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[PMID]: 28747736 [Au] Autor: Li Y; Cheng H; Xiao FL; Liang B; Zhou FS; Li P; Zheng XD; Sun LD; Yang S; Zhang XJ [Ad] Endereço: Institute of Dermatology and Department of Dermatology, No.1 Hospital, Anhui Medical University, Hefei, Anhui, China. [Ti] Título: Association of UBASH3A gene polymorphism and atopic dermatitis in the Chinese Han population. [So] Source: Genes Immun;18(3):158-162, 2017 09. [Is] ISSN: 1476-5470 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Genome-wide association studies have revealed a large number of genetic-risk loci for many autoimmune diseases. One clear finding emerging from the published genetic studies of autoimmunity is that different autoimmune diseases share susceptibility loci. Recent evidence has demonstrated that UBASH3A gene was associated with multiple autoimmune diseases. The aim of this study was to explore the association between UBASH3A single-nucleotide polymorphisms (SNPs) and atopic dermatitis (AD) in a Chinese Han population. In total, three UBASH3A SNPs (rs11203203, rs3788013 and rs1893592) were genotyped using TaqMan genotyping assays in a Chinese Han population (1012 cases and 1362 controls). Among these SNPs, we selected the SNP rs1893592 with association values of P<5 × 10 for AD in the TaqMan genotyping assay data for further replication in the independent Chinese replication samples (1080 cases and 1367 controls) using a Sequenom MassARRAY system. We combined the association results in two stages using meta-analysis. We found that rs1893592 in UBASH3A showed association with AD (P=1.29 × 10 , odds ratio=1.16). These results showed that UBASH3A gene SNP is associated with susceptibility to AD. Further fine mapping and functional studies will be required to identify true causal variant in the UBASH3A gene and its exact role in the pathogenesis of AD. [Mh] Termos MeSH primário: Proteínas Adaptadoras de Transdução de Sinal/genética Dermatite Atópica/genética Polimorfismo de Nucleotídeo Único [Mh] Termos MeSH secundário: Adulto Estudos de Casos e Controles Criança Pré-Escolar China Feminino Seres Humanos Lactente Masculino [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Adaptor Proteins, Signal Transducing); 0 (UBASH3A protein, human) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180307 [Lr] Data última revisão: 180307 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170728 [St] Status: MEDLINE [do] DOI: 10.1038/gene.2017.15

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[PMID]: 29292947 [Au] Autor: Ståhle M; Bradley M [Ad] Endereço: Karolinska Universitetssjukhuset - Hudkliniken Stockholm, Sweden Karolinska Universitetssjukhuset - Hudkliniken Stockholm, Sweden. [Ti] Título: Komplexa diagnoser med samsjuklighet.. [So] Source: Lakartidningen;114, 2017 11 21. [Is] ISSN: 1652-7518 [Cp] País de publicação: Sweden [La] Idioma: swe [Mh] Termos MeSH primário: Dermatite Atópica/diagnóstico Psoríase/diagnóstico [Mh] Termos MeSH secundário: Comorbidade Dermatite Atópica/epidemiologia Dermatite Atópica/terapia Seres Humanos Psoríase/epidemiologia Psoríase/terapia [Pt] Tipo de publicação: INTRODUCTORY JOURNAL ARTICLE [Em] Mês de entrada: 1803 [Cu] Atualização por classe: 180306 [Lr] Data última revisão: 180306 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 180103 [St] Status: MEDLINE

