RESUMEN
BACKGROUND: Palmoplantar pustulosis (PPP) sometimes presents with nail lesions, which affect the patients' quality of life (QOL). However, little is known about nail lesions in PPP, and there is currently no established method for assessing them. OBJECTIVE: This study aimed to analyze the impact of PPP-related nail lesions with the patients' QOL. In addition, we considered whether they might constitute a risk factor of pustulotic arthro-osteitis (PAO).' METHODS: A total of 178 patients with PPP were enrolled. Among the 178 patients, 66 patients participated in the following quality of life questionnaires; GHQ28, DLQI, and Skindex-16. The severity of the nail lesions was classified according to the Nail Psoriasis Severity Index (NAPSI), and the types of nail lesion were investigated. RESULTS: The DLQI, Skindex-16 and PPPASI scores were significantly higher in patients with nail lesions than in those without them. Indentions, transverse ridging, and nail thickening were relatively common in PPP. Nail lesions were unrelated to the presence of PAO complications, but leukonychia and discoloration were likely to be related to PAO lesion site. CONCLUSIONS: The study demonstrated that the presence of nail lesions is associated with a decreased QOL regardless of the severity of the skin lesions. The nail lesions were not a risk factor of PAO, but a predictor of skin lesion severity and PAO lesion site. Given this association, indention, transverse ridging, and thickening of the nail, currently not included in the NAPSI, should be added as an assessment item in the evaluation of PPP nail lesions.
Asunto(s)
Osteítis , Psoriasis , Enfermedad Aguda , Enfermedad Crónica , Humanos , Osteítis/complicaciones , Psoriasis/complicaciones , Psoriasis/diagnóstico , Calidad de VidaRESUMEN
Paradoxical reaction (PR) occurs when a drug elicits a reaction contrary to what was expected. To clarify the clinical features and genetic background of individuals susceptible to PR, we analyzed the clinical course of patients in whom psoriatic eruptions worsened or newly developed during tumor necrosis factor (TNF) antagonist administration and the role of focal infections and genetic variations. Of 125 patients who received TNF antagonist therapy for psoriasis, acrodermatitis continua of Hallopeau (ACH), generalized pustular psoriasis (GPP), or palmoplantar pustular psoriasis (PPP), eight patients with PