RESUMEN
BACKGROUND: Autoimmune pulmonary alveolar proteinosis (APAP) is a diffuse lung disease that causes abnormal accumulation of lipoproteins in the alveoli; however, its pathogenesis remains unclear. Recently, APAP cases have been reported during the course of dermatomyositis. The combination of these two diseases may be coincidental; however, it may have been overlooked because differentiating APAP from a flare-up of interstitial pneumonia associated with dermatomyositis is challenging. This didactic case demonstrates the need for early APAP scrutiny. CASE PRESENTATION: A 50-year-old woman was diagnosed with anti-melanoma differentiation-associated gene 5 (anti-MDA5) antibody-positive dermatitis and interstitial pneumonia in April 2021. The patient was treated with corticosteroids, tacrolimus, and cyclophosphamide pulse therapy for interstitial pneumonia complicated by MDA5 antibody-positive dermatitis, which improved the symptoms and interstitial pneumonia. Eight months after the start of treatment, a new interstitial shadow appeared that worsened. Therefore, three additional courses of cyclophosphamide pulse therapy were administered; however, the respiratory symptoms and interstitial shadows did not improve. Respiratory failure progressed, and 14 months after treatment initiation, bronchoscopy revealed turbid alveolar lavage fluid, numerous foamy macrophages, and numerous periodic acid-Schiff-positive unstructured materials. Blood test results revealed high anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) antibody levels, leading to a diagnosis of APAP. The patient underwent whole-lung lavage, and the respiratory disturbance promptly improved. Anti-GM-CSF antibodies were measured from the cryopreserved serum samples collected at the time of diagnosis of anti-MDA5 antibody-positive dermatitis, and 10 months later, both values were significantly higher than normal. CONCLUSIONS: This is the first report of anti-MDA5 antibody-positive dermatomyositis complicated by interstitial pneumonia with APAP, which may develop during immunosuppressive therapy and be misdiagnosed as a re-exacerbation of interstitial pneumonia. In anti-MDA5 antibody-positive dermatomyositis, APAP comorbidity may have been overlooked, and early evaluation with bronchoalveolar lavage fluid and anti-GM-CSF antibody measurements should be considered, keeping the development of APAP in mind.
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Enfermedades Autoinmunes , Dermatitis , Dermatomiositis , Enfermedades Pulmonares Intersticiales , Proteinosis Alveolar Pulmonar , Femenino , Humanos , Persona de Mediana Edad , Proteinosis Alveolar Pulmonar/complicaciones , Proteinosis Alveolar Pulmonar/diagnóstico , Proteinosis Alveolar Pulmonar/tratamiento farmacológico , Dermatomiositis/complicaciones , Dermatomiositis/tratamiento farmacológico , Autoanticuerpos , Enfermedades Pulmonares Intersticiales/complicaciones , Enfermedades Pulmonares Intersticiales/diagnóstico , Enfermedades Pulmonares Intersticiales/tratamiento farmacológico , Ciclofosfamida/uso terapéutico , Dermatitis/complicaciones , Helicasa Inducida por Interferón IFIH1RESUMEN
The protein long interspersed nuclear elements-1 (LINE-1) serves as a useful surrogate marker of global methylation but little is known for Merkel cell carcinoma. LINE-1 expression was found only in Merkel cell polyomavirus (MCPyV)-positive Merkel cell carcinomas but not in MCPyV-negative Merkel cell carcinomas, suggesting that epigenetic dysregulation may be associated with MCPyV expression.
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Carcinoma de Células de Merkel , Poliomavirus de Células de Merkel , Infecciones por Polyomavirus , Neoplasias Cutáneas , Infecciones Tumorales por Virus , Biomarcadores , Carcinoma de Células de Merkel/genética , Carcinoma de Células de Merkel/patología , Humanos , Poliomavirus de Células de Merkel/genética , Neoplasias Cutáneas/patologíaRESUMEN
An 82-year-old man, who was healthy and had worked as a farmer, experienced worsening neurological symptoms over a seven-month period, which eventually caused his death. Multiple fluctuating brain lesions were detected radiographically. Clinically, sarcoidosis was ranked high among the differential diagnoses because of the presence of skin lesions showing granulomatous inflammation, confirmed by biopsy. The patient's cerebrospinal fluid was also examined, but no definitive diagnosis was made while he was alive. An autopsy revealed multiple granulomatous amebic encephalitis lesions in the brain. Genetic and immunohistochemical analyses identified Balamuthia (B.) mandrillaris, a free-living ameba, which resides in soil and fresh water, as the causative organism. A retrospective examination revealed B. mandrillaris in the biopsied skin as well as cerebrospinal fluid, strongly suggesting that the ameba had spread into the brain percutaneously. Few studies have detailed the cutaneous pathology of B. mandrillaris infections. In general, granulomatous amebic encephalitis is extremely difficult to diagnose without autopsy, but the present case provides a clue that could allow similar cases to be diagnosed earlier; that is, the presence of skin lesions.
