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PURPOSE: Biallelic variants in TBC1D24, which encodes a protein that regulates vesicular transport, are frequently identified in patients with DOORS (deafness, onychodystrophy, osteodystrophy, intellectual disability [previously referred to as mental retardation], and seizures) syndrome. The aim of the study was to identify a genetic cause in families with DOORS syndrome and without a TBC1D24 variant. METHODS: Exome or Sanger sequencing was performed in individuals with a clinical diagnosis of DOORS syndrome without TBC1D24 variants. RESULTS: We identified the same truncating variant in ATP6V1B2 (NM_001693.4:c.1516C>T; p.Arg506*) in nine individuals from eight unrelated families with DOORS syndrome. This variant was already reported in individuals with dominant deafness onychodystrophy (DDOD) syndrome. Deafness was present in all individuals, along with onychodystrophy and abnormal fingers and/or toes. All families but one had developmental delay or intellectual disability and five individuals had epilepsy. We also describe two additional families with DDOD syndrome in whom the same variant was found. CONCLUSION: We expand the phenotype associated with ATP6V1B2 and propose another causal gene for DOORS syndrome. This finding suggests that DDOD and DOORS syndromes might lie on a spectrum of clinically and molecularly related conditions.
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Epilepsia , Discapacidad Intelectual , Uñas Malformadas , ATPasas de Translocación de Protón Vacuolares , Epilepsia/genética , Exoma , Proteínas Activadoras de GTPasa , Humanos , Discapacidad Intelectual/genética , Uñas Malformadas/genética , Fenotipo , ATPasas de Translocación de Protón Vacuolares/genéticaRESUMEN
INTRODUCTION: Application of topical products by individuals is inherently variable and accurate dosing can be difficult to control. Variation of the dose used under optimal conditions in drug trials is unknown. METHODS: This trial was part of a double-blind, randomized, placebo-controlled good clinical practice (GCP) study designed to investigate the local tolerability and safety on healthy skin of captopril 1% ointment versus a placebo ointment. Volunteers were instructed to apply an even layer of test ointment on a 51 cm(2) test area on the arm twice daily over a 3-week period. At weekly follow-up visits, tubes were weighed and adherence to treatment checked. RESULTS: Of the 37 recruited volunteers, 36 (17 women, 19 men) completed the study. Their mean age was 24 (18-35) years. A 13.6-fold difference in the applied amount was found ranging from 1.26 mg/cm(2) to 17.19 mg/cm(2) per application at week 4, with median 5.60 mg/cm(2) applied versus 2 mg/cm(2) (standard for good application) resulting in a 2.8-fold over-dosage. CONCLUSION: There was a major variation of test ointment application studied under GCP conditions with adherent participants. In dermatological practice, the variation is assumed to be even higher. This should be taken into account in clinical trials, especially dose-finding studies typically operating with 3-5-fold increments.
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Administración Cutánea , Pomadas/administración & dosificación , Adolescente , Adulto , Benchmarking , Método Doble Ciego , Femenino , Humanos , Masculino , Piel , Adulto JovenRESUMEN
BACKGROUND: The rare hereditary disorder "dominant deafness and onychodystrophy (DDOD) syndrome" (OMIM 124480) has been described in a few case reports. No putative DDOD gene or locus has been mapped and the cause of the disorder remains unknown. MAIN OBSERVATIONS: We present here three male family members in three generations with sensori-neural deafness, onychodystrophy and brachydactyly inherited via autosomal dominant transmission. The family members presented with absent fingernails on the first and fifth digits. As to the feet, there were absent nails on second to fifth toes in two family members, whereas the third family member only had absent nails on the fifth toe. The proband had late dentition and his father a history of late dentition, but otherwise the teeth appeared normal. Comparative genomic hybridization array analysis (Agilent 400k oligoarray) of the proband did not detect any copy number variation. CONCLUSION: This Danish family fits within the spectrum of dominant deafness and onychodystrophy syndrome and further characterises this rare disorder.
