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1.
Acta Derm Venereol ; 103: adv7312, 2023 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-37021597

RESUMO

SwedAD, a Swedish nationwide registry for patients with atopic dermatitis receiving systemic pharmacotherapy, was launched on 1 September 2019. We describe here the establishment of a user-friendly registry to the benefit of patients with atopic dermatitis. By 5 November 2022, 38 clinics had recorded 931 treatment episodes in 850 patients with an approximate national coverage rate of 40%. Characteristics at enrolment included median Eczema Area and Severity Index (EASI) 10.2 (interquartile range 4.0, 19.4), Patient-Oriented Eczema Measure (POEM) 18.0 (10.0, 24.0), Dermatology Life Quality Index (DLQI) 11.0 (5.0, 19.0) and Peak Itch Numerical Rating Scale-11 (NRS-11) 6.0 (3.0, 8.0). At 3 months, median EASI was 3.2 (1.0, 7.3) and POEM, DLQI, and NRS-11 were improved. Regional coverage varied, reflecting the distribution of dermatologists, the ratio of public to private healthcare, and difficulties in recruiting certain clinics. This study highlights the importance of a nationwide registry when managing systemic pharmacotherapy of atopic dermatitis.


Assuntos
Dermatite Atópica , Eczema , Humanos , Dermatite Atópica/tratamento farmacológico , Suécia , Índice de Gravidade de Doença , Sistema de Registros , Qualidade de Vida
3.
Differentiation ; 119: 19-27, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34029921

RESUMO

A proper skin barrier function requires constant formation of stratum corneum, i.e. the outermost layer of epidermis composed of terminally differentiated keratinocytes. The complex process of converting proliferative basal keratinocytes into corneocytes relies on programmed changes in the activity of many well-established genes. Much remains however to be investigated about this process, e.g. in conjunction with epidermal barrier defects due to genetic errors as in ichthyosis. To this end, we re-analyzed two sets of microarray-data comparing altered gene expression in differentiated vs. proliferating keratinocytes and in the skin of patients with autosomal recessive congenital ichthyosis (ARCI) vs. healthy controls, respectively. We thus identified 24 genes to be upregulated in both sets of array and not previously associated with keratinocyte differentiation. For 10 of these genes (AKR1B10, BLNK, ENDOU, GCNT4, GLTP, RHCG, SLC15A1, TMEM45B, TMEM86A and VSNL1), qPCR analysis confirmed the array results and subsequent immunostainings of normal epidermis showed superficial expression of several of the proteins. Furthermore, induction of keratinocyte differentiation using phorbol esters (PMA) resulted in increased expression of eight of the genes, whereas siRNA silencing of PPARδ, a transcription factor supporting differentiation, had the opposite effect. In summary, our results identify ten new candidate genes seemingly involved in human epidermal keratinocyte differentiation and possibly important for epidermal repair in a genetic skin disease characterized by barrier failure.


Assuntos
Diferenciação Celular/genética , Córnea/metabolismo , Ictiose/genética , PPAR delta/genética , Pele/crescimento & desenvolvimento , Proliferação de Células/genética , Córnea/crescimento & desenvolvimento , Epiderme/crescimento & desenvolvimento , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Humanos , Ictiose/patologia , Queratinócitos/metabolismo , Proteínas de Membrana/genética , Organogênese/genética , PPAR delta/antagonistas & inibidores , Ésteres de Forbol/farmacologia , RNA Interferente Pequeno/genética
4.
Exp Dermatol ; 28(10): 1164-1171, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-30372788

RESUMO

Autosomal recessive congenital ichthyosis (ARCI) is a group of monogenic skin disorders caused by mutations in any of at least 12 different genes, many of which are involved in the epidermal synthesis of ω-O-acylceramides (acylCer). AcylCer are essential precursors of the corneocyte lipid envelope crosslinked by transglutaminase-1 (TGm-1), or a yet unidentified enzyme, for normal skin barrier formation. We hypothesized that inactivating TGM1 mutations will lead to a compensatory overexpression of the transcripts involved in skin barrier repair, including many other ARCI-causing genes. Using microarray, we examined the global mRNA expression profile in skin biopsies from five ARCI patients with TGM1 mutations and four healthy controls. There were a total of 599 significantly differentially expressed genes (adjusted P < 0.05), out of which 272 showed more than 1.5 log2fold-change (FC) up- or down-regulation. Functional classification of the latter group of transcripts showed enrichment of mRNA encoding proteins mainly associated with biological pathways involved in keratinocyte differentiation and immune response. Moreover, the expression of seven out of twelve ARCI-causing genes was significantly increased (FC = 0.98-2.05). Also, many of the genes involved in keratinocyte differentiation (cornified envelope formation) and immune response (antimicrobial peptides and proinflammatory cytokines) were upregulated. The results from the microarray analysis were also verified for selected genes at the mRNA level by qPCR and at the protein level by semi-quantitative immunofluorescence. The upregulation of these genes might reflect a compensatory induction of acylCer biosynthesis as a part of a global barrier repair response in the patient's epidermis.