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Amebiasis , Amoeba , Balamuthia mandrillaris , Dermatitis , Encefalitis , Encefalitis Infecciosa , Anciano de 80 o más Años , Amebiasis/diagnóstico , Autopsia , Encéfalo/patología , Dermatitis/patología , Granuloma/patología , Humanos , Encefalitis Infecciosa/patología , Masculino , Estudios RetrospectivosRESUMEN
BACKGROUND: Rothmund-Thomson syndrome (RTS) is an autosomal recessive genetic disorder characterized by poikiloderma of the face, small stature, sparse scalp hair, juvenile cataract, radial aplasia, and predisposition to cancers. Due to the rarity of RTS, the situation of patients with RTS in Japan has not been elucidated. METHODS: In 2010 and 2020, following the results of a primary questionnaire survey, a secondary questionnaire survey on RTS was conducted nationwide to investigate the number of RTS cases and their associated skin lesions, bone lesions, other clinical features, and quality of life in Japan. RESULTS: In 2010 and 2020, 10 and eight patients with RTS were recruited, respectively. Skin lesions such as poikiloderma, erythema, pigmentation, and abnormal scalp hair were observed in almost all cases. Bone lesions were observed in four cases in the 2010 and 2020 surveys, respectively. Two cases had mutations in the RECQL4 gene in the 2020 survey. CONCLUSIONS: Two nationwide surveys have shown the actual situation of patients with RTS in Japan. Cutaneous and bone manifestations are important for the diagnosis of RTS. However, many patients have no RECQL4 mutations. The novel causative gene of RTS should be further elucidated.
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Síndrome Rothmund-Thomson , Humanos , Japón/epidemiología , Mutación , Calidad de Vida , Síndrome Rothmund-Thomson/diagnóstico , Síndrome Rothmund-Thomson/epidemiología , Síndrome Rothmund-Thomson/genética , Encuestas y CuestionariosRESUMEN
OBJECTIVE: The Japanese Society of Pressure Ulcers (JSPU) has two purposes: first, to improve knowledge and skills among health professionals related to preventing and managing pressure ulcers (PUs); and second, to represent those in the field managing PUs, including with government and health authorities. Since 2006, JSPU has conducted fact-finding surveys about every four years to identify PU prevalence in Japan (2006, 2010, 2013 and 2016). Based on the prevalence identified by these surveys, an attempt was made to validate the achievements of JSPU's activities. METHOD: Information from one-day surveys of hospitals, long-term care health facilities, long-term care welfare facilities, and home visit nursing care stations was analysed. We used generalised estimating equations to estimate the proportions of PUs and their 95% confidence intervals (CIs) for each survey. RESULTS: A total of 662,419 patients in 2631 facilities participated in the surveys. The estimated proportions for all facilities (95% CI) in chronological order, from the first to the fourth survey, were: 2.67% (2.52-2.83); 2.61% (2.43-2.80); 1.99% (1.83-2.17); and 1.79% (1.65-1.94), respectively. In all facility types, the proportion of PUs was lower in the fourth survey than the first survey. CONCLUSION: The proportion of PUs showed a decreasing trend and was low according to global standards, demonstrating the efficacy of JSPU's activities.