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BACKGROUND: Corticosteroids are used to treat dermatoses, including allergic contact dermatitis, but can also cause contact allergy. The frequency of corticosteroid allergy varies between studies and is influenced by treatment traditions and availability. AIM: To estimate the prevalence of tixocortol-21-pivalate, budesonide and hydrocortisone-17-butyrate allergy in a Danish patch test population and characterize individuals with corticosteroid allergy. MATERIALS/METHODS: Three thousand five hundred and ninety-four patients were patch tested with tixocortol-21-pivalate, budesonide, and hydrocortisone-17-butyrate. Characterization was performed according to the MOAHLFA index and duration of disease. RESULTS: Two per cent had a steroid allergy: 0.8% had a tixocortol-21-pivalate allergy, 1% a budesonide allergy, and 1% a hydrocortisone-17-butyrate allergy. Tixocortol-21-pivalate and budesonide allergy were associated with atopic dermatitis in crude analyses, but only tixocortol-21-pivalate allergy and atopic dermatitis remained associated in adjusted analyses. Leg dermatitis was uniquely associated with tixocortol-21-pivalate allergy. Hydrocortisone-17-butyrate allergy was associated with duration of disease in both crude and adjusted analyses. DISCUSSION/CONCLUSION: Chronic dermatoses (atopic dermatitis and leg dermatitis) were identified as risk factors for group A corticosteroid allergy, probably because of more pronounced exposure to group A steroids resulting from ease of access that is exploited by patients with a chronic dermatosis. The duration of disease rather than the dermatosis itself seemed to be important for group B and D2 corticosteroid allergy.
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Budesonida/efectos adversos , Dermatitis Alérgica por Contacto/epidemiología , Fármacos Dermatológicos/efectos adversos , Hidrocortisona/análogos & derivados , Adulto , Enfermedad Crónica , Dinamarca/epidemiología , Dermatitis Alérgica por Contacto/etiología , Dermatitis Atópica/inducido químicamente , Dermatitis Atópica/epidemiología , Dermatitis Profesional/epidemiología , Dermatitis Profesional/etiología , Dermatosis Facial/inducido químicamente , Dermatosis Facial/epidemiología , Femenino , Dermatosis de la Mano/inducido químicamente , Humanos , Hidrocortisona/efectos adversos , Dermatosis de la Pierna/inducido químicamente , Dermatosis de la Pierna/epidemiología , Masculino , Persona de Mediana Edad , Pruebas del Parche , Prevalencia , Factores de RiesgoRESUMEN
Lipid rafts are cholesterol-rich plasma membrane domains that regulate signal transduction. Because our earlier work indicated that raft disruption inhibited proliferation and caused cell death, we investigated here the role of membrane cholesterol, the crucial raft constituent, in the regulation of the phosphatidylinositol-3 kinase (PI3K)/Akt pathway. Raft disruption was achieved in normal human keratinocytes and precancerous (HaCaT) or transformed (A431) keratinocytes by cholesterol extraction or inactivation with methyl-beta-cyclodextrin, filipin III, or 5-cholestene-5-beta-ol. Lipid raft disruption did not affect PI3K binding to its main target, the epidermal growth factor receptor, nor its ability to convert phosphatidylinositol 4,5-bisphosphate to phosphatidylinositol 3,4,5-trisphosphate but impaired Akt phosphorylation at the regulatory sites Thr(308) and Ser(473). Diminished Akt activity resulted in deactivation of mammalian target of rapamycin, activation of FoxO3a, and increased sensitivity to apoptosis stimuli. Lipid raft disruption abrogated the binding of Akt and the major Akt kinase, phosphatidylinositol-dependent kinase 1, to the membrane by pleckstrin-homology domains. Thus, the integrity of lipid rafts is required for the activity of Akt and cell survival and may serve as a potential pharmacological target in the treatment of epidermal cancers.
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Queratinocitos/metabolismo , Microdominios de Membrana/metabolismo , Lesiones Precancerosas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/fisiología , Proteínas Quinasas Dependientes de 3-Fosfoinosítido , Transporte Activo de Núcleo Celular/fisiología , Antibióticos Antineoplásicos/farmacología , Antineoplásicos Fitogénicos/farmacología , Apoptosis/fisiología , Línea Celular Transformada , Colesterol/metabolismo , Doxorrubicina/farmacología , Células Epidérmicas , Epidermis/metabolismo , Etopósido/farmacología , Proteína Forkhead Box O3 , Factores de Transcripción Forkhead/metabolismo , Gliceraldehído-3-Fosfato Deshidrogenasa (Fosforilante)/fisiología , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Queratinocitos/citología , Fosfatidilinositol 3-Quinasas/metabolismo , Lesiones Precancerosas/patología , Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de Señal/efectos de los fármacos , Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Serina-Treonina Quinasas TORRESUMEN
The use of laptop computers is increasing, and many children and young adults spend hours with their laptops on their laps daily. We report a case with erythema ab igne on the thigh of a 17-year-old girl, induced by use of laptop computers four to five hours daily for nine months.