Assuntos
Ictiose Lamelar/genética , Pele/metabolismo , Transglutaminases/genética , Adulto , Idoso de 80 Anos ou mais , Biópsia , Estudos de Casos e Controles , Diferenciação Celular , Ceramidas/biossíntese , Imunofluorescência , Regulação da Expressão Gênica , Ontologia Genética , Humanos , Ictiose Lamelar/metabolismo , Ictiose Lamelar/patologia , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase/métodos , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Pele/patologia , Absorção Cutânea/genética , Absorção Cutânea/fisiologia , Transcriptoma , Transglutaminases/deficiência , Regulação para Cima
5.
J Am Acad Dermatol ; 79(3): 487-494, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29477734

RESUMO

BACKGROUND: Heterozygous mutations in caspase recruitment domain family member 14 gene (CARD14) have been shown to be associated with psoriasis and familial pityriasis rubra pilaris (PRP). Many subjects with CARD14 mutations display features of both disorders, which can result in diagnostic uncertainty. In addition, these eruptions are often recalcitrant to conventional psoriasis therapies such as methotrexate, oral retinoids, and tumor necrosis factor-α inhibitors. OBJECTIVE: We sought to describe the clinical characteristics, family history, and response to therapy in subjects with papulosquamous eruptions due to mutations in CARD14. METHODS: Subjects were referred for genetic testing as part of a registry of subjects with inherited disorders of keratinization. DNA was isolated from blood or saliva, and multiplex targeted sequencing or whole exome sequencing was performed. Clinical histories of subjects with CARD14 mutations were reviewed. RESULTS: We identified 15 kindreds with CARD14-associated papulosquamous eruption (CAPE). Characteristic features of CAPE include early age of onset; prominent involvement of the cheeks, chin, and ears; family history of psoriasis or PRP; minimal response to conventional topical and systemic psoriasis therapies; and improvement with ustekinumab. LIMITATIONS: Relatively small sample size. CONCLUSIONS: Many subjects with CARD14 mutations display characteristics of both psoriasis and PRP. We propose the term CARD14-associated papulosquamous eruption to describe this spectrum of disease. Subjects with clinical features suggestive of CAPE should undergo CARD14 sequencing and may benefit from treatment with ustekinumab.


Assuntos
Proteínas Adaptadoras de Sinalização CARD/genética , Fármacos Dermatológicos/uso terapêutico , Dermatoses Faciais/genética , Guanilato Ciclase/genética , Proteínas de Membrana/genética , Dermatopatias Papuloescamosas/tratamento farmacológico , Dermatopatias Papuloescamosas/genética , Ustekinumab/uso terapêutico , Idade de Início , Criança , Pré-Escolar , Testes Genéticos , Humanos , Lactente , Recém-Nascido , Fenótipo , Pitiríase Rubra Pilar/genética , Psoríase/genética , Psoríase/terapia , Retratamento
6.
Exp Dermatol ; 27(2): 196-199, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29094393

RESUMO

Immunofluorescence (IF) and in situ proximity ligation assay (isPLA) are techniques that are used for in situ protein expression and colocalisation analysis, respectively. However, an efficient quantitative method to analyse both IF and isPLA staining on skin sections is lacking. Therefore, we developed a new method for semi-automatic quantitative layer-by-layer measurement of protein expression and colocalisation in skin sections using the free open-source software CellProfiler. As a proof of principle, IF and isPLA of ichthyosis-related proteins TGm-1 and SDR9C7 were examined. The results indicate that this new method can be used for protein expression and colocalisation analysis in skin sections.


Assuntos
Processamento de Imagem Assistida por Computador/métodos , Microscopia de Fluorescência , Pele/patologia , Epiderme/metabolismo , Perfilação da Expressão Gênica , Humanos , Ictiose/metabolismo , Oxirredutases/metabolismo , Reconhecimento Automatizado de Padrão , Processamento de Proteína Pós-Traducional , Proteômica , Pele/metabolismo , Software , Transglutaminases/metabolismo
7.
Hum Mol Genet ; 26(6): 1070-1077, 2017 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-28158657

RESUMO

Revertant mosaicism (RM) is a naturally occurring phenomenon where the pathogenic effect of a germline mutation is corrected by a second somatic event. Development of healthy-looking skin due to RM has been observed in patients with various inherited skin disorders, but not in connexin-related disease. We aimed to clarify the underlying molecular mechanisms of suspected RM in the skin of a patient with keratitis-ichthyosis-deafness (KID) syndrome. The patient was diagnosed with KID syndrome due to characteristic skin lesions, hearing deficiency and keratitis. Investigation of GJB2 encoding connexin (Cx) 26 revealed heterozygosity for the recurrent de novo germline mutation, c.148G > A, p.Asp50Asn. At age 20, the patient developed spots of healthy-looking skin that grew in size and number within widespread erythrokeratodermic lesions. Ultra-deep sequencing of two healthy-looking skin biopsies identified five somatic nonsynonymous mutations, independently present in cis with the p.Asp50Asn mutation. Functional studies of Cx26 in HeLa cells revealed co-expression of Cx26-Asp50Asn and wild-type Cx26 in gap junction channel plaques. However, Cx26-Asp50Asn with the second-site mutations identified in the patient displayed no formation of gap junction channel plaques. We argue that the second-site mutations independently inhibit Cx26-Asp50Asn expression in gap junction channels, reverting the dominant negative effect of the p.Asp50Asn mutation. To our knowledge, this is the first time RM has been reported to result in the development of healthy-looking skin in a patient with KID syndrome.


Assuntos
Conexina 26/genética , Mutação em Linhagem Germinativa/genética , Ceratite/genética , Mosaicismo , Adulto , Conexina 26/biossíntese , Junções Comunicantes/genética , Junções Comunicantes/patologia , Regulação da Expressão Gênica , Genótipo , Células HeLa , Heterozigoto , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Ceratite/patologia , Masculino , Mutação de Sentido Incorreto , Pele/metabolismo , Pele/patologia
8.
Acta Derm Venereol ; 96(7): 932-937, 2016 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-27025581

RESUMO

Autosomal recessive congenital ichthyosis (ARCI) represents a heterogeneous group of rare disorders of cornification with 3 major subtypes: harlequin ichthyosis (HI), lamellar ichthyosis (LI) and congenital ichthyosiform erythroderma (CIE). A 4th subtype has also been proposed: pleomorphic ichthyosis (PI), characterized by marked skin changes at birth and subsequently mild symptoms. In nationwide screenings of suspected cases of ARCI in Denmark and Sweden, we identified 132 patients (age range 0.1-86 years) classified as HI (n = 7), LI (n = 70), CIE (n = 17) and PI (n = 38). At birth, a collodion membrane or similar severe hyperkeratosis was reported in almost all patients with HI and LI, and in nearly half of patients with CIE and PI. Persistent ectropion was more common in HI (85%) and LI (57%), than in CIE (35%) and PI (5%). Anhidrosis was a frequent problem in all 4 groups (58-100%). A scoring (0-4) of ichthyosis/ery-thema past infancy showed widely different mean values in the subgroups: HI (3.2/3.1), LI (2.4/0.6), CIE (1.8/1.6), PI (1.1/0.3). Novel or recurrent mutations were found in 113 patients: TGM1 (n = 56), NIPAL4 (n = 15), ALOX12B (n = 15), ABCA12 (n = 8), ALOXE3 (n = 9), SLC27A4 (n = 5), CYP4F22 (n = 3), PNPLA1 (n = 1) and ABHD5 (n = 1). In conclusion, by performing a deep phenotyping and gene screening, ARCI can be definitely diagnosed in 85% of cases in Scandinavia, with a prevalence of 1:100,000 and > 8 different aetiologies.


Assuntos
Eritrodermia Ictiosiforme Congênita/epidemiologia , Eritrodermia Ictiosiforme Congênita/genética , Mutação/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Consanguinidade , Análise Mutacional de DNA , Dinamarca/epidemiologia , Feminino , Genes Recessivos , Predisposição Genética para Doença , Testes Genéticos , Genótipo , Humanos , Eritrodermia Ictiosiforme Congênita/classificação , Lactente , Masculino , Pessoa de Meia-Idade , Suécia/epidemiologia
10.
Acta Derm Venereol ; 94(6): 707-10, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24604124

RESUMO

Palmoplantar keratoderma of the Gamborg-Nielsen type (PPK-GN) is a rare autosomal recessive skin disorder described in patients from Sweden. Mal de Meleda (MDM) is also a rare autosomal recessive inherited PPK first reported in 5 families from the island of Meleda. The 2 conditions phenotypically overlap and are characterised by palmoplantar erythematous hyperkeratotic plaques. The genetic background giving rise to PPK-GN has hitherto been unknown, whereas MDM is known to be caused by mutations in the gene encoding secreted Ly-6/uPAR-related protein 1, SLURP-1. In the present study we scrutinised individuals affected by PPK-GN for mutations in the SLURP1 gene and identified 2 different mutations. Fourteen Swedish patients were homozygous for a previously described mutation, c.43T>C, while one individual was a compound heterozygote with one copy of a novel mutation, c.280T>A, in addition to one copy of the c.43T>C mutation. Hereby we confirm that PPK-GN is an allelic variant of MDM.


Assuntos
Antígenos Ly/genética , Ceratodermia Palmar e Plantar/genética , Mutação , Ativador de Plasminogênio Tipo Uroquinase/genética , Adulto , Pré-Escolar , Análise Mutacional de DNA , Feminino , Predisposição Genética para Doença , Haplótipos , Heterozigoto , Homozigoto , Humanos , Ceratodermia Palmar e Plantar/classificação , Ceratodermia Palmar e Plantar/diagnóstico , Masculino , Linhagem , Fenótipo , Suécia
11.
Hum Mutat ; 34(4): 587-94, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23316014

RESUMO

Missense mutations affecting membrane-bound transcription factor protease site 2 (MBTPS2) have been associated with Ichthyosis Follicularis with Atrichia and Photophobia (IFAP) syndrome with or without BRESHECK syndrome, with keratosis follicularis spinulosa decalvans, and Olmsted syndrome. This metalloprotease activates, by intramembranous trimming in conjunction with the protease MBTPS1, regulatory factors involved in sterol control of transcription and in cellular stress response. In this study, 11 different MBTPS2 missense mutations detected in patients from 13 unrelated families were correlated with the clinical phenotype, with their effect on cellular growth in media without lipids, and their potential role for sterol control of transcription. Seven variants were novel [c.774C>G (p.I258M); c.758G>C (p.G253A); c.686T>C (p.F229S); c.1427T>C (p.L476S); c.1430A>T (p.D477V); c.1499G>A (p.G500D); c.1538T>C (p.L513P)], four had previously been reported in unrelated sibships [c.261G>A (p.M87I); c.1286G>A (p.R429H); c.1424T>C (p.F475S); c.1523A>G (p.N508S)]. In the enzyme, the mutations cluster in transmembrane domains. Amino-acid exchanges near the active site are more detrimental to functionality of the enzyme and, clinically, associated with more severe phenotypes. In male patients, a genotype-phenotype correlation begins to emerge, linking the site of the mutation in MBTPS2 with the clinical outcome described as IFAP syndrome with or without BRESHECK syndrome, keratosis follicularis spinulosa decalvans, X-linked, Olmsted syndrome, or possibly further X-linked traits with an oculocutaneous component.


Assuntos
Alopecia/genética , Estudos de Associação Genética , Ictiose/genética , Metaloendopeptidases/genética , Mutação de Sentido Incorreto , Fotofobia/genética , Adolescente , Alelos , Alopecia/diagnóstico , Animais , Linhagem Celular , Criança , Pré-Escolar , Feminino , Teste de Complementação Genética , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/genética , Humanos , Ictiose/diagnóstico , Masculino , Metaloendopeptidases/química , Metaloendopeptidases/metabolismo , Repetições de Microssatélites , Fenótipo , Fotofobia/diagnóstico , Polimorfismo de Nucleotídeo Único , Transporte Proteico , Dermatopatias Genéticas/diagnóstico , Dermatopatias Genéticas/genética , Adulto Jovem
12.
Acta Derm Venereol ; 93(3): 309-13, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-22930352

RESUMO

A Danish-Swedish collaboration was established to identify and classify a Danish cohort of patients with epidermolytic ichthyosis, also known as epidermolytic hyperkeratosis. Patients were recruited from 5 dermatology departments in Denmark, and data were obtained using a structured questionnaire and a systematic examination together with photographs, histopathological descriptions and blood samples for mutational analysis. Sixteen patients from 12 families with generalized or naevoid epidermolytic ichthyosis and ichthyosis bullosa of Siemens were identified. Five families had mutations in K1 and 6 families had mutations in K10. Nine patients had been treated with systemic retinoids (etretinate, acitretin, isotretinoin or alitretinoin), but only 3 patients had acceptable treatment responses and chose to continue therapy. In conclusion epidermolytic ichthyosis is a rare disease with a prevalence of approximately 1 in 350,000 in Denmark and a high percentage of de novo mutations (75%). We identified 4 novel disease-causing mutations.


Assuntos
Hiperceratose Epidermolítica/genética , Hiperceratose Epidermolítica/patologia , Queratina-10/genética , Queratina-1/genética , Mutação , Pele/patologia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Análise Mutacional de DNA , Dinamarca/epidemiologia , Feminino , Predisposição Genética para Doença , Humanos , Hiperceratose Epidermolítica/tratamento farmacológico , Hiperceratose Epidermolítica/epidemiologia , Lactente , Masculino , Linhagem , Fenótipo , Prevalência , Retinoides/uso terapêutico , Pele/efeitos dos fármacos , Inquéritos e Questionários , Resultado do Tratamento , Adulto Jovem
13.
Exp Dermatol ; 19(7): 674-81, 2010 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-20456496

RESUMO

Disorders of keratinization are often treated with vitamin A derivatives (retinoids) which affect keratinocyte differentiation, including keratin (KRT) gene expression. In vivo, suprabasal keratinocytes normally express only keratin (K) 1, K2 and K10, but after topical application of all-trans retinoic acid (ATRA), the granular cells will additionally express K4 and K13, i.e. keratins normally present in oral mucosa and in cultured epidermal keratinocytes. To learn more about the retinoid regulation of keratin expression under in vivo-like conditions, we cultured keratinocytes on de-epidermized dermis in only 0.5% serum. These cells produce a normal-looking epidermis that expresses high mRNA levels of KRT1, KRT2 and KRT10, but minimal amounts of KRT4 and KRT13. Addition of ATRA to the medium for 48 h caused a dose-dependent increase in KRT4/KRT13 and a down-regulation of KRT2 mRNA. An increase in K4 protein was also found. The response was greater than the up-regulation of another retinoid-regulated gene, CRABPII. By studying 10 retinoids with different affinities for the retinoic acid receptors (RAR) and retinoid X receptors (RXR) isoforms, the reciprocal expression of KRT2 and KRT4/KRT13 could be connected with agonists for RARalpha. Two of these agonists, CD336/Am580 and CD2081, altered the expression profile with similar potency as the pan-RAR agonists ATRA and CD367. Co-addition of a pan-RAR antagonist (CD3106/AGN193109) markedly inhibited the induction of KRT4/KRT13 expression, whereas the down-regulation of KRT2 was less affected. In conclusion, RARalpha agonists elicit a reciprocal modulation of KRT2 and KRT4/KRT13 expression in human epidermis, but whether or not the keratin genes also possess RARalpha-specific regulatory elements is still unclear.


Assuntos
Queratinas/metabolismo , Receptores do Ácido Retinoico/metabolismo , Retinoides/metabolismo , Retinoides/farmacologia , Pele/efeitos dos fármacos , Pele/metabolismo , Benzoatos/metabolismo , Benzoatos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Técnicas In Vitro , Queratina-13/genética , Queratina-13/metabolismo , Queratina-2/genética , Queratina-2/metabolismo , Queratina-4/genética , Queratina-4/metabolismo , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Queratinas/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores do Ácido Retinoico/agonistas , Receptor alfa de Ácido Retinoico , Receptores X de Retinoides/metabolismo , Tetra-Hidronaftalenos/metabolismo , Tetra-Hidronaftalenos/farmacologia , Tretinoína/metabolismo , Tretinoína/farmacologia
14.
J Invest Dermatol ; 130(2): 438-43, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19890349

RESUMO

Infants born with autosomal recessive congenital ichthyosis (ARCI) are often encapsulated in a collodion membrane, which shows a lamellar or erythrodermic type of ichthyosis upon shedding. However, some babies show a nearly normal underlying skin after several weeks, a phenotype called "self-healing collodion baby" (SHCB). Mutations in two genes, TGM1 and ALOX12B, have previously been implicated in the etiology of SHCB, but the full genotypic spectrum remains to be determined. DNA sequencing in 11 Swedish and 4 Danish SHCB patients showed ALOX12B mutations in eight cases, ALOXE3 mutations in three cases, and TGM1 mutations in one case. In three patients, we could not find mutations in any of the known ARCI genes. In all cases, a spontaneous shedding of the collodion membrane occurred 2-4 weeks after birth. When re-examined at 2-37 years of age, the patients showed skin xerosis, a mild or focal scaling, palmar hyperlinearity with keratoderma, and a frequent appearance of red cheeks and anhidrosis. Thus, we propose replacing SHCB with the term "self-improving collodion ichthyosis" (SICI). In conclusion, ALOX12B mutations are the leading cause of SICI in Scandinavia, followed by ALOXE3 mutations, which have not been previously associated with this variant of ARCI.


Assuntos
Araquidonato 12-Lipoxigenase/genética , Ictiose/genética , Lipoxigenase/genética , Mutação , Transglutaminases/genética , Adolescente , Adulto , Criança , Pré-Escolar , Dinamarca , Feminino , Genótipo , Humanos , Ictiose/diagnóstico , Masculino , Suécia
15.
J Dermatol Sci ; 53(3): 198-206, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19157792

RESUMO

BACKGROUND: Epidermolysis bullosa simplex (EBS) is an autosomal inherited mechano-bullous disease, characterized by intraepidermal blistering and skin fragility caused by mutations in the keratin (KRT) 5 or 14 genes. Despite a vast knowledge about the intermediate filament pathology in this disease, the progress in therapy has been slow. Animal models and well-characterized continuous cell culture models of EBS are needed prior to clinical testing. OBJECTIVES: Our aim was to generate immortalized cell lines as an in vitro model for the study of EBS and test a chemical chaperone, trimethylamine N-oxide (TMAO), as a putative novel therapy. METHODS: We generated four immortalized cell lines, two each from an EBS patient with a KRT5-mutation (V186L) and a healthy control, using human papillomavirus 16 (HPV16) E6E7 as transducer. Cell lines were established in serum-free and serum-containing medium and assessed for growth characteristics, keratin expression profiles, ability to differentiate in organotypic cultures, and response to heat stress with and without the presence of TMAO. RESULTS: All cell lines have been expanded >160 population doublings and their cellular characteristics are similar. However, the formation of cytoplasmic keratin filament aggregates in response to heat-shock treatment differed between EBS and normal cell lines. Notably, serum-free established EBS-cell line was most vulnerable to heat shock but both cell lines exhibited significant reduction in the number of keratin aggregates containing cells by TMAO. CONCLUSION: The immortalized cell lines represent a suitable model for studying novel therapies for EBS. TMAO is a promising new agent for future development as a novel EBS therapy.


Assuntos
Citoesqueleto/efeitos dos fármacos , Epidermólise Bolhosa Simples/patologia , Temperatura Alta/efeitos adversos , Queratina-5/genética , Queratinócitos/patologia , Queratinas/metabolismo , Metilaminas/farmacologia , Apoptose/efeitos dos fármacos , Biópsia , Estudos de Casos e Controles , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Citoesqueleto/metabolismo , Epidermólise Bolhosa Simples/genética , Epidermólise Bolhosa Simples/metabolismo , Humanos , Técnicas In Vitro , Queratina-5/metabolismo , Queratinócitos/metabolismo , Modelos Biológicos , Mutação/genética , Oxidantes/farmacologia , Pele/metabolismo , Pele/patologia
16.
Acta Derm Venereol ; 88(1): 4-14, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18176742

RESUMO

Congenital ichthyosis is a collective name for a group of monogenetic disorders of cornification, sometimes associated with systemic symptoms. There may be an abnormal quality or quantity of scale produced, abnormal thickness of stratum corneum or abnormal keratinocyte kinetics, often associated with skin inflammation. Pruritus, skin fragility, ectropion and anhidrosis are sometimes associated with the rare types of ichthyosis. Three important mechanisms are involved in the action of topical agents used in the treatment of ichthyosis: hydration, lubrication and keratolysis. The latter effect can also be achieved with systemic retinoids. For ichthyosis with an increased tendency towards skin infections, antimicrobials are another group of widely used agents. Considering that patients with ichthyosis are potential mega-users of topical therapy, with an estimated lifetime consumption of approximately one tonne cream per capita, surprisingly few controlled trials of the various treatments have been performed. Moreover, nearly all therapeutic principles were established long before the recent increase in knowledge about the aetiology and pathophysiology of ichthyosis. This calls for new ideas and intensified efforts to develop future ichthyosis therapies.