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Úlcera por Presión , Humanos , Úlcera por Presión/epidemiología , Úlcera por Presión/prevención & control , Japón/epidemiologíaRESUMEN
BACKGROUND: Circulating monocytes are classified into three subsets according to their CD14 and CD16 expressions. Here we investigated all three subsets in patients with squamous cell carcinoma of the head and neck (SCCHN). METHODS: Peripheral blood from 54 patients with SCCHN and 24 healthy donors (HDs) was tested for flowcytometry. Immunohistochemical staining of the primary tumor was performed. SCCHN cells were co-cultured with human monocytes in vitro. RESULTS: The level of intermediate monocytes was significantly lower in SCCHN than in HDs. The expression levels of HLA-G, PD-L1, and CD51 on intermediate monocytes was evidently greater in patients with SCCHN. In vitro co-culturing of SCCHN cells with monocytes revealed a significant increase in CD51 expression levels on monocytes. The decrease in expression levels of the maturation markers CX3CR1 and CD68 was significantly correlated to poor clinical outcomes. CONCLUSION: The level of intermediate monocytes was decreased in cancer patients in favor of immature and expressed immunosuppressive molecules.
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Neoplasias de Cabeza y Cuello/inmunología , Monocitos/inmunología , Carcinoma de Células Escamosas de Cabeza y Cuello/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Antígeno B7-H1/metabolismo , Circulación Sanguínea , Femenino , Citometría de Flujo , Antígenos HLA-G , Humanos , Inmunofenotipificación , Receptores de Lipopolisacáridos/metabolismo , Masculino , Persona de Mediana Edad , Receptores de IgG/metabolismo , Regulación hacia ArribaRESUMEN
OBJECTIVES: Anti-melanoma differentiation-associated gene 5 (MDA5) autoantibody-positive and age at onset ≥60 years are poor prognosis factors in polymyositis (PM) and dermatomyositis (DM) associated with interstitial lung disease (ILD) among Japanese patients. However, the influence of age on the clinical features of anti-MDA5 autoantibody-positive patients with DM remains unclear. METHODS: We retrospectively examined 40 patients with DM and anti-MDA5 autoantibodies according to age. We compared patients aged <60 and ≥60 years with respect to clinical features including laboratory test findings, high-resolution lung computed tomography data, treatment content, and complications such as infections and prognosis. We also examined clinical features between surviving and deceased patients in the older patient group. RESULTS: Of 40 enrolled patients, 13 were classified as old and 27 as young. Older patients had significantly fewer clinical symptoms including arthralgia/arthritis (p < .01), skin ulceration (p = .02), and higher mortality than younger patients (p = .02) complicated with rapidly progressive ILD (RP-ILD), combination immunosuppressive therapy, and strictly controlled infections. CONCLUSION: Clinical features and mortality of anti-MDA5 autoantibody-positive DM patients were influenced by age. Patients aged ≥60 years had a worse prognosis, and combination immunosuppressive therapy was often ineffective for RP-ILD in older patients.
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Autoanticuerpos/inmunología , Dermatomiositis/patología , Helicasa Inducida por Interferón IFIH1/inmunología , Adulto , Factores de Edad , Anciano , Dermatomiositis/tratamiento farmacológico , Dermatomiositis/epidemiología , Dermatomiositis/inmunología , Femenino , Humanos , Inmunosupresores/uso terapéutico , Masculino , Persona de Mediana Edad , MortalidadRESUMEN
Ischemia-reperfusion (I/R) is associated with various pathogenic conditions, and there has been increasing evidence that cutaneous I/R injury is associated with the pathogenesis of pressure ulcers (PUs), especially at the early stage presenting as non-blanchable erythema. Several studies demonstrated that oxidative stress is a key player in I/R injury, and the inhibition of oxidative stress may be capable of protecting tissue damage after I/R injury in various organs including skin. Dimethyl fumarate (DMF) approved by the Food and Drug Administration is Nrf2 activator, and recent studies revealed the antioxidative and anti-inflammatory effects of DMF on I/R injury in animal models. Our objective was to assess the effects of oral administration of DMF on the development of PUs after cutaneous I/R injury in mice. We found that DMF administration significantly decreased the size of PUs after cutaneous I/R. Cutaneous I/R-induced oxidative stress was also significantly inhibited by DMF in OKD48 mice, in which oxidative stress can be visually assessed. In addition, DMF treatment decreased hypoxic area, the numbers of apoptotic cells, and vascular loss in I/R area. DMF treatment suppressed the infiltration of MPO+ neutrophils and the production of proinflammatory cytokines in I/R site after cutaneous I/R injury. in vitro experiments, DMF treatment suppressed the production of reactive oxygen species in pericyte-like cells. These results suggest that DMF treatment might prevent the formation of PUs induced by cutaneous I/R injury via suppressing oxidative stress and subsequent inflammation. DMF treatment during the early phase of decubitus ulcers might protect against further progression.
