RESUMEN
The basement membrane zone is the interface between the epidermis and dermis, and it is disrupted in several skin conditions. Here, we report the results of a comprehensive investigation into the structural and molecular factors of the basement membrane zone in vitiligo, a dermatological disorder characterised by depigmented patches on the skin. Using electron microscopy and immunofluorescence staining, we confirmed abnormal basement membrane zone morphology and disrupted basement membrane zone architecture in human vitiliginous skin. Furthermore, we identified elevated expression of matrix metalloproteinase 2 (MMP2) in human dermal fibroblasts as a key factor responsible for basement membrane zone matrix degradation. In our in vitro and ex vivo models, overexpression of MMP2 in fibroblasts led to basement membrane zone disruption and melanocyte disappearance. Importantly, we reveal that the loss of melanocytes in vitiligo is primarily linked to their weakened adhesion to the basement membrane, mediated by binding between integrin ß1 and laminin and discoidin domain receptor 1 and collagen IV. Finally, inhibition of matrix metalloproteinase 2 expression reversed depigmentation in a mouse model of vitiligo. In conclusion, our research shows the importance of basement membrane zone integrity in melanocyte residence and offers new avenues for therapeutic interventions to address this challenging skin condition. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Membrana Basal , Melanocitos , Vitíligo , Vitíligo/patología , Vitíligo/metabolismo , Melanocitos/patología , Melanocitos/metabolismo , Membrana Basal/patología , Membrana Basal/metabolismo , Humanos , Animales , Ratones , Metaloproteinasa 2 de la Matriz/metabolismo , Fibroblastos/patología , Fibroblastos/metabolismo , Masculino , Femenino , Modelos Animales de Enfermedad , Ratones Endogámicos C57BLRESUMEN
BACKGROUND: Cutavirus (CuV) is associated with mycosis fungoides; however, the CuV status in parapsoriasis en plaques (PP), a premalignant inflammatory condition of mycosis fungoides, has not been fully delineated. METHODS: Fifty-five Japanese patients with chronic inflammatory skin diseases, including 13 patients with PP, were studied. RESULTS: CuV DNA was detected significantly more frequently in biopsies of the lesional skin from patients with PP (38%; 4 of 13) than in those from patients with other inflammatory skin diseases (2%; 1 of 42; P = .009). All CuV-positive PP cases were of the large-plaque parapsoriasis (LPP) subtype. The viral loads ranged from 83 450 to 2 164 170 copies/103 cells. We recovered near-full-length CuV sequences from the CuV-positive LPP biopsies, all of which were of the Japanese/Asian genotype. The CuV genome appeared to be present within lymphoid cells infiltrating the epidermis and dermis. CuV NS1 and VP1 gene transcripts were also detected in the affected tissues. CONCLUSIONS: The detection of high levels of CuV DNA with the expression of viral mRNA suggests a potential role for CuV in the pathogenesis of LPP, making it necessary to study further the impact of CuV, especially regarding the viral genotype, on the outcomes of patients with CuV-positive LPP.
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Micosis Fungoide , Parapsoriasis , Humanos , Micosis Fungoide/virología , Micosis Fungoide/patología , Masculino , Femenino , Persona de Mediana Edad , Anciano , Parapsoriasis/virología , Parapsoriasis/patología , Adulto , ADN Viral/genética , Piel/patología , Piel/virología , Carga Viral , Japón , Anciano de 80 o más Años , Biopsia , Neoplasias Cutáneas/virología , Neoplasias Cutáneas/patología , Lesiones Precancerosas/virología , Lesiones Precancerosas/patología , Virus ADN/genética , Virus ADN/aislamiento & purificación , Virus ADN/clasificaciónRESUMEN
BACKGROUND: Cutavirus (CuV) is associated with mycosis fungoides; however, the CuV status in parapsoriasis en plaques (PP), a premalignant inflammatory condition of mycosis fungoides, has not been fully delineated. METHODS: Fifty-five Japanese patients with chronic inflammatory skin diseases, including 13 patients with PP, were studied. RESULTS: CuV DNA was detected significantly more frequently in biopsies of the lesional skin from patients with PP (38% [4/13]) than in those from patients with other inflammatory skin diseases (2% [1/42]; P = 0.009). All CuV-positive PP cases were of the large plaque parapsoriasis (LPP) subtype. The viral loads ranged from 83,450 to 2,164,170 copies/103 cells. We recovered near-full-length CuV sequences from the CuV-positive LPP biopsies, all of which were of the Japanese/Asian genotype. The CuV genome appeared to be present within lymphoid cells infiltrating the epidermis and dermis. CuV NS1 and VP1 gene transcripts were also detected in the affected tissues. CONCLUSIONS: The preferential detection of high levels of CuV DNA with the expression of viral mRNA suggests a potential role for CuV in the pathogenesis of LPP, making it necessary to study further the impact of CuV, especially regarding the viral genotype, on the outcomes of patients with CuV-positive LPP.
