esclerodermia Sistémica/sangre , Índice de Severidad de la Enfermedad , Resultado del TratamientoAsunto(s)
Absceso/inmunología , Anticuerpos Monoclonales/efectos adversos , Fármacos Dermatológicos/efectos adversos , Psoriasis/tratamiento farmacológico , Infecciones Cutáneas Estafilocócicas/inmunología , Absceso/diagnóstico por imagen , Absceso/microbiología , Absceso/terapia , Adulto , Antibacterianos/uso terapéutico , Anticuerpos Monoclonales Humanizados , Drenaje , Humanos , Imagen por Resonancia Magnética , Masculino , Staphylococcus aureus Resistente a Meticilina/aislamiento & purificación , Persona de Mediana Edad , Psoriasis/inmunología , Receptores de Interleucina-17/antagonistas & inhibidores , Receptores de Interleucina-17/inmunología , Infecciones Cutáneas Estafilocócicas/diagnóstico por imagen , Infecciones Cutáneas Estafilocócicas/microbiología , Infecciones Cutáneas Estafilocócicas/terapiaAsunto(s)
Antibacterianos/uso terapéutico , Hipertermia Inducida , Infecciones por Mycobacterium no Tuberculosas/diagnóstico , Mycobacterium marinum/aislamiento & purificación , Anciano , Animales , Biopsia , Terapia Combinada/métodos , Antebrazo , Mano , Humanos , Masculino , Persona de Mediana Edad , Infecciones por Mycobacterium no Tuberculosas/microbiología , Infecciones por Mycobacterium no Tuberculosas/patología , Infecciones por Mycobacterium no Tuberculosas/terapia , Piel/microbiología , Piel/patología , Resultado del TratamientoRESUMEN
Localized scleroderma is an inflammatory disorder affecting the skin and underlying tissues, a certain subset of which develops other autoimmune diseases on the basis of a prominent autoimmune background. We here report a unique case of linear scleroderma presenting with a sclerotic plaque on the left thigh, multiple lymphadenopathy in bilateral inguinal and para-aortic lymph nodes, and hepatosplenomegaly, who later developed polymyositis. We describe the detailed disease course of our case and discuss the clinical significance of multiple lymphadenopathy in localized scleroderma based on a review of published work.
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Enfermedades Autoinmunes/patología , Linfadenopatía/patología , Linfedema/inmunología , Polimiositis/patología , Esclerodermia Localizada/patología , Autoanticuerpos/sangre , Enfermedades Autoinmunes/diagnóstico por imagen , Enfermedades Autoinmunes/tratamiento farmacológico , Enfermedades Autoinmunes/inmunología , Centriolos/inmunología , Electromiografía , Fascia/diagnóstico por imagen , Fascia/patología , Femenino , Glucocorticoides/uso terapéutico , Hepatomegalia/diagnóstico por imagen , Hepatomegalia/inmunología , Humanos , Ganglios Linfáticos/patología , Linfadenopatía/diagnóstico por imagen , Linfadenopatía/tratamiento farmacológico , Linfadenopatía/inmunología , Linfedema/diagnóstico por imagen , Imagen por Resonancia Magnética , Persona de Mediana Edad , Músculo Esquelético/diagnóstico por imagen , Músculo Esquelético/enzimología , Músculo Esquelético/patología , Polimiositis/diagnóstico por imagen , Polimiositis/tratamiento farmacológico , Polimiositis/inmunología , Prednisolona/uso terapéutico , Esclerodermia Localizada/diagnóstico por imagen , Esclerodermia Localizada/tratamiento farmacológico , Esclerodermia Localizada/inmunología , Piel/patología , Esplenomegalia/diagnóstico por imagen , Esplenomegalia/inmunología , Tomografía Computarizada por Rayos XRESUMEN
Systemic sclerosis (SSc) is characterized by disturbed blood circulation. The effect of ambrisentan, an endothelin-A receptor-selective antagonist, on impaired peripheral circulation in SSc remains largely elusive. Here we show SSc patients, whose clinical symptoms such as cyanosis and Raynaud's phenomenon, were ameliorated by the treatment with ambrisentan. Additionally, objective evaluations with thermography showed improvement of hand coldness in steady-state and cold challenge tests. Ambrisentan might have a potential to improve peripheral circulation in SSc.
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Antagonistas de los Receptores de la Endotelina A/uso terapéutico , Fenilpropionatos/uso terapéutico , Piridazinas/uso terapéutico , Enfermedad de Raynaud/tratamiento farmacológico , Esclerodermia Sistémica/tratamiento farmacológico , Anciano , Femenino , Humanos , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
AIM: To determine serum galectin-1 levels and their clinical associations in patients with systemic sclerosis (SSc). METHOD: Serum galectin-1 levels were examined by enzyme-linked immunosorbent assay in 66 patients with SSc and 24 healthy individuals. RESULTS: No significant differences were observed in serum galectin-1 levels between patients with SSc (9.4 ± 5.6 ng/mL), and healthy individuals (8.9 ± 1.3 ng/mL). Among patients with SSc, no significant differences were seen in serum galectin-1 levels between those with diffuse cutaneous SSc (8.8 ± 5.7 ng/mL; n = 31) and those with limited cutaneous SSc (10.0 ± 5.4 ng/mL; n = 35). Patients with SSc who had increased galectin-1 levels less often had pitting scars/digital ulcers than those with normal galectin-1 levels (17% vs. 49%; P < 0.01). Consistently, galectin-1 levels were significantly lower in SSc patients with pitting scars/digital ulcers than in those without pitting scars/digital ulcers (6.9 ± 4.8 vs. 10.9 ± 5.5 ng/mL; P < 0.01). CONCLUSION: These results suggest that galectin-1 is a protective factor against the development of digital vasculopathy in SSc. In addition, measurement of serum galectin-1 levels may be useful for risk stratification for the development of digital vasculopathy in the early phase of SSc.
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Cicatriz/etiología , Galectina 1/sangre , Esclerodermia Sistémica/sangre , Úlcera Cutánea/etiología , Adolescente , Adulto , Anciano , Biomarcadores/sangre , Estudios de Casos y Controles , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores Protectores , Factores de Riesgo , Esclerodermia Sistémica/complicaciones , Esclerodermia Sistémica/diagnóstico , Adulto JovenRESUMEN
Patients with systemic sclerosis (SSc) have an increased risk of malignancy compared with the general population. Recently, SSc patients with anti-RNA polymerase III antibody have been reported to have an increased risk of malignancy as compared with those with other disease-specific autoantibodies in US, European and Australian populations. Therefore, we studied the relationship between disease-specific autoantibodies and malignancy in 261 Japanese SSc patients. The prevalence of malignancy was significantly higher in patients with anti-RNA polymerase III antibody (7/22, 31.8%) than in those with anti-topoisomerase I antibody (2/82, 2.4%) and in those with anticentromere antibody (8/137, 5.8%). Importantly, among seven patients with anti-RNA polymerase III antibody and malignancy, three patients (42.9%) developed malignancy from 6 months before to 12 months after SSc onset. Thus, malignancy complication in Japanese SSc patients with anti-RNA polymerase III antibody is as high as that in other races, suggesting that SSc patients with anti-RNA polymerase III antibody share the same pathological process among different ethnic groups.
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Anticuerpos Antinucleares/sangre , Neoplasias/etnología , ARN Polimerasa III/inmunología , Esclerodermia Sistémica/sangre , ADN-Topoisomerasas de Tipo I/inmunología , Femenino , Humanos , Incidencia , Japón/epidemiología , Masculino , Persona de Mediana Edad , Neoplasias/epidemiologíaRESUMEN
OBJECTIVES: Chemerin is a member of adipocytokines with a chemoattractant effect on plasmacytoid dendritic cells and macrophages and pro-angiogenic properties. We investigated the potential role of chemerin in the development of SSc. METHODS: Chemerin expression was evaluated by immunostaining and/or real-time quantitative RT-PCR in human and murine skin. The mechanisms regulating chemerin expression in dermal fibroblasts and endothelial cells were examined using the gene silencing technique and chromatin immunoprecipitation. Serum chemerin levels were determined by ELISA in 64 SSc patients and 19 healthy subjects. RESULTS: In SSc lesional skin, chemerin was up-regulated in small blood vessels, while it was down-regulated in fibroblasts surrounded with thickened collagen bundles. The decreased expression of chemerin was significantly reversed by TGF-ß1 antisense oligonucleotide in cultured SSc dermal fibroblasts and chemerin expression was markedly decreased in dermal fibroblasts of bleomycin-treated mice. Gene silencing of transcription factor Fli1, which binds to the chemerin promoter, induced chemerin expression in human dermal microvascular endothelial cells and Fli1(+/-) mice exhibited elevated chemerin expression in dermal blood vessels. Serum chemerin levels inversely correlated with estimated glomerular filtration rate in SSc patients with renal dysfunction. In SSc patients with normal renal function, patients with digital ulcers had higher serum chemerin levels than those without. CONCLUSION: Chemerin is down-regulated in SSc dermal fibroblasts by autocrine TGF-ß, while it is up-regulated in SSc dermal blood vessels through endothelial Fli1 deficiency. Increased chemerin expression in dermal blood vessels may be associated with the development of digital ulcers in SSc.