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Dimetilfumarato/farmacología , Úlcera por Presión/etiología , Úlcera por Presión/prevención & control , Daño por Reperfusión/complicaciones , Administración Oral , Animales , Dimetilfumarato/administración & dosificación , Modelos Animales de Enfermedad , Ratones , Ratones Endogámicos C57BL , Estrés OxidativoRESUMEN
PURPOSE: Sarcopenia is characterized by depletion of skeletal muscle mass (SMM) and can cause increased postoperative complication in free flap procedure. One of the most important considerations while deciding the indication of the procedure is patients' survival. This study aimed to verify the relationship between low SMM and survival in patients who undergo oral cancer resection using free flap. METHODS: SMM was evaluated using the skeletal muscle index (SMI cm2 /m2 ), which was defined using cross-sectional areas of skeletal muscles on computed tomography at the level of the third lumbar vertebrae normalized for height. Overall, 111 patients who underwent primary oral cancer resection and free flaps were included. Multivariate Cox regression analyses were used to evaluate the prognostic factors for survival. RESULTS: A total of 25 patients (22.5%) were diagnosed with low SMM. The mean SMI was 42.2 cm2 /m2 . Multivariable analyses showed that increased age (hazard ratio [HR]; 4.98, p = .004), infiltrative growth pattern INF-c (HR; 3.83, p = .037), and low SMM (HR; 2.59, p = .034) were significant negative prognostic factors for overall survival. Increased age (HR; 3.18, p = .005), extra-nodal extension (HR; 3.30, p = .001), and low SMM (HR; 2.42, p = .017) were significant negative prognostic factors for disease-free survival. CONCLUSIONS: Low SMM is a significant negative prognostic factor for overall and disease-free survival in oral cancer patients undergoing free flap. Future prospective studies are warranted to identify effective preoperative exercise and nutrition programs to improve low skeletal muscle and survival rate in patients undergoing free flap procedures.
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Colgajos Tisulares Libres , Neoplasias de la Boca , Supervivencia sin Enfermedad , Humanos , Neoplasias de la Boca/cirugía , Músculo Esquelético , Pronóstico , Estudios Prospectivos , Estudios RetrospectivosRESUMEN
Objectives: Overactive bladder (OAB) is a clinical diagnosis defined with the presence of urinary urgency, usually accompanied by frequency and nocturia, with or without urgency urinary incontinence. Objective was to evaluate the demographic and clinical characteristics of Japanese systemic sclerosis (SSc) patients with OAB.Methods: OAB was diagnosed by OAB symptom score (OABSS) in 104 Japanese SSc patients (93 women and 11 men). Differential diseases of OAB were conducted by urologists.Results: The prevalence of OAB in SSc patients was 27.9% (29/104). SSc patients with OAB were characterized by old age, a long history of morbidity (15.4 vs. 11.2 years, p < .01), high anti-centromere antibody positive rate (75.9 vs. 44%, p < .05), high incidence of gastroesophageal reflux disease (93.1 vs. 73.3%, p < .05), low anti-SS-A antibody positive rate (6.9 vs. 26.8%, p < .05), and low incidence of internal lung disease (17.9 vs. 45.7%, p < .05) compared to SSc patients without OAB.Conclusion: This is the first study that evaluated the prevalence and clinical features of OAB in Japanese SSc patients. Since SSc patients might be prone to develop OAB, it was thought that OAB should be noted as one of the complications of SSc patients.