RESUMEN
Leucine-rich α-2 glycoprotein (LRG), one of the acute phase proteins mainly produced by the liver, similar to C-reactive protein, has been recognized as an inflammatory biomarker for rheumatoid arthritis and inflammatory bowel diseases. We recently demonstrated that LRG was also increased in the sera of psoriasis patients and correlated well with disease activity with a sensitivity and specificity much higher than C-reactive protein; however, whether LRG mechanistically contributed to the pathogenesis of psoriasis remained unclear. In this study, we explored the role of LRG in psoriasiform inflammation using LRG-knockout (KO) mice in an imiquimod (IMQ)-mediated model. Following topical treatment with IMQ, serum levels of LRG and its expression in the liver were abruptly elevated. Similarly, an acute surge of proinflammatory cytokines was observed in the liver, including IL-1ß, TNF-α, and IL-6, although LRG-KO mice showed delayed responses. LRG-KO mice showed less skin inflammation in the IMQ model than wild-type mice. K5.Stat3C mice developed psoriasis-like lesions following tape stripping, which also abruptly induced LRG expression in the liver. A deficiency of Lrg mitigated tape stripping-induced lesions, similar to the IMQ model. These results indicate that LRG modulates both feed-forward and feedback loops of cytokines in the skin-liver axis involved with psoriasiform inflammation.
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Biomarcadores/metabolismo , Glicoproteínas/metabolismo , Hígado/metabolismo , Psoriasis/inmunología , Piel/metabolismo , Animales , Citocinas/metabolismo , Modelos Animales de Enfermedad , Glicoproteínas/genética , Humanos , Imiquimod , Mediadores de Inflamación/metabolismo , Hígado/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Piel/patología , Regulación hacia ArribaRESUMEN
BACKGROUND: Schnitzler syndrome is a rare disorder with chronic urticaria, and there is no report summarizing the current status in Japan. METHODS: A nationwide survey of major dermatology departments in Japan was conducted in 2019. We further performed a systematic search of PubMed and Ichushi-Web, using the keywords "Schnitzler syndrome" and "Japan" then contacted the corresponding authors or physicians for further information. RESULTS: Excluding duplicates, a total of 36 clinically diagnosed cases were identified from 1994 through the spring of 2022, with a male to female ratio of 1:1. The median age of onset was 56.5 years. It took 3.3 years from the first symptom, mostly urticaria, to reach the final diagnosis. The current status of 30 cases was ascertained; two patients developed B-cell lymphoma. SchS treatment was generally effective with high doses of corticosteroids, but symptoms sometimes recurred after tapering. Colchicine was administered in 17 cases and was effective in 8, but showed no effect in the others. Tocilizumab, used in six cases, improved laboratory abnormalities and symptoms, but lost its efficacy after several years. Rituximab, used in five cases, was effective in reducing serum IgM levels or lymphoma mass, but not in inflammatory symptoms. Four cases were treated with IL-1 targeting therapy, either anakinra or canakinumab, and achieved complete remission, except one case with diffuse large B-cell lymphoma. CONCLUSIONS: Since Schnitzler syndrome is a rare disease, the continuous collection and long-term follow-up of clinical information is essential for its appropriate treatment and further understanding of its pathophysiology.
