RESUMO
BACKGROUND: No efficient treatment has yet been established for epidermolytic ichthyosis (EI), which is caused by pathogenic variants of KRT1 or KRT10. Patients with ichthyosis with confetti (IWC) have multiple normal-appearing spots, caused by the revertant somatic recombination of pathogenic variants that occurs at each spot independently. Additionally, some patients with EI have large areas of normal skin due to revertant postzygotic mosaicism. OBJECTIVES: To assess the feasibility of transplanting cultured epidermal autografts (CEAs) produced from revertant epidermal keratinocytes in patients with EI and IWC. METHODS: We performed a clinical trial of treatment with CEAs produced from each patient's own revertant epidermal keratinocytes as a proof-of-concept study. This was a single-arm, open, unmasked, uncontrolled, single-assignment, treatment-purpose study. The primary outcome was the percentage area that lacked recurrence of ichthyosis lesions 4 weeks after the final transplant. The secondary outcome was the percentage area lacking recurrence of ichthyosis lesions 24 weeks after the initial transplantation. The trial was registered with the Japan Registry of Clinical Trials (jRCTb041190097). RESULTS: We successfully produced CEAs from genetically confirmed revertant skin from two patients with mosaic EI and from one patient with IWC and confirmed by amplicon sequencing and droplet digital polymerase chain reaction analysis that the CEAs mainly consisted of revertant wild-type cells. Single-cell RNA sequencing analysis confirmed the normal proliferation and safety profiling of CEAs. CEAs were transplanted onto desquamated lesional sites in the patients. Four weeks post-transplantation, the percentage area lacking recurrence of ichthyosis lesions in the three patients was 40%, 100% and 100% respectively, although recurrence of ichthyosis lesions was seen at the site of CEA transplantation in all three patients at 24 weeks post-transplantation. CONCLUSIONS: CEAs from normal skin have the potential to be a safe and local treatment option for EI and IWC.
Epidermolytic ichthyosis is a rare skin condition that causes redness, blistering and thickening of the skin. There is currently no effective treatment for the disease, which is caused by mutations in the genes KRT1 or KRT10. People with a type of the disease called 'ichthyosis with confetti' have many normal-appearing spots that are caused by the natural repair of the gene mutations. Some people with epidermolytic ichthyosis have large areas of healthy skin as a result of genetic mutations having been corrected. In this study, we successfully produced skin grafts from the healthy skin of two patients with epidermolytic ichthyosis and one with 'ichthyosis with confetti'. We confirmed that the skin grafts mainly consisted of repaired skin cells. A technique called 'single-cell RNA sequencing' confirmed the skin cells in the skin grafts behaved like healthy skin cells and that the grafts were safe. Overall, our study findings suggest that skin grafts taken from skin consisting of genetically normal keratinocytes that have undergone self-repair have potential to be a safe treatment option for patients with severe epidermolytic ichthyosis and 'ichthyosis with confetti'.
Assuntos
Hiperceratose Epidermolítica , Queratinócitos , Humanos , Hiperceratose Epidermolítica/genética , Hiperceratose Epidermolítica/patologia , Masculino , Feminino , Queratinócitos/transplante , Criança , Adulto , Transplante de Pele/métodos , Autoenxertos , Epiderme/transplante , Epiderme/patologia , Queratina-10/genética , Adolescente , Estudos de Viabilidade , Queratina-1/genética , Adulto Jovem , Estudo de Prova de Conceito , Transplante Autólogo , Resultado do Tratamento , Pré-Escolar , Mosaicismo , Ictiose/genética , Ictiose/cirurgia , Ictiose/patologiaRESUMO
BACKGROUND: Congenital ichthyoses sometimes present with severe skin symptoms that significantly affect the patient's quality of life (QOL). Symptomatic treatments are the mainstay therapies, and their efficacy is limited and inadequate. OBJECTIVE: To assess the disease severity and QOL in patients with congenital ichthyoses, and to investigate the effectiveness of current treatments. METHODS: We conducted a questionnaire-based Japan-wide epidemiological survey of patients with congenital ichthyosis who received medical care from 1 January 2016-31 December 2020. Effectiveness of past and current treatments was assessed. The outcomes were the physician's assessment, disease severity assessed using the clinical ichthyosis score (CIS), and the disease burden estimated using the Dermatology Life Quality Index (DLQI), the Children's Dermatology Life Quality Index (CDLQI), and the Infants' Dermatitis Quality of Life Index. RESULTS: One hundred patients with 14 ichthyosis subtypes from 47 institutes were included in the final analysis. The CDLQI score showed a positive correlation with CIS (rs = 0.59, p = 0.004), while the DLQI score showed no significant correlation (rs = 0.13, p = 0.33). All existing medications were effective for many patients. Etretinate improved QOL and reduced CIS, but side effects including bone growth retardation were reported. Decreased treatment willingness was observed in patients with very low and very high CIS. CONCLUSION: QOL scores were found to correlate with CIS in children, but not in adults. Considering the adverse events, it is speculated that etretinate is not indicated for children with mild cases. Petrolatum was the most commonly used medication, even in patients who were reluctant to receive treatment.
Assuntos
Etretinato , Ictiose Lamelar , Ictiose , Criança , Adulto , Lactente , Humanos , Qualidade de Vida , Japão/epidemiologia , Estudos Transversais , Índice de Gravidade de Doença , Ictiose/tratamento farmacológico , Ictiose/epidemiologia , Resultado do TratamentoAssuntos
Linfoma Difuso de Grandes Células B , Micose Fungoide , Neoplasias Cutâneas , Humanos , Linfoma Difuso de Grandes Células B/diagnóstico , Micose Fungoide/patologia , Pele/patologia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/patologia , Masculino , Pessoa de Meia-Idade , Febre/etiologia , Prurido/etiologia , Eritema/etiologiaRESUMO
Superficial epidermolytic ichthyosis (SEI) is an autosomal dominant inherited ichthyosis. SEI is caused by mutations in KRT2 and frequently shows erythroderma and widespread blistering at birth. We report the clinical manifestations of two patients from a Japanese family with SEI caused by a hotspot mutation, p.Glu487Lys, in KRT2. In addition, we summarize previous reports on SEI patients with the identical mutation. One of the two patients had disease onset at the age of 7 months. The other patient's age of onset is unknown, but it was in childhood. Neither of the two patients showed erythroderma. To perform deep phenotyping, we studied the age of onset and the frequency of erythroderma in 34 reported SEI cases with the p.Glu487Lys mutation, including the present cases. Among the cases with sufficient clinical information, 44.4% of the cases that were due to p.Glu487Lys in KRT2 occurred at birth. Erythroderma was observed in 11.1% of the cases with p.Glu487Lys in KRT2.
Assuntos
Dermatite Esfoliativa , Hiperceratose Epidermolítica , Queratina-2 , Dermatite Esfoliativa/genética , Humanos , Hiperceratose Epidermolítica/genética , Lactente , Recém-Nascido , Queratina-2/genética , MutaçãoRESUMO
Learning of most motor skills is constrained in a species-specific manner. However, the proximate mechanisms underlying species-specific learned behaviors remain poorly understood. Songbirds acquire species-specific songs through learning, which is hypothesized to depend on species-specific patterns of gene expression in functionally specialized brain regions for vocal learning and production, called song nuclei. Here, we leveraged two closely related songbird species, zebra finch, owl finch, and their interspecific first-generation (F1) hybrids, to relate transcriptional regulatory divergence between species with the production of species-specific songs. We quantified genome-wide gene expression in both species and compared this with allele-specific expression in F1 hybrids to identify genes whose expression in song nuclei is regulated by species divergence in either cis- or trans-regulation. We found that divergence in transcriptional regulation altered the expression of approximately 10% of total transcribed genes and was linked to differential gene expression between the two species. Furthermore, trans-regulatory changes were more prevalent than cis-regulatory and were associated with synaptic formation and transmission in song nucleus RA, the avian analog of the mammalian laryngeal motor cortex. We identified brain-derived neurotrophic factor (BDNF) as an upstream mediator of trans-regulated genes in RA, with a significant correlation between individual variation in BDNF expression level and species-specific song phenotypes in F1 hybrids. This was supported by the fact that the pharmacological overactivation of BDNF receptors altered the expression of its trans-regulated genes in the RA, thus disrupting the learned song structures of adult zebra finch songs at the acoustic and sequence levels. These results demonstrate functional neurogenetic associations between divergence in region-specific transcriptional regulation and species-specific learned behaviors.