Assuntos
Fármacos Dermatológicos/uso terapêutico , Ictiose/terapia , Anti-Infecciosos/uso terapêutico , Fármacos Dermatológicos/efeitos adversos , Emolientes/uso terapêutico , Terapia Genética , Humanos , Ictiose/classificação , Ictiose/genética , Ictiose/patologia , Recém-Nascido , Ceratolíticos/uso terapêutico , Retinoides/efeitos adversos , Retinoides/uso terapêutico , Pele/patologia , Pele/fisiopatologia
17.
Am J Clin Dermatol ; 7(2): 121-31, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-16605292

RESUMO

INTRODUCTION: Although several controlled clinical trials have demonstrated the efficacy and good tolerability of 1% pimecrolimus cream for the treatment of atopic dermatitis, the results of these trials may not apply to real-life usage. The objective of this study was to evaluate the safety and efficacy of a pimecrolimus-based regimen in daily practice. METHODS: This was a 6-month, open-label, multicenter study in 947 patients aged >or=3 months with atopic dermatitis of all severities. The investigators incorporated 1% pimecrolimus cream into patients' standard treatment protocols on the basis of their clinical diagnosis. Use of topical corticosteroids was allowed at the discretion of the physician. Safety and tolerability were evaluated by monitoring adverse events. Efficacy was evaluated by recording changes in the Investigators' Global Assessment scores and pruritus scores at each visit. RESULTS: No clinically unexpected adverse events were reported. The discontinuation rate for adverse events was 2.3%. The disease improvement rate was 53.7% at week 1 and 66.9% at week 24. The pimecrolimus-based regimen was particularly effective for the treatment of lesions involving the face (improvement rate: 61.9% at week 1 and 76.7% at week 24). The greatest therapeutic response was experienced by pediatric patients with mild or moderate disease. Nonetheless, 64% and 65% of infants and children, respectively, with severe/very severe facial disease at baseline were clear/almost clear of signs of atopic dermatitis on their face at week 24. In patients aged <18 years, most of the improvement occurred within the first week of treatment, while in adults a progressive improvement was observed over the entire study period. Worsening of disease by the end of the study occurred in 9.5% of patients and was most frequent in adults (12.6%). The discontinuation rate for unsatisfactory therapeutic effect was 4.8%. The mean number of treatment days was 135.6 (SD 53.2). The mean drug consumption (non-US centers only) was 4.2 g per treatment day. Drug consumption decreased over time as disease improved. In total, 47% of patients who completed the study never used topical corticosteroids over 6 months. CONCLUSION: In daily practice, incorporation of 1% pimecrolimus cream into patients' standard treatment regimen is well tolerated and improves atopic dermatitis in approximately two-thirds of patients. Disease improvement is particularly evident on the face. The greatest therapeutic response is experienced by pediatric patients with mild or moderate disease. In these patients, most of the improvement is observed within 1 week from the start of treatment.


Assuntos
Dermatite Atópica/tratamento farmacológico , Fármacos Dermatológicos/administração & dosagem , Fármacos Dermatológicos/efeitos adversos , Tacrolimo/análogos & derivados , Administração Tópica , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Tacrolimo/administração & dosagem , Tacrolimo/efeitos adversos
18.
Acta Derm Venereol Suppl (Stockh) ; (213): 34-47, 2003 May.
Artigo em Inglês | MEDLINE | ID: mdl-12822194

RESUMO

Congenital ichthyosis comprises a rare group of usually monogenetic diseases that present at birth as a collodion phenotype or as variable degrees of ichtHyosiform erythroderma, with or without superficial blisters. Depending on which gene mutation causes the disease, the skin problems later in life may range from a severe lamellar or bullous ichthyosis to mild or only focally expressed hyperkeratotic lesions. It is obviously important, but sometimes painstakingly difficult, to make a correct diagnosis already in infancy. Fortunately, recent advances in our understanding of the molecular genetics of ichthyosis have led to several new diagnostic tools that are continuously being updated. Based on this development, and on our own 5 years of experience in a national genodermatosis centre, we describe 127 cases of congenital ichthyosis examined in childhood or adulthood. Applying a combination of phenotypic and genotypic criteria, the patients were classified into three main groups: 1) Bullous ichthyosis (epidermolytic hyperkeratosis) and related disorders due to keratin mutations (n = 21); 2) Non-bullous ichthyosiform erythroderma and lamellar ichthyosis mainly due to transglutaminase 1 mutations (n = 80); 3) Syndromic ichthyosis, i.e. systemic (multi-organ) diseases due to many different causes (n = 26). Each group could be further stratified into 4-11 entities using mutation analysis, electron microscopy of epidermis and various other techniques. Our findings are discussed in relation to recent data in the literature emphasizing the clinical usefulness of various diagnostic procedures for ichthyosis.