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[PMID]: 29292944 [Au] Autor: Bradley M; Wahlgren CF [Ad] Endereço: Institutionen för Medicin - Hudkliniken, Karolinska i Solna Stockholm, Sweden Institutionen för Medicin - Department of dermatology Stockholm, Sweden. [Ti] Título: Nya läkemedel mot atopiskt eksem väntar på godkännande - Bättre förståelse av den molekylära sjukdomsmekanismen kan ge fler och bättre verktyg för behandling.. [So] Source: Lakartidningen;114, 2017 Nov 21. [Is] ISSN: 1652-7518 [Cp] País de publicação: Sweden [La] Idioma: swe [Ab] Resumo: New treatments for atopic dermatitis Atopic dermatitis is one of the most common skin disorders in Sweden. The pathogenesis is a complex counterplay between a defect skin barrier and an abnormal immune response that can be caused by genetic and/or environmental factors. Atopic dermatitis has a huge negative impact on quality of life. New and more specific treatments are under way and hopefully we will, in the near future, better treat even the more severe cases of atopic dermatitis. [Mh] Termos MeSH primário: Dermatite Atópica/tratamento farmacológico Fármacos Dermatológicos/uso terapêutico [Mh] Termos MeSH secundário: Anticorpos Monoclonais/uso terapêutico Compostos de Boro/uso terapêutico Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico Dermatite Atópica/metabolismo Dermatite Atópica/fisiopatologia Aprovação de Drogas Emolientes/uso terapêutico Seres Humanos Pele/metabolismo Pele/fisiopatologia [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Antibodies, Monoclonal); 0 (Boron Compounds); 0 (Bridged Bicyclo Compounds, Heterocyclic); 0 (Dermatologic Agents); 0 (Emollients) [Em] Mês de entrada: 1803 [Cu] Atualização por classe: 180306 [Lr] Data última revisão: 180306 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 180103 [St] Status: MEDLINE

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[PMID]: 29292940 [Au] Autor: Johansson E [Ad] Endereço: Karolinska Institutet - Enheten för dermatologi och venereologi, Institutionen för medicin Solna Stockholm, Sweden Karolinska Institutet - Enheten för dermatologi och venereologi, Institutionen för medicin Solna Stockholm, Sweden. [Ti] Título: Atopiskt eksem vanligt i alla åldrar - Nya rön om samsjuklighet till atopiskt eksem.. [So] Source: Lakartidningen;114, 2017 Nov 21. [Is] ISSN: 1652-7518 [Cp] País de publicação: Sweden [La] Idioma: swe [Ab] Resumo: Atopic eczema common at all ages Eczema (atopic dermatitis) is an inflammatory skin disorder with dry skin and recurrent episodes of inflammation and itch. Onset is most common the first two years of life, but also occurs among older children, adolescents and adults. The prevalence of eczema has increased in Sweden and other industrialized countries the last decades; 15-30% of children and 2-10% of adults are affected. Approximately half of children with eczema early in life are in remission in adolescence. However, many of these will relapse later in life, often as hand eczema. Children with eczema are at increased risk to develop IgE sensitization to common food- and airborne allergens, food allergy, asthma and rhinitis. In addition, recent studies have reported that having eczema is associated with non-allergic disorders such as ADHD, depression and anxiety, epilepsy, overweight and obesity, cardiovascular disease, and different kinds of malignancies. There are also studies that have not found an association between eczema and the above mentioned non-allergic comorbidities. Thus, the association between eczema and non-allergic comorbidities are still largely unknown. [Mh] Termos MeSH primário: Dermatite Atópica [Mh] Termos MeSH secundário: Adolescente Adulto Fatores Etários Idoso Asma/epidemiologia Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia Criança Pré-Escolar Comorbidade Dermatite Atópica/diagnóstico Dermatite Atópica/epidemiologia Dermatite Atópica/etiologia Dermatite Atópica/patologia Seres Humanos Imunoglobulina E/imunologia Lactente Meia-Idade Rinite/epidemiologia Adulto Jovem [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 37341-29-0 (Immunoglobulin E) [Em] Mês de entrada: 1803 [Cu] Atualização por classe: 180306 [Lr] Data última revisão: 180306 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 180103 [St] Status: MEDLINE