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Urticaria Crónica , Síndrome de Schnitzler , Urticaria , Humanos , Masculino , Femenino , Persona de Mediana Edad , Síndrome de Schnitzler/diagnóstico , Síndrome de Schnitzler/tratamiento farmacológico , Urticaria/diagnóstico , Proteína Antagonista del Receptor de Interleucina 1/uso terapéutico , Urticaria Crónica/tratamiento farmacológico , Japón/epidemiologíaRESUMEN
BACKGROUND: Human polyomaviruses (HPyVs) have been associated with several cutaneous inflammatory conditions. More investigation is needed to identify further presentations of cutaneous pathology associated with HPyVs. Our aim was to investigate the possible association of skin-tropic HPyVs with folliculitis, particularly eosinophilic pustular folliculitis (EPF). METHODS: This study included 55 Japanese patients, comprising 13 patients with EPF and 42 patients with suppurative folliculitis. HPyV DNAs were detected by quantitative polymerase chain reaction. Expression of viral antigen and geographically related viral genotypes were also assessed. RESULTS: Human polyomavirus 6 (HPyV6) DNA was found in 9 of 13 (69%) patients with EPF, a rate significantly higher than that found in suppurative folliculitis (1/42; 2%). Of the 7 HPyV6 DNA-positive EPF specimens analyzed, 4 were positive for HPyV6 small tumor antigen. All the HPyV6 strains detected in this study were of the Asian/Japanese genotype. CONCLUSIONS: The predominant detection of HPyV6 DNA and the expression of viral antigen suggest a possible association between HPyV6 infection and EPF in a subset of patients. Worldwide studies are warranted to determine whether Asian/Japanese genotype HPyV6 is associated preferentially with the incidence and pathogenesis of this eosinophil-related skin disease that has an ethnic predilection for the East Asian population.
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Eosinofilia/virología , Foliculitis/virología , Polyomaviridae/aislamiento & purificación , Infecciones por Polyomavirus , Enfermedades Cutáneas Vesiculoampollosas/virología , Antígenos Virales , ADN Viral/genética , Humanos , Infecciones por Polyomavirus/diagnósticoRESUMEN
OBJECTIVE: Anti-aminoacyl-tRNA synthetase (anti-ARS) antibodies are useful for identifying a clinical subset of patients with idiopathic inflammatory myopathies (IIMs). Anti-OJ antibodies, which recognize multi-enzyme synthetase complexes including isoleucyl-tRNA synthetase (IARS) and lysyl-tRNA synthetase (KARS), are among the anti-ARS antibodies. Although testing antibodies to other ARSs have been used clinically, no validated immunoassays for detecting anti-OJ antibodies are available. We aimed to establish an anti-OJ ELISA. METHODS: Serum samples were collected from 279 patients with IIMs and 22 patients with idiopathic interstitial pneumonia. Sixty-four of the samples that had been confirmed to be negative for anti-OJ by standard immunoprecipitation were used as the negative control, and 12 anti-OJ-positive reference sera were used as the positive control. Antibodies to IARS and KARS were assayed by ELISA using biotinylated recombinant proteins generated by in vitro transcription/translation. RESULTS: The anti-OJ-positive sera strongly reacted with the KARS and IARS recombinant proteins in ELISA. Although all 12 reference sera were positive in the anti-KARS ELISA, 4 of the 64 anti-OJ-negative sera were also weakly positive. The sensitivity and the specificity were 100% and 93.8%, respectively. Since our anti-KARS ELISA performed well, showing a high agreement with the results for immunoprecipitation (Cohen's κ > 0.8), the remaining 237 samples were also tested. Thirteen anti-KARS-positive sera were newly found by ELISA, all of which were anti-OJ positive by immunoprecipitation. CONCLUSION: Immunoassays for detecting anti-OJ antibodies using KARS and IARS recombinant proteins were developed. Our ELISAs performed well, with very high agreement of the results by immunoprecipitation and can be applied to the first reliable, easy-to-use measurement assays for anti-OJ antibodies.