Assuntos
Tentilhões/genética , Fatores de Transcrição/fisiologia , Vocalização Animal/fisiologia , Animais , Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Tentilhões/fisiologia , Regulação da Expressão Gênica/genética , Variação Genética/genética , Aprendizagem/fisiologia , Neurônios/metabolismo , Aves Canoras/genética , Aves Canoras/fisiologia , Especificidade da Espécie , Fatores de Transcrição/genética , TranscriptomaRESUMO
The aim of this study is to investigate whether or not spatial congruency between tactile and auditory stimuli would influence the tactile roughness discrimination of stimuli presented to the fingers or cheeks. In the experiment, when abrasive films were passively presented to the participants, white noise bursts were simultaneously presented from the same or different side, either near or far from the head. The results showed that when white noise was presented from the same side as the tactile stimuli, especially from near the head, the discrimination sensitivity on the cheeks was higher than when sound was absent or presented from a different side. A similar pattern was observed in discrimination by the fingers but it was not significant. The roughness discrimination by the fingers was also influenced by the presentation of sound close to the head, but significant differences between conditions with and without sounds were observed at the decisional level. Thus, the spatial congruency between tactile and auditory information selectively modulated the roughness sensitivity of the skin on the cheek, especially when the sound source was close to the head.
Assuntos
Estimulação Acústica , Percepção Auditiva/fisiologia , Som , Percepção do Tato/fisiologia , Adulto , Feminino , Humanos , Masculino , Adulto JovemRESUMO
We investigated the effects of non-native language (English) exposure on event-related potentials (ERPs) in first- and second-year (four- and five-year-old) preschool Japanese native speakers while they listened to semantically congruent and incongruent Japanese sentences. The children were divided into a non-native language exposed group (exposed group) and a group without such experiences (control group) on the basis of their exposure to non-native language. We compared the ERPs recorded from the two groups in each of the two preschool years. N400 was observed both in the first- and second-year preschoolers. Differences owing to exposure to non-native language appeared in the second-year preschoolers but not in the first-year preschoolers. In the second-year preschoolers, the N400 onset in the exposed group was shorter than that in the control group, but there was no difference in the N400 offset between the exposed and control groups. Furthermore, the scalp distribution of the N400 in the exposed group was broader than that in the control group. These results indicate that the time course and scalp distribution of semantic processing for native language sentences in young children fluctuated depending on exposure to non-native language.
Assuntos
Potenciais Evocados Auditivos/fisiologia , Semântica , Percepção da Fala/fisiologia , Estimulação Acústica/métodos , Fatores Etários , Análise de Variância , Mapeamento Encefálico , Pré-Escolar , Eletroencefalografia/métodos , Feminino , Humanos , Masculino , Fatores de Tempo , VocabulárioRESUMO
Event-related potentials (ERPs) were recorded during the evaluation of the appropriateness of cooperative actions between two people. We used pictures of pass-and-receive actions as one type of cooperative actions, in which one person passed an object and another reached out to receive it with a preshaped hand. Eleven participants judged whether the receiving actions were appropriate or inappropriate in relation to the passing ones. The inappropriate actions elicited a widely distributed and parietal maximum N400 as compared with the appropriate ones. These results suggest that the N400 is evoked in the incongruous context in which two people perform inappropriate cooperative actions and is related to the semantic processing that involves the prediction of interpersonal action sequences.
Assuntos
Córtex Cerebral/fisiologia , Potenciais Evocados/fisiologia , Julgamento/fisiologia , Comportamento Social , Adulto , Mapeamento Encefálico , Córtex Cerebral/anatomia & histologia , Feminino , Mãos/inervação , Mãos/fisiologia , Humanos , Masculino , Processos Mentais/fisiologia , Lobo Parietal/anatomia & histologia , Lobo Parietal/fisiologia , Desempenho Psicomotor/fisiologia , Tempo de Reação/fisiologia , Valores de Referência , Fatores de Tempo , Adulto JovemRESUMO
We report two psychophysical experiments designed to investigate the effects of non touch-produced sounds on the tactile perception of roughness and length. Previous studies have demonstrated that the tactile roughness perception of object surfaces is modified by sounds elicited by rubbing the surfaces. In this study, we examined the crossmodal effects of non touch-produced sounds such as white noise (Experiment 1) and pure tones (Experiment 2). Participants touched abrasive paper, synchronizing their touch with changes in the intensity of sounds or with the onset of beeps (control condition), and judged the tactile roughness or length of the stimuli, using the magnitude estimation method. Although the white noise (complex sound) significantly decreased the slope of the roughness estimation function, it did not affect that of the length estimation function. Pure tones had no effect on roughness or length perception. The results revealed that complex sounds selectively affected tactile roughness perception, even when they were seemingly irrelevant to the exploration of the surfaces. We suggest that the processing of complex sounds may be related to the processing of tactile roughness, whereas it is independent of tactile length processing.