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[PMID]: 28460633 [Au] Autor: Zhang Z; Zheng W; Xie H; Chai R; Wang J; Zhang H; He S [Ad] Endereço: Allergy and Clinical Immunology Research Centre, The First Affiliated Hospital of Jinzhou Medical University, No. 2, Section 5, Renmin Street, Guta District, Jinzhou, 121001, Liaoning, People's Republic of China. [Ti] Título: Up-regulated expression of substance P in CD8 T cells and NK1R on monocytes of atopic dermatitis. [So] Source: J Transl Med;15(1):93, 2017 May 01. [Is] ISSN: 1479-5876 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: BACKGROUND: Large numbers of CD8 T cells were observed in atopic dermatitis (AD) skin, and monocytes from AD patients showed increased prostaglandin E2 production. However, little is known about the expression of substance P (SP) and its receptor NK1R in blood leukocytes of patients with AD. OBJECTIVE: To explore the expression of SP and NK1R in leukocytes of AD and the influence of allergens on SP and NK1R expression. METHODS: The expression levels of SP and NK1R in patients with AD were examined by flow cytometry, ELISA and a mouse AD model. RESULTS: The plasma SP level was 4.9-fold higher in patients with AD than in HC subjects. Both the percentage of SP expression in the population and mean fluorescence intensity (MFI) of SP expression were elevated in CD8 T cells in the blood of AD patients. However, both the CD14 NK1R population and MFI of NK1R expression on CD14 cells were enhanced in the blood of AD patients. Allergens ASWE, HDME and PPE failed to up-regulate SP expression in CD8 T cells. However, allergens ASWE and HDME both enhanced NK1R expression on CD14 blood leukocytes regardless of AD or HC subjects. OVA-sensitized AD mice showed an elevated proportion and MFI of SP-expressing CD8 T cells in the blood, which agrees with the SP expression situation in human AD blood. Injection of SP into mouse skin did not up-regulate NK1R expression on monocytes. CONCLUSIONS: An elevated plasma SP level, up-regulated expression of SP and NK1R indicate that the SP/NK1R complex is important in the development of AD. Therefore, SP and NK1R antagonist or blocker agents may help to treat patients with AD. Trial registration Registration number: ChiCTR-BOC-16010279; Registration date: Dec., 28, 2016; retrospectively registered. [Mh] Termos MeSH primário: Linfócitos T CD8-Positivos/imunologia Dermatite Atópica/genética Dermatite Atópica/imunologia Monócitos/patologia Receptores da Neurocinina-1/metabolismo Substância P/genética Regulação para Cima/genética [Mh] Termos MeSH secundário: Adolescente Adulto Idoso Alérgenos/imunologia Animais Estudos de Casos e Controles Dermatite Atópica/sangue Citometria de Fluxo Seres Humanos Camundongos Endogâmicos BALB C Meia-Idade Ovalbumina/imunologia Substância P/sangue Substância P/metabolismo Adulto Jovem [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Allergens); 0 (Receptors, Neurokinin-1); 33507-63-0 (Substance P); 9006-59-1 (Ovalbumin) [Em] Mês de entrada: 1803 [Cu] Atualização por classe: 180305 [Lr] Data última revisão: 180305 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170503 [St] Status: MEDLINE [do] DOI: 10.1186/s12967-017-1196-6

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[PMID]: 29353721 [Au] Autor: Purushothaman B; Arumugam P; Kulsi G; Song JM [Ad] Endereço: College of Pharmacy, Seoul National University, Seoul 151-742, South Korea. [Ti] Título: Design, synthesis, and biological evaluation of novel catecholopyrimidine based PDE4 inhibitor for the treatment of atopic dermatitis. [So] Source: Eur J Med Chem;145:673-690, 2018 Feb 10. [Is] ISSN: 1768-3254 [Cp] País de publicação: France [La] Idioma: eng [Ab] Resumo: Selective inhibition of phosphodiesterase (PDE) 4B favorably suppresses the synthesis of inflammatory cytokines and subsequently arrest the development of atopic dermatitis via modulating the intracellular cAMP levels. Considering the side effects of corticosteroids, selective PDE4 inhibition could constitute an effective alternative therapy for the treatment of atopic dermatitis (AD). In this study, a series of novel catechol based compounds bearing