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Autoanticuerpos/aislamiento & purificación , Isoleucina-ARNt Ligasa/metabolismo , Lisina-ARNt Ligasa/metabolismo , Miositis/diagnóstico , Adulto , Anciano , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Autoanticuerpos/metabolismo , Estudios de Casos y Controles , Ensayo de Inmunoadsorción Enzimática/métodos , Estudios de Factibilidad , Femenino , Voluntarios Sanos , Humanos , Isoleucina-ARNt Ligasa/inmunología , Lisina-ARNt Ligasa/inmunología , Masculino , Persona de Mediana Edad , Miositis/sangre , Miositis/inmunología , Proteínas Recombinantes/inmunología , Proteínas Recombinantes/metabolismo , Reproducibilidad de los Resultados , Adulto JovenRESUMEN
OBJECTIVE: Systemc sclerosis (SSc) is an autoimmune disorder characterized by fibrosis of the skin and internal organs. Recently, it has been shown that leucine-rich α-2 glycoprotein (LRG) functions as a modulator of transforming growth factor-ß (TGF-ß) signaling in fibrosis. We aimed to characterize the effect of LRG in SSc model and SSc patients. METHODS: Histological analysis was performed on LRG knockout (KO) and wild type (WT) mouse in the skin and the lung after bleomycin administration. Serum LRG levels were measured during the injection period. Gene expression analysis of the skin and lung tissue from LRG KO and WT mice was performed. In addition, serum LRG levels were determined in SSc patients and healthy controls. RESULTS: LRG KO mice display an inhibition of fibrosis in the skin in association with a decrease of dermal thickness, collagen deposition, and phospho-Smad3 expression after bleomycin. Serum LRG concentration significantly increased in WT mice after bleomycin. There was also a suppression of inflammation and fibrosis in the LRG KO mouse lung indicated by a reduction of lung weight, collagen content, and phospho-Smad3 expression after bleomycin. Gene expressions of TGF-ß and Smad2/3 were significantly reduced in LRG KO mice. Serum LRG levels in SSc patients were significantly higher than those in controls. CONCLUSION: LRG promotes fibrotic processes in SSc model through TGF-ß-Smad3 signaling, and LRG can be a biomarker for SSc in humans and also a potential therapeutic target for SSc.
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Glicoproteínas , Fibrosis Pulmonar , Esclerodermia Sistémica , Animales , Bleomicina , Modelos Animales de Enfermedad , Fibroblastos , Fibrosis , Glicoproteínas/genética , Humanos , Ratones , Fibrosis Pulmonar/inducido químicamente , Esclerodermia Sistémica/inducido químicamente , Esclerodermia Sistémica/genética , Esclerodermia Sistémica/patología , Piel/patología , Factor de Crecimiento Transformador betaRESUMEN
BACKGROUND: Human skin microorganisms have been associated with various skin diseases. However, most studies have focused on bacterial communities, and little is known about normally resident skin viruses such as the Polyomaviridae and their association with cutaneous disorders. METHODS: We investigated the infection levels of Merkel cell polyomavirus (MCPyV), human polyomavirus 6 (HPyV6), and human polyomavirus 7 (HPyV7), using triplet skin swabs collected from lesional and nonlesional skins of 86 Japanese patients with inflammatory skin diseases and mycosis fungoides, and from 149 healthy control individuals. RESULTS: This age-matched case-control study provides the first analyses of the loads of polyomaviruses in association with various skin diseases. The viral loads were significantly higher for HPyV6/HPyV7 and lower for MCPyV in patients with psoriasis. The viral load variation was observed not only at lesion sites, but also at clinically unaffected skin sites in most of the patients. The viral strains tested were all of the Asian/Japanese genotype. CONCLUSIONS: Our findings suggest a covariation in the infection levels of cutaneous polyomaviruses in certain inflammatory skin conditions. Worldwide prospective longitudinal studies are warranted to understand the influence of such alterations on the pathogenesis of inflammatory skin disorders.