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Quimiocinas/metabolismo , Células Endoteliales/metabolismo , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Proteína Proto-Oncogénica c-fli-1/deficiencia , Esclerodermia Sistémica/complicaciones , Úlcera/etiología , Úlcera/metabolismo , Anciano , Animales , Bleomicina/efectos adversos , Estudios de Casos y Controles , Células Cultivadas , Modelos Animales de Enfermedad , Células Endoteliales/efectos de los fármacos , Células Endoteliales/patología , Femenino , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Fibroblastos/patología , Dedos , Silenciador del Gen , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Persona de Mediana Edad , Oligonucleótidos Antisentido/farmacología , Proteína Proto-Oncogénica c-fli-1/genética , Proteína Proto-Oncogénica c-fli-1/metabolismo , Esclerodermia Sistémica/metabolismo , Piel/irrigación sanguínea , Piel/patología , Factor de Crecimiento Transformador beta1/metabolismo , Úlcera/inducido químicamenteRESUMEN
Previous studies have demonstrated that B cells play critical roles in autoimmune disorders including systemic sclerosis (SSc) and systemic lupus erythematosus (SLE). However, the effectiveness of rituximab (RTX), a chimeric anti-CD20 antibody, for SSc-associated interstitial lung disease (ILD) or SLE disease activity remains controversial. We herein report an SSc patient with severely progressed ILD and concomitant SLE treated by two cycles of RTX at baseline and half a year later. This treatment improved ILD and SLE activities, along with reduction of dermal sclerosis and serum anti-topoisomerase I antibody levels. In addition, our detailed time-course data indicate that half a year may be appropriate as an interval between each cycle of RTX therapy aimed at SSc-associated ILD or SLE. Overall, the current report could pave the way to establish RTX as a disease-modifying drug for patients with SSc and/or SLE showing resistance to other already approved medications.
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Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Enfermedades Pulmonares Intersticiales/terapia , Lupus Eritematoso Sistémico/terapia , Esclerodermia Sistémica/terapia , Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Autoanticuerpos/sangre , Linfocitos B/inmunología , ADN-Topoisomerasas de Tipo I/inmunología , Femenino , Humanos , Enfermedades Pulmonares Intersticiales/complicaciones , Enfermedades Pulmonares Intersticiales/inmunología , Lupus Eritematoso Sistémico/complicaciones , Lupus Eritematoso Sistémico/inmunología , Persona de Mediana Edad , Rituximab , Esclerodermia Sistémica/complicaciones , Esclerodermia Sistémica/inmunología , Resultado del TratamientoRESUMEN
INTRODUCTION: Although the pathogenesis of systemic sclerosis (SSc) still remains unknown, recent studies have demonstrated that endothelins are deeply involved in the developmental process of fibrosis and vasculopathy associated with SSc, and a dual endothelin receptor antagonist, bosentan, has a potential to serve as a disease modifying drug for this disorder. Importantly, endothelin-1 (ET-1) exerts a pro-fibrotic effect on normal dermal fibroblasts and bosentan reverses the pro-fibrotic phenotype of SSc dermal fibroblasts. The purpose of this study was to clarify the details of molecular mechanisms underlying the effects of ET-1 and bosentan on dermal fibroblasts, which have not been well studied. METHODS: The mRNA levels of target genes and the expression and phosphorylation levels of target proteins were determined by reverse transcription real-time PCR and immunoblotting, respectively. Promoter assays were performed using a sequential deletion of human α2 (I) collagen (COL1A2) promoter. DNA affinity precipitation and chromatin immunoprecipitation were employed to evaluate the DNA binding ability of Fli1. Fli1 protein levels in murine skin were evaluated by immunostaining. RESULTS: In normal fibroblasts, ET-1 activated c-Abl and protein kinase C (PKC)-δ and induced Fli1 phosphorylation at threonine 312, leading to the decreased DNA binding of Fli1, a potent repressor of the COL1A2 gene, and the increase in type I collagen expression. On the other hand, bosentan reduced the expression of c-Abl and PKC-δ, the nuclear localization of PKC-δ, and Fli1 phosphorylation, resulting in the increased DNA binding of Fli1 and the suppression of type I collagen expression in SSc fibroblasts. In bleomycin-treated mice, bosentan prevented dermal fibrosis and increased Fli1 expression in lesional dermal fibroblasts. CONCLUSIONS: ET-1 exerts a potent pro-fibrotic effect on normal fibroblasts by activating "c-Abl - PKC-δ - Fli1" pathway. Bosentan reverses the pro-fibrotic phenotype of SSc fibroblasts and prevents the development of dermal fibrosis in bleomycin-treated mice by blocking this signaling pathway. Although the efficacy of bosentan for dermal and pulmonary fibrosis is limited in SSc, the present observation definitely provides us with a useful clue to further explore the potential of the upcoming new dual endothelin receptor antagonists as disease modifying drugs for SSc.