pyrimidine as the core have been synthesized and screened for the PDE4 inhibitory properties. The PDE4 selectivity of the active compounds over other PDEs has been investigated. Compound 23 bearing pyrimidine core functionalized with catechol, pyridine and trifluoromethyl groups can effectively inhibit the PDE4B with IC value in nanomolar range (IC = 15 ±â€¯0.4 nM). Compound 23 exhibited seven fold higher selectivity towards PDE4B over PDE4D. Molecular Docking study confirmed its stronger affinity towards catalytic domain of PDE4B. In-vivo analysis confirmed that compound 23 effectively alleviated the symptoms of atopic dermatitis in DNCB-treated Balb/c mice by suppressing the synthesis of inflammatory mediators such as TNF-α, and Ig-E. Taken together, this study suggested that compound 23 could be an effective PDE4 inhibitor for the potential treatment of AD. [Mh] Termos MeSH primário: Catecóis/farmacologia Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo Dermatite Atópica/tratamento farmacológico Desenho de Drogas Inibidores da Fosfodiesterase 4/farmacologia Pirimidinas/farmacologia [Mh] Termos MeSH secundário: Animais Catecóis/síntese química Catecóis/química Cristalografia por Raios X Dermatite Atópica/metabolismo Dermatite Atópica/patologia Relação Dose-Resposta a Droga Masculino Camundongos Camundongos Endogâmicos BALB C Modelos Moleculares Estrutura Molecular Inibidores da Fosfodiesterase 4/síntese química Inibidores da Fosfodiesterase 4/química Pirimidinas/síntese química Pirimidinas/química Relação Estrutura-Atividade [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Catechols); 0 (Phosphodiesterase 4 Inhibitors); 0 (Pyrimidines); EC 3.1.4.17 (Cyclic Nucleotide Phosphodiesterases, Type 4) [Em] Mês de entrada: 1803 [Cu] Atualização por classe: 180302 [Lr] Data última revisão: 180302 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 180123 [St] Status: MEDLINE

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[PMID]: 29386434 [Au] Autor: Watanabe K [Ad] Endereço: Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences. [Ti] Título: [From a Ph.D. Thesis: Understanding the Past, Predicting the Future]. [So] Source: Yakugaku Zasshi;138(2):211-219, 2018. [Is] ISSN: 1347-5231 [Cp] País de publicação: Japan [La] Idioma: jpn [Ab] Resumo: 　Posey et al. have reported multiple molecular diagnoses in 4.5% of cases (101/2076) in which whole-exome sequencing was informative. Distinct disease phenotypes affect different organ systems, whereas overlapping disease phenotypes are more likely to be caused by two genes encoding proteins that interact within the same pathway. My research projects at the Niigata University of Pharmacy have investigated underlying mechanisms involved in human disease, including fatty acid metabolism, diabetic cardiomyopathy, atopic dermatitis, colitis, hepatitis, etc. Three students from abroad graduated this year from the Department of Clinical Pharmacology, Niigata University of Pharmacy and Applied Life Sciences. These students reported on treatments for heart disease, non-alcoholic steatohepatitis and atopic dermatitis, as well as the underlying mechanisms involved in each. The titles of these reports are "Study of the role of cardiac 14-3-3η protein in cardiac inflammation and adverse cardiac remodeling during heart failure in mice", "Non-alcoholic steatohepatitis: onset of mechanisms under diabetic background and treatment strategies" and "The role of HMGB1 and its cascade signaling pathway in atopic dermatitis". It can be concluded from these three theses that oxidative stress and inflammation are among the principal mechanisms underlying these diseases. [Mh] Termos MeSH primário: Dermatite Atópica Proteína HMGB1 Insuficiência Cardíaca Hepatopatia Gordurosa não Alcoólica [Mh] Termos MeSH secundário: Proteínas 14-3-3 Proteínas Quinases Ativadas por AMP Animais Dermatite Atópica/genética Complicações do Diabetes Estresse do Retículo Endoplasmático