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Infecciones por Polyomavirus/epidemiología , Poliomavirus/aislamiento & purificación , Enfermedades de la Piel/epidemiología , Piel/virología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , ADN Viral/aislamiento & purificación , Femenino , Humanos , Japón/epidemiología , Masculino , Poliomavirus de Células de Merkel/aislamiento & purificación , Persona de Mediana Edad , Micosis Fungoide/epidemiología , Micosis Fungoide/virología , Prevalencia , Psoriasis/virología , Enfermedades de la Piel/virología , Neoplasias Cutáneas/epidemiología , Neoplasias Cutáneas/virología , Infecciones Tumorales por Virus/epidemiología , Infecciones Tumorales por Virus/virología , Carga ViralRESUMEN
BACKGROUND: Fontan patients exhibit a high prevalence of abnormal glucose metabolism (AGM). We aimed to characterize AGM and clarify its association with Fontan pathophysiology. METHODS: We prospectively evaluated AGM with plasma glucose dynamics [mg/dL; fasting glucose (FPG), and maximum glucose increase (PG-spike)] during oral glucose tolerance test and hemoglobin A1c (HbA1c) in 276 consecutive Fontan patients (aged 19⯱â¯7â¯years). Of these, 176 patients had serial AGM assessments with a mean interval of 6.5â¯years. RESULTS: Initial analysis revealed a high prevalence of impaired glucose tolerance (38.4%) and diabetes mellitus (DM) (4.7%), and positive family history, high HbA1c, and high central venous pressure independently predicted presence of DM. HbA1c was independently determined by hypersplenism and presence of DM (Pâ¯<â¯.05). Serial assessments revealed an increased PG-spike and a decreased HbA1c (Pâ¯<â¯.001 for both). Prevalence of DM increased (6.3% to 10.3%), and positive family history, high liver enzymes, and AGM predicted new onset of DM (Pâ¯<â¯.05 for all). Twenty-one patients died during 7.1-year follow-up. FPG (Pâ¯<â¯.01) and PG-spike (Pâ¯<â¯.05) independently predicted all-cause mortality. Particularly, patients with FPGâ¯≤â¯74 and/or PG-spike ≥85 had a mortality rate 8.7 times higher than those without (Pâ¯=â¯.0129). CONCLUSIONS: AGM progressed even in young adult Fontan patients, and HbA1c showed limited predictive value for progression. Oral glucose tolerance test plays important roles in uncovering unique Fontan AGM as well as predicting all-cause mortality.
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Diabetes Mellitus/metabolismo , Ayuno/sangre , Procedimiento de Fontan , Glucosa/metabolismo , Hemoglobina Glucada/metabolismo , Adolescente , Adulto , Glucemia/metabolismo , Estudios de Casos y Controles , Causas de Muerte , Niño , Estudios Transversales , Diabetes Mellitus/epidemiología , Diabetes Mellitus/mortalidad , Progresión de la Enfermedad , Femenino , Prueba de Tolerancia a la Glucosa , Cardiopatías Congénitas/metabolismo , Humanos , Hiperesplenismo/metabolismo , Hepatopatías/metabolismo , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Prevalencia , Estudios Prospectivos , Adulto JovenRESUMEN
Background: Despite the pathogenetic potential of human polyomavirus 6 (HPyV6) and human polyomavirus 7 (HPyV7), they have been found in the normal skin of healthy individuals. However, little is known about the prevalence, infection levels, and geographical variations of these polyomaviruses in the skin. Methods: Using skin swabs from 470 participants aged 2-98 years, we estimated the prevalence of copy numbers of HPyV6 and HPyV7 with respect to age and ethnicity. Phylogenetic analyses were conducted based on viral sequences obtained from Asian and white populations. Results: This study provides the first analyses of the age-specific prevalence and levels of HPyV6 and HPyV7 infections in normal skin. Comparisons of age groups revealed that the prevalence and viral loads were significantly higher in elderly persons. Phylogenetic analyses demonstrated the existence of Asian/Japanese-specific strains genetically distinct from strains prevalent in the skin of the white population studied. Conclusions: This large study suggests that HPyV6 and HPyV7 infections in the skin are highly prevalent in elderly adults. Further research is warranted to understand whether persistent infection with high viral loads in the skin could be a risk factor for the development of HPyV6- and HPyV7-associated skin disorders.