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Esclerodermia Sistémica/complicaciones , Vejiga Urinaria Hiperactiva/epidemiología , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Prevalencia , Vejiga Urinaria Hiperactiva/complicaciones , Vejiga Urinaria Hiperactiva/patologíaRESUMEN
The efficacy and safety of botulinum toxin B (BTX-B) for treatment of Raynaud's phenomenon and digital ulcers in patients with systemic sclerosis was assessed. A total of 45 patients with systemic sclerosis who had Raynaud's phenomenon were blinded and divided randomly into 4 groups: a no-treatment control group, and 3 treatment groups, using 250, 1,000 or 2,000 international units (U) of BTX-B injections in the hand with more severe symptoms. Four weeks after injection, pain/numbness visual analogue scale scores and Raynaud's score in the groups treated with 1,000 and 2,000 U BTX-B were significantly lower than in the control group and the group treated with 250 U BTX-B. These beneficial effects were sustained until 16 weeks after the single injection. At 4 weeks after injection skin temperature recovery in the group treated with 2,000 U BTX-B was significantly improved. The numbers of digital ulcers in the groups treated with 1,000 and 2,000 U BTX-B were significantly lower than in the control group. In conclusion, 1,000 and 2,000 U BTX-B injections significantly suppressed the activity of Raynaud's phenomenon and digital ulcers in patients with SSc without serious adverse events.
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Inhibidores de la Liberación de Acetilcolina/administración & dosificación , Toxinas Botulínicas Tipo A/administración & dosificación , Enfermedad de Raynaud/tratamiento farmacológico , Esclerodermia Sistémica/complicaciones , Úlcera Cutánea/tratamiento farmacológico , Inhibidores de la Liberación de Acetilcolina/efectos adversos , Anciano , Toxinas Botulínicas Tipo A/efectos adversos , Femenino , Humanos , Inyecciones , Japón , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Enfermedad de Raynaud/diagnóstico , Enfermedad de Raynaud/etiología , Enfermedad de Raynaud/fisiopatología , Método Simple Ciego , Temperatura Cutánea/efectos de los fármacos , Úlcera Cutánea/diagnóstico , Úlcera Cutánea/etiología , Úlcera Cutánea/fisiopatología , Factores de Tiempo , Resultado del Tratamiento , Cicatrización de Heridas/efectos de los fármacosRESUMEN
Cutaneous collagenous vasculopathy (CCV) is a rare acquired idiopathic microangiopathy characterised by the progressive development of diffuse asymptomatic telangiectasias over the skin. Histologically, the presence of a thick hyaline collagenous wall around the affected capillaries, comprising the accumulation of collagen type IV, is noted. We herein report the case of a 17-year-old Japanese boy with symmetrical patches of diffuse telangiectasias on the bilateral extremities that persisted for 10 months. A histological examination revealed dilated capillaries in the papillary dermis surrounded by thick perivascular deposition of hyaline-like materials, which stained positive for periodic acid-Schiff and collagen type IV. We additionally performed a review of 26 CCV patients previously reported in the English literature and summarised the clinical and histological features of generalised telangiectatic disorders, such as CCV, generalised essential telangiectasia and hereditary haemorrhagic telangiectasia. To establish an accurate diagnosis, it is important for dermatologists to recognise the clinical and histological characteristics of CCV and the importance of the histological analysis.
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Enfermedades del Colágeno/diagnóstico , Enfermedades Cutáneas Vasculares/diagnóstico , Telangiectasia/diagnóstico , Adolescente , Enfermedades del Colágeno/patología , Humanos , Japón , Masculino , Piel/irrigación sanguínea , Enfermedades Cutáneas Vasculares/patología , Telangiectasia/patologíaRESUMEN
Ischaemia-reperfusion (I/R) is involved in the development of various organ diseases. There has been increasing evidence that cutaneous I/R injury is associated with the pathogenesis of pressure ulcers (PUs), especially at the early stage presenting as non-blanchable erythema. However, there is no evidence-based treatment for early-stage PUs. Our objective was to assess the effects of topical steroid on the development of PUs after cutaneous I/R injury in mice. Cutaneous I/R was performed by trapping the dorsal skin between two magnetic plates for 12 h, followed by plate removal. Topical application of betamethasone butyrate propionate (BBP) in I/R areas significantly increased the size of PUs after I/R. The number of thromboses was increased, and CD31(+) vessels were decreased in the I/R area treated with topical BBP. The number of oxidative stress-associated DNA-damaged cells and apoptotic cells in the I/R area was increased by topical BBP treatment. In addition, the mRNA level of NADPH oxidase 4 (Nox4), the essential enzyme that produces reactive oxygen species, was significantly increased and that of NF-E2-related factor 2 (Nrf2), a transcription factor that regulates the expression of antioxidant proteins, was inhibited in the I/R area treated by BBP. The number of CD68(+) macrophages and the level of transforming growth factor-beta in lesional skin were also decreased by BBP. These results suggest that a topical steroid might accelerate the formation of PUs induced by cutaneous I/R injury by aggravating oxidative stress-induced tissue damage. Topical steroids might not be recommended for the treatment of acute-phase decubitus ulcers.
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Betametasona/análogos & derivados , Contraindicaciones de los Medicamentos , Úlcera por Presión/tratamiento farmacológico , Daño por Reperfusión/complicaciones , Administración Cutánea , Animales , Apoptosis/efectos de los fármacos , Betametasona/efectos adversos , Citocinas/metabolismo , Evaluación Preclínica de Medicamentos , Macrófagos/efectos de los fármacos , Masculino , Ratones Endogámicos C57BL , Estrés Oxidativo/efectos de los fármacos , Úlcera por Presión/etiología , Daño por Reperfusión/metabolismo , Piel/irrigación sanguíneaRESUMEN
Atypical progeroid syndrome (APS), including atypical Werner syndrome (AWS), is a disorder of premature ageing caused by mutation of the lamin A gene, the same causal gene involved in Hutchinson-Gilford syndrome (HGS). We previously reported the first Japanese case of APS/AWS with a LMNA mutation (p.D300N). Recently, it has been reported that UVA induced abnormal truncated form of lamin A, called progerin, as well as HGS-like abnormal nuclear structures in normal human fibroblasts, being more frequent in the elderly, suggesting that lamin A may be involved in the regulation of photoageing. The objective of this study was to elucidate the sensitivity to cell damage induced by oxidative stress or UVA in fibroblasts from APS/AWS patient. Using immunofluorescence staining and flow cytometry analysis, the amount of early apoptotic cells and degree of intra-cellular reactive oxygen species (ROS) generation were higher in H2 02 - or UVA-treated APS/AWS fibroblasts than in normal fibroblasts, suggesting that repeated UV exposure may induce premature ageing of the skin in APS/AWS patients and that protecting against sunlight is possibly important for delaying the emergence of APS/AWS symptoms. In addition, we demonstrated that H2 O2 -, or UVA-induced apoptosis and necrosis in normal and APS/AWS fibroblasts were enhanced by farnesyltransferase inhibitor (FTI) treatment, indicating that FTI might not be useful for treating our APS/AWS patient.
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Lamina Tipo A/genética , Mutación Missense , Síndrome de Werner/genética , Síndrome de Werner/patología , Sustitución de Aminoácidos , Apoptosis/efectos de los fármacos , Apoptosis/genética , Apoptosis/efectos de la radiación , Células Cultivadas , Inhibidores Enzimáticos/farmacología , Farnesiltransferasa/antagonistas & inhibidores , Fibroblastos/metabolismo , Fibroblastos/patología , Fibroblastos/efectos de la radiación , Humanos , Peróxido de Hidrógeno/toxicidad , Necrosis , Estrés Oxidativo , Quinolonas/farmacología , Piel/metabolismo , Piel/patología , Piel/efectos de la radiación , Rayos Ultravioleta/efectos adversos , Síndrome de Werner/metabolismoRESUMEN
Our research group recently demonstrated that pericytes are major sources of the secreted glycoprotein and integrin ligand lactadherin (MFG-E8) in B16 melanoma tumors, and that MFG-E8 promotes angiogenesis via enhanced PDGF-PDGFRß signaling mediated by integrin-growth factor receptor crosstalk. However, sources of MFG-E8 and its possible roles in skin physiology are not well characterized. The objective of this study was to characterize the involvement of MFG-E8 in skin wound healing. In the dermis of normal murine and human skin, accumulations of MFG-E8 were found around CD31(+) blood vessels, and MFG-E8 colocalized with PDGFRß(+), αSMA(+), and NG2(+) pericytes. MFG-E8 protein and mRNA levels were elevated in the dermis during full-thickness wound healing in mice. MFG-E8 was diffusely present in granulation tissue and was localized around blood vessels. Wound healing was delayed in MFG-E8 knockout mice, compared with the wild type, and myofibroblast and vessel numbers in wound areas were significantly reduced in knockout mice. Inhibition of MFG-E8 production with siRNA attenuated the formation of capillary-like structures in vitro. Expression of MFG-E8 in fibrous human granulation tissue with scant blood vessels was less than that in granulation tissue with many blood vessels. These findings suggest that MFG-E8 promotes cutaneous wound healing by enhancing angiogenesis.