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Ternary lipid compositions in model membranes segregate into large-scale liquid-ordered (L(o)) and liquid-disordered (L(d)) phases. Here, we show mum-sized lipid domain separation leading to vesicle formation in unperturbed human HaCaT keratinocytes. Budding vesicles in the apical portion of the plasma membrane were predominantly labelled with L(d) markers 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate, 1,1'-dilinoleyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate, 1,1'-didodecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate and weakly stained by L(o) marker fluorescein-labeled cholera toxin B subunit which labels ganglioside GM(1) enriched plasma membrane rafts. Cholesterol depletion with methyl-beta-cyclodextrin enhanced DiI vesiculation, GM(1)/DiI domain separation and was accompanied by a detachment of the subcortical cytoskeleton from the plasma membrane. Based on these observations we describe the energetic requirements for plasma membrane vesiculation. We propose that the decrease in total 'L(o)/L(d)' boundary line tension arising from the coalescence of smaller L(d)-like domains makes it energetically favourable for L(d)-like domains to bend from flat mum-sized surfaces to cap-like budding vesicles. Thus living cells may utilize membrane line tension energies as a control mechanism of exocytic events.
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Fenómenos Biofísicos , Vesículas Citoplasmáticas/química , Lípidos/química , Adhesividad/efectos de los fármacos , Fenómenos Biofísicos/efectos de los fármacos , Carbocianinas/metabolismo , Línea Celular , Supervivencia Celular/efectos de los fármacos , Vesículas Citoplasmáticas/efectos de los fármacos , Citoesqueleto/efectos de los fármacos , Citoesqueleto/metabolismo , Exocitosis/efectos de los fármacos , Humanos , Queratinocitos/efectos de los fármacos , Queratinocitos/ultraestructura , beta-Ciclodextrinas/farmacologíaRESUMEN
In cultured keratinocytes, focal junctions are enriched in major constituents of lipid rafts, such as GM1 ganglioside, phosphoinositides, caveolins and flotillins. We have therefore speculated that focal junctions represent superrafts formed by coalescence of microdomains into large areas containing liquid-ordered (L(o)) lipids. Indeed, values of maximal fluorescence recovery after photobleaching revealed that the long-range mobility of cholera toxin B subunit (CTB, marker of L(o)) was approximately 1.5-fold retarded within the focal junctions compared to the surrounding membrane. However, 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI-C(18:0)), which specifically partitions to the liquid-disordered (L(d)), non-raft phase, was also enriched in focal junctions and its mobility was slightly retarded. Cross-linking of GM1 by CTB or raft aggregation by methyl-beta-cyclodextrin further decreased the recovery of DiI-C(18:0). We propose a model in which focal junctions impose lateral heterogeneity in the plasma membrane by entrapment of lipid microdomains between dense arrays of immobilized transmembrane molecules which can enmesh otherwise freely percolating L(d) phase lipids.
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Membrana Celular/fisiología , Uniones Intercelulares/fisiología , Fluidez de la Membrana , Microdominios de Membrana/fisiología , Biomarcadores/análisis , Línea Celular , Recuperación de Fluorescencia tras Fotoblanqueo , Humanos , Membrana Dobles de Lípidos/metabolismo , Microscopía Confocal , TransfecciónRESUMEN
Normal and immortalized keratinocytes demonstrate large aggregates of lipid rafts, detectable by membrane staining with fluorescently tagged cholera toxin (CTx). As lipid rafts are known to regulate the function of many surface receptors, we wished to investigate their impact on the EGFR in HaCaT cells. When rafts were disrupted by cholesterol sequestration with methyl-beta-cyclodextrin (MbetaCD) or filipin III, EGFR rearranged into approximately micrometer large clusters outside the CTx(bright) raft aggregates. These clusters contained high concentrations of activated, tyrosine-phosphorylated EGFR exhibiting greatly reduced mobility in the fluorescence recovery after photobleaching experiments. EGFR activation led to the stimulation of extracellular signal-regulated kinase 2, the phosphorylated form of which translocated to the nucleus and stimulated growth of the MbetaCD-treated cells. Experiments with the specific antagonistic antibody proved that the activation of EGFR by lipid raft disruption occurred without the participation of the ligand. We hypothesize that cholesterol depletion leads to the release of EGFR from the damaged rafts into the small confined areas of the membrane, where the receptor molecules are likely to be spontaneously activated owing to a very high density and/or separation from the inhibitory factors remaining in the surrounding portions of the membrane.