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Infecciones por Polyomavirus/epidemiología , Infecciones por Polyomavirus/virología , Poliomavirus/clasificación , Poliomavirus/aislamiento & purificación , Piel/virología , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Enfermedades Asintomáticas , Niño , Preescolar , Estudios de Cohortes , ADN Viral/química , ADN Viral/genética , Etnicidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Filogeografía , Poliomavirus/genética , Prevalencia , Análisis de Secuencia de ADN , Carga Viral , Adulto JovenRESUMEN
Background: Merkel cell polyomavirus (MCPyV) is a ubiquitous cutaneous virus that causes Merkel cell carcinoma, which develops preferentially in white populations from Europe and North America. However, the genomic variations of MCPyV among ethnic groups have not been well delineated, and even less is known regarding alterations in the noncoding control region (NCCR) in the general population. Methods: MCPyV strains recovered from skin swab specimens from 250 healthy participants with distinct ethnicities and geographic origins were subjected to sequencing analysis of the NCCR. Results: A 25-base pair tandem repeat caused by a 25-base pair insertion within the NCCR was found predominantly in Japanese and East Asian individuals. Based on the presence of 2 other insertions and a deletion, the NCCR could be classified further into 5 genotypes. This tandem repeat was also found exclusively in the NCCR from Japanese patients with Merkel cell carcinoma, while other genotypes were detected in white patients from Europe and North America. Conclusions: Our results suggest that the MCPyV NCCR varies according to ethnicity and that assessing the short NCCR sequence provides a rapid and simple means for identification of the Japanese and East Asian variant genotype. It remains to be established whether these NCCR variations are associated differentially with the pathogenesis of MCPyV-driven Merkel cell carcinoma between regions with varying endemicity.
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Variación Genética/genética , Poliomavirus de Células de Merkel/genética , Infecciones por Polyomavirus/virología , Piel/virología , Anciano , Pueblo Asiatico/genética , Carcinoma de Células de Merkel/virología , ADN Viral/genética , Europa (Continente) , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , América del Norte , Filogenia , Neoplasias Cutáneas/virología , Infecciones Tumorales por Virus/virologíaAsunto(s)
Dermatitis Atópica , Humanos , Dermatitis Atópica/tratamiento farmacológico , Dermatitis Atópica/inducido químicamente , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales/uso terapéutico , Biomarcadores , Resultado del Tratamiento , Índice de Severidad de la EnfermedadAsunto(s)
Antiinfecciosos Locales/efectos adversos , Biguanidas/efectos adversos , Dermatitis Alérgica por Contacto/diagnóstico , Dermatitis Alérgica por Contacto/etiología , Dermatitis Irritante/diagnóstico , Dermatitis Irritante/etiología , Glucuronatos/efectos adversos , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pruebas del Parche , Gravedad del PacienteRESUMEN
BACKGROUND: Despite the oncogenic potential of Merkel cell polyomavirus (MCPyV), it has been found in the normal skin of healthy individuals; however, little is known about geographical variations in the ecology of MCPyV in this tissue. METHODS: This study included 284 Japanese participants. Sun-unexposed arm and sun-exposed forehead skin swab samples were obtained and analyzed for MCPyV infection, using quantitative polymerase chain reaction. Phylogenetic analyses were also conducted, based on the full-length genes encoding MCPyV large T antigen and viral protein 1. RESULTS: This study provides the first analyses of the age-specific prevalence and levels of MCPyV infection in normal skin. Steep increases in prevalence and viral load were observed in individuals aged >40 years. MCPyV infections with a high viral load were predominantly observed in the foreheads of subjects aged >60 years, among whom a high burden of MCPyV tended to persist. Phylogenetic analyses showed that all of the gene sequences obtained in this study clustered in a major clade, suggesting the existence of an Asian/Japanese genotype. CONCLUSIONS: This large study suggests that MCPyV infection with high viral loads is prevalent in the sun-exposed skin of elderly adults, making it necessary to follow up this cohort for possible transformation of MCPyV to a pathogenetic form.