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Antígenos de Superficie/fisiología , Dermis/fisiología , Neovascularización Fisiológica , Fenómenos Fisiológicos de la Piel , Cicatrización de Heridas , Animales , Línea Celular , Tejido de Granulación/fisiología , Células Endoteliales de la Vena Umbilical Humana/citología , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas de la Leche , Miocitos del Músculo Liso/citología , Miofibroblastos/citología , Pericitos/citologíaRESUMEN
The precise mechanisms of tissue fibrosis have not yet been elucidated in systemic sclerosis (SSc). However, studies of the regulation of DNA methylation, the most widely studied epigenetic mechanism, have confirmed the involvement of the TET family proteins, recently identified DNA demethylases, in the pathogenesis of SSc. The mRNA levels of TET family members were compared in normal and SSc fibroblasts. The effects of hypoxia and siRNA specific to HIF-1α on TET expression were also examined. Global methylation status was analysed by LUMA. The presence of 5-hydroxymethylcytosine (5hmC) in SSc was examined by immunohistochemistry. The level of TET1 mRNA in SSc fibroblasts was elevated by 1.68 fold compared with that of normal fibroblasts, but the expression levels of TET2 and TET3 were comparable between both cell types. The expression levels of DNMT1 and DNMT3B mRNA have a tendency to elevate in SSc fibroblasts. Among TET family members, the expression of TET1 was exclusively induced by hypoxia via HIF-1α-independent pathways in SSc fibroblasts, but not in normal fibroblasts. The methylation level was decreased in SSc fibroblasts relative to normal fibroblasts, and 5hmC was present in dermal fibroblasts of skin sections from patients with SSc. TET1 expression in SSc fibroblasts was abnormally regulated in the hypoxic environment and accompanied by global DNA hypomethylation, suggesting the involvement of aberrant DNA methylation in the pathogenesis of SSc.
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Metilación de ADN , Fibroblastos/enzimología , Oxigenasas de Función Mixta/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Esclerodermia Sistémica/enzimología , Estudios de Casos y Controles , Células Cultivadas , ADN (Citosina-5-)-Metiltransferasa 1 , ADN (Citosina-5-)-Metiltransferasas/metabolismo , Humanos , Hipoxia/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , ADN Metiltransferasa 3BRESUMEN
LEOPARD syndrome (LS) is an autosomal dominant condition with multiple anomalies, including multiple lentigines. LS is caused by mutations in PTPN11, encoding the protein tyrosine phosphatase, SHP-2. We report here 2 unrelated Japanese cases of LS with different PTPN11 mutations (p.Y279C and p.T468P). To elucidate the pathogenesis of multiple lentigines in LS, ultrastructural and immunohistochemical analyses of lentigines and non-lesional skin were performed. Numerous mature giant melanosomes in melanocytes and keratinocytes were observed in lentigines. In addition, the levels of expression of endothelin-1 (ET-1), phosphorylated Akt, mTOR and STAT3 in the epidermis in lentigines were significantly elevated compared with non-lesional skin. In in vitro assays, melanin synthesis in human melanoma cells expressing SHP-2 with LS-associated mutations was higher than in cells expressing normal SHP-2, suggesting that LS-associated SHP-2 mutations might enhance melanin synthesis in melanocytes, and that the activation of Akt/mTOR signalling may contribute to this process.