Insuficiência Cardíaca/genética Seres Humanos Camundongos Hepatopatia Gordurosa não Alcoólica/etiologia Hepatopatia Gordurosa não Alcoólica/terapia Estresse Oxidativo Patologia Molecular Sequenciamento Completo do Exoma [Pt] Tipo de publicação: JOURNAL ARTICLE; REVIEW [Nm] Nome de substância: 0 (14-3-3 Proteins); 0 (HMGB1 Protein); EC 2.7.11.31 (AMP-Activated Protein Kinases) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180228 [Lr] Data última revisão: 180228 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 180202 [St] Status: MEDLINE [do] DOI: 10.1248/yakushi.17-00111

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[PMID]: 29367526 [Au] Autor: Ishitsuka Y [Ad] Endereço: Department of Dermatology, Faculty of Medicine, University of Tsukuba. [Ti] Título: [The formation of skin barrier and defective barrier-associated skin diseases]. [So] Source: Nihon Rinsho Meneki Gakkai Kaishi;40(6):416-427, 2017. [Is] ISSN: 1349-7413 [Cp] País de publicação: Japan [La] Idioma: jpn [Ab] Resumo:   Since the discovery of loss-of-function mutations in filaggrin (FLG) gene in atopic dermatitis (AD) individuals, significant attention has been paid against the skin barrier as an initial starting point of atopic march. Although FLG is a significant cornification-associated gene, skin barrier formation is a complex process mediated by an array of genes with specific functions. In this article, the mechanism of physical skin barrier formation is reviewed in detail, focusing on specific gene functions and inherited disorders caused by genetic aberrations. Additionally, the mechanism of percutaneous sensitization with environmental allergens in association with FLG-deficiency is reviewed in order to clarify the link between defective skin barrier and atopic march. Finally, updated knowledge of psoriasis pathophysiology in connection with genetic defect in skin barrier is reviewed. This article would provide a novel opportunity to understand the allergic/autoimmune disorders from the viewpoint of non-classical immune cells. [Mh] Termos MeSH primário: Dermatopatias/genética Dermatopatias/imunologia Pele/imunologia [Mh] Termos MeSH secundário: Dermatite Atópica/genética Dermatite Atópica/imunologia Seres Humanos Proteínas de Filamentos Intermediários/genética Mutação com Perda de Função Psoríase/genética Psoríase/imunologia [Pt] Tipo de publicação: JOURNAL ARTICLE; REVIEW [Nm] Nome de substância: 0 (Intermediate Filament Proteins); 0 (filaggrin) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180227 [Lr] Data última revisão: 180227 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 180126 [St] Status: MEDLINE [do] DOI: 10.2177/jsci.40.416

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[PMID]: 29297666 [Au] Autor: Pikina AP; Shkoporov AN; Kulagina EV; Khokhlova EV; Chaplin AV; Volodin NN; Kafarskaya LI; Korotkly NG; Efimov BA [Ti] Título: Comparative Genotyping of Staphylococcus aureus Strains Isolated from Skin Lesions, Nasal Cavities, and Feces of Children with Atopic Dermatitis. [So] Source: Vestn Ross Akad Med Nauk;71(5):367-74, 2016. [Is] ISSN: 0869-6047 [Cp] País de publicação: Russia (Federation) [La] Idioma: eng [Ab] Resumo: Background: The lesion of skin of the majority atopic dermatitis patients is chronically colonized by bacteria belonging to the species Staphylococcus aureus. Topical antibacterial and anti-inflammatory therapy treatment are often ineffective due to fast recolonization by S. aureus and exacerbation of allergic process. Aims: Our aim was to determine a frequency of S. aureus colonization in skin lesions, mucous membranes of the nasal cavity and intestine of children with atopic dermatitis, to compare the genotypes of Staphylococcus aureus strains isolated from different biotopes of atopic dermatitis patients, and to clarify whether the intestinal and nasal cavities microbiota may act as a source of S. aureus recolonization of skin lesions. Materials