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Poliomavirus de Células de Merkel/aislamiento & purificación , Infecciones por Polyomavirus/virología , Piel/virología , Infecciones Tumorales por Virus/virología , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Pueblo Asiatico , Niño , Preescolar , Estudios de Cohortes , ADN Viral , Femenino , Variación Genética , Humanos , Japón , Masculino , Poliomavirus de Células de Merkel/clasificación , Poliomavirus de Células de Merkel/genética , Persona de Mediana Edad , Filogenia , Infecciones por Polyomavirus/epidemiología , Prevalencia , Infecciones Tumorales por Virus/epidemiología , Carga Viral , Adulto JovenRESUMEN
Left pulmonary artery sling (LPAS) is a rare vascular anomaly. The left pulmonary artery arises distally from the right pulmonary artery on the right side of the trachea and passes between the trachea and esophagus towards the left lung, compressing the lower trachea. LPAS is associated with congenital tracheal stenosis, which frequently requires early surgical intervention and has a poor prognosis due to severe airway obstruction after birth. Therefore, LPAS should be prenatally diagnosed to prepare for surgical intervention for tracheal stenosis. To the best of our knowledge, there are few reports on prenatal echocardiographic findings in LPAS. We report three prenatal cases of LPAS, which resulted in respiratory symptoms. We discuss fetal ultrasound findings and highlight the abnormal rotation of the fetal cardiac axis to the right as a useful sign in the prenatal screening of LPAS.
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Arteria Pulmonar/anomalías , Estenosis Traqueal/etiología , Ultrasonografía Prenatal/métodos , Malformaciones Vasculares/diagnóstico , Adulto , Ecocardiografía , Femenino , Humanos , Recién Nacido , Masculino , Persona de Mediana Edad , Embarazo , Arteria Pulmonar/diagnóstico por imagen , Malformaciones Vasculares/complicacionesRESUMEN
Cathepsins (CTSs) are lysosomal cysteine proteases that play an important role in the turnover of intracellular proteins and extracellular proteins, such as the degradation of extracellular matrices and the processing of antigenic proteins. A CTS inhibitor, NC-2300, not only suppresses bone erosion by inhibition of cathepsin K (CTSK), but also ameliorates paw swelling at inflamed joints in adjuvant-induced arthritis in rats. It has been demonstrated that the amelioration of joint inflammation by NC-2300 is mediated by the downregulation of cytokine expression in dendritic cells, which are essential for Th17 activation. In this work, we studied the role for CTSs in the pathogenesis of psoriasis-like lesion in K5.Stat3C mice, a mouse model of psoriasis, in which Th17 contributes to lesion development similar to psoriasis. Psoriatic lesions expressed increased levels of Ctsk and Ctss mRNA compared with uninvolved skin and normal control skin. Similarly, the epidermis and dermis in K5.Stat3C mice demonstrated increased CTSK activities, which were sensitive to NC-2300. Topical treatment with NC-2300 significantly ameliorated 12-O-tetradecanoylphorbol-13-acetate-induced psoriasis-like lesions in K5.Stat3C mice, and downregulated the expression of IL-12, IL-23, and Th17 cytokines. In vitro experiments revealed that TLR7 activation of bone marrow-derived myeloid dendritic cells led to increase in IL-23 at mRNA and protein levels, which were downregulated by NC-2300. These results suggest that CTSK plays a role in development of psoriatic lesions through TLR7-dependent Th17 polarization.