Assuntos
Ictiose , Adulto , Humanos , Ictiose/genética , Ictiose/patologia , Lactente , Recém-Nascido , Suécia
19.
Acta Derm Venereol ; 83(1): 24-30, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-12636018

RESUMO

Congenital (non-bullous) ichthyosis is a rare group of keratinizing disorders which can be tentatively subclassified based on clinical criteria, analysis of transglutaminase 1 gene mutations and electron microscopy of epidermis. We studied 83 patients who were all on topical therapy and in 16 cases also on oral retinoids. Three main groups of patients were distinguished: (A) those with transglutaminase 1 gene mutations (n=44), (B) those without transglutaminase 1 gene mutations showing a coarse, generalized scaling (n=19), and (C) those without transglutaminase 1 gene mutations showing only fine or focal scaling (n=20). On clinical scoring, patients in group A were more hyperkeratotic and less erythematous than those in group B (p < 0.05). Anhidrosis was recorded in nearly all patients (> or = 80%), but ectropion and a collodion phenotype at birth were more common in group A versus other groups. Ultrastructurally, a high frequency of type I (Anton-Lamprecht's classification) was found in all three groups (37-63%), 20 cases of type II in group A and a few cases of types III and IV in groups B and C, respectively. In conclusion, transglutaminase 1 gene mutation is a major cause of congenital ichthyosis in Sweden and Estonia, and is often associated with severe scaling and ultrastructural type II in corneocytes. The transglutaminase-unrelated cases are more heterogeneous, probably reflecting a more varied aetiology.


Assuntos
Ictiose Lamelar/genética , Ictiose Lamelar/ultraestrutura , Transglutaminases/genética , Adolescente , Adulto , Fatores Etários , Idoso , Criança , Pré-Escolar , Estônia/epidemiologia , Feminino , Humanos , Ictiose Lamelar/tratamento farmacológico , Ictiose Lamelar/epidemiologia , Lactente , Masculino , Pessoa de Meia-Idade , Mutação , Fatores Sexuais , Pele/ultraestrutura , Suécia/epidemiologia
20.
J Invest Dermatol ; 121(5): 1013-20, 2003 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-14708600

RESUMO

Epidermolytic hyperkeratosis is a rare autosomal dominant inherited skin disorder caused by keratin 1 or keratin 10 mutations. Keratins are major structural proteins of the epidermis, and in keratinocytes committed to terminal differentiation the intermediate filaments are composed of keratin 1 and keratin 10 heterodimers. The majority of reported mutations (86.6%) are heterozygous single point mutations and most of these are located in the 1A and 2B regions of the highly conserved keratin alpha-helical rod domain. We have studied eight Scandinavian families with epidermolytic hyperkeratosis and identified three point mutations, two codon deletions, two splice site mutations, and a complex deletion/insertion. Two of the point mutations were in the KRT1 gene (F191C and K177N) and the other was in KRT10 (L453P). All three patients had associated palmoplantar keratoderma. The splice site mutations in KRT1 both caused a large deletion removing 22 codons (delta176-197) from the 1A helical domain. Codon deletions were found in KRT1 (delta170-173) and in KRT10 (delta161-162) in two patients with a severe phenotype. A final patient had a more complex mutation with a large deletion (442 bp) together with a large insertion (214 bp) of unknown origin that caused deletion of exon 6 in KRT1. In conclusion, we have found eight novel keratin mutations that cause epidermolytic hyperkeratosis with differing phenotypes. Even when a large part of keratin 1 (46 amino acids) is deleted, surprisingly mild phenotypes can result, suggesting that genotype-phenotype relationships in epidermolytic hyperkeratosis are complex and do not solely depend on the type of mutation but also depend on interactions between the behavior of the mutant protein and the cellular environment.


Assuntos
Hiperceratose Epidermolítica/genética , Queratinas/genética , Mutação , Adolescente , Adulto , Criança , Éxons , Deleção de Genes , Humanos , Queratina-10 , Ceratodermia Palmar e Plantar/genética , Fenótipo , Splicing de RNA
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