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Queratinocitos/ultraestructura , Síndrome LEOPARD/genética , Síndrome LEOPARD/patología , Melanocitos/ultraestructura , Melanoma/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genética , Adolescente , Endotelina-1/análisis , Femenino , Humanos , Síndrome LEOPARD/metabolismo , Melaninas/biosíntesis , Melanocitos/metabolismo , Melanoma/genética , Melanosomas/ultraestructura , Mutación , Fosforilación , Proteína Tirosina Fosfatasa no Receptora Tipo 11/metabolismo , Proteínas Proto-Oncogénicas c-akt/análisis , Proteínas Proto-Oncogénicas c-akt/metabolismo , Factor de Transcripción STAT3/análisis , Transducción de Señal , Piel/química , Piel/ultraestructura , Serina-Treonina Quinasas TOR/análisis , Serina-Treonina Quinasas TOR/metabolismo , Células Tumorales Cultivadas , Adulto JovenRESUMEN
Nephrogenic systemic fibrosis (NSF) is characterized by systemic fibrosis and abnormal calcification in patients with severe renal dysfunction. It is considered that gadolinium (Gd)-containing contrast agents used for magnetic resonance imaging trigger the development of NSF. However, the causative role of Gd and the mechanism of Gd-induced fibrosis and calcification in NSF are unknown. Recently, it has been known that endothelin-1 (ET-1)/ET receptor (ETR) signalling regulates fibrosis and calcification. The objective was to elucidate the role of ET-1/ETR signalling in Gd-induced fibrosis and calcification in NSF. First, we demonstrated that Gd enhanced proliferation and calcification of human adipose tissue-derived mesenchymal stem cells (hMSC) in vitro. Next, we examined the expression of ET-1 and ETR-A in hMSC using proliferation or calcification assay. ET-1 and ETR-A expression in hMSC treated with Gd were elevated. ET-1/ETR signalling inhibitor, bosentan, inhibited Gd-induced proliferation and calcification of hMSC. In addition, bosentan inhibited Gd-induced phosphorylation of ERK and Akt in hMSC. Plasma ET-1 levels of the patients were significantly higher than these of normal individuals and systemic sclerosis patients. In immunofluorescence staining, the expression of ETR-A in fibroblasts in dermal fibrosis lesion of NSF was increased. We conclude that Gd induces proliferation and calcification of hMSC via enhancement of ET-1/ETR signalling. Our results contribute to understand the pathogenesis of NSF.
Asunto(s)
Endotelina-1/metabolismo , Dermopatía Fibrosante Nefrogénica/metabolismo , Receptor de Endotelina A/metabolismo , Adolescente , Bosentán , Calcinosis/etiología , Calcinosis/metabolismo , Calcinosis/patología , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Medios de Contraste/efectos adversos , Antagonistas de los Receptores de Endotelina/farmacología , Endotelina-1/sangre , Gadolinio/efectos adversos , Humanos , Imagen por Resonancia Magnética/efectos adversos , Masculino , Células Madre Mesenquimatosas/efectos de los fármacos , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/patología , Persona de Mediana Edad , Dermopatía Fibrosante Nefrogénica/etiología , Dermopatía Fibrosante Nefrogénica/patología , Transducción de Señal/efectos de los fármacos , Sulfonamidas/farmacologíaRESUMEN
Atopic dermatitis (AD) is a common chronic inflammatory skin disease characterized by recurrent, pruritic, and localized eczema. Various types of new drugs have been recently investigated for treating AD. The efficacy and safety of abrocitinib in treating AD has been reported in clinical trials, but the real-world data from Japan has not been reported. Herein, we analyzed 12 Japanese patients with AD treated with 100 mg of abrocitinib using our real-world data. We also performed transcriptome analysis with peripheral blood to investigate the effects of abrocitinib on cytokine expressions and inflammatory pathways in AD from three patients. This study included patients with moderate to severe AD treated with abrocitinib at Gunma University Hospital, Japan. All patients were systemic treatment-naïve. All patients received a 100-mg dose of abrocitinib daily, and used strong or very strong topical steroids and moisturizers. The Eczema Area and Severity Index (EASI) response analysis revealed that after 4 weeks, 25% (three of 12) of the cases reached a 75% reduction in the EASI score (EASI-75) and a 90% reduction in the EASI score (EASI-90). After 12 weeks, 83.3.% (10 of 12), 41.6% (five of 12), and 16.7% (two of 12) of the patients reached EASI-50, a 75% reduction in the EASI score (EASI-75), and EASI-90. Peak Pruritus Numerical Rating Scale was achieved in nine patients (75%) at week 12. The most frequent adverse reaction was acne (six cases [50%]). Gene Ontology pathway analysis using Differentially expressed genes from RNA sequencing analysis revealed attenuation of defense responses to biotic stimulus, virus, and cytokines. Th2 cytokine expression was not suppressed, but several chemokines, especially CXCL1, were suppressed by abrocitinib treatment. Our results indicate abrocitinib as a fast-acting and highly antipruritic agent that is effective for moderate skin eruptions.