and Methods: Bacteriological examination of fecal samples, skin, and nasal swabs was conducted in 38 atopic dermatitis patients. The pure bacterial cultures of S. aureus were identified using API Staph (Biomerieux, France) and Vitek 2 MS (Biomerieux, France). Isolates of S. aureus were subjected to genotyping by analysis of rRNA internal 16S-23S rRNA spacer regions and high resolution melting analysis (HMR) of polymorphic spa X-regions. Results: 99% S. aureus strains were successfully identified using MALDI-TOF mass-spectrometry. S. aureus cultures were isolated from all biotopes in 31,6% of children, from skin and nasal cavities ­ in 42% of cases, from skin and feces ­ in 2,6% of cases, only from skin ­ in 10,5%, from nasal cavities and feces ­ in 2,6%, and only from nasal cavities ­ in 2,6% of cases. In 8% of children, S. aureus was not detected in any of the biotopes. Genotyping of the isolates enabled the detection of 17 different genotypes. A match between the genotypes of skin and nasal strains, and skin and fecal strains was observed in 88% and 61% of the cases respectively. Conclusions: The observed a high-frequency matching genotypes suggests the possibility of migration of S. aureus strains inside biotopes in humans and the absence of specialization to colonization of any of the niches. [Mh] Termos MeSH primário: Dermatite Atópica/microbiologia Fezes/microbiologia Genótipo Cavidade Nasal/microbiologia Pele/microbiologia Staphylococcus aureus [Mh] Termos MeSH secundário: Técnicas Bacteriológicas/métodos Criança Contagem de Colônia Microbiana/métodos Feminino Seres Humanos Masculino Staphylococcus aureus/genética Staphylococcus aureus/isolamento & purificação [Pt] Tipo de publicação: JOURNAL ARTICLE [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180220 [Lr] Data última revisão: 180220 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 180104 [St] Status: MEDLINE [do] DOI: 10.15690/vramn695

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[PMID]: 29195486 [Au] Autor: Shukla S; Feldman SR; Strowd LC [Ad] Endereço: a University of Maryland School of Medicine , Baltimore , MD , USA. [Ti] Título: A safety review of the medications used to treat atopic dermatitis. [So] Source: Expert Opin Drug Saf;17(2):179-183, 2018 Feb. [Is] ISSN: 1744-764X [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: INTRODUCTION: Atopic dermatitis (AD) is a common disease in children and adults which causes severe physical discomfort and psychosocial distress. Recently novel therapies for AD have been FDA approved for use which creates the need to review the safety surrounding current FDA approved AD medications. Areas covered: Published clinical studies involving topical and oral FDA approved medications for AD are included in this review. Authors used PubMed research database to search for clinical trials involving AD patients. Expert opinion: AD is a common disease which currently has limited FDA approved medications. Given the chronicity of this disease, medications are needed which control disease while minimizing side effects to allow for long term use. Newer approved medications show promise but safety data is limited given their relatively new utilization for AD. [Mh] Termos MeSH primário: Dermatite Atópica/tratamento farmacológico Fármacos Dermatológicos/administração & dosagem [Mh] Termos MeSH secundário: Administração Cutânea Administração Oral Adulto Criança Dermatite Atópica/patologia Fármacos Dermatológicos/efeitos adversos Aprovação de Drogas Seres Humanos Estados Unidos United States Food and Drug Administration [Pt] Tipo de publicação: JOURNAL ARTICLE; REVIEW [Nm] Nome de substância: 0 (Dermatologic Agents) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180215 [Lr] Data última revisão: 180215 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171203 [St] Status: MEDLINE [do] DOI: 10.1080/14740338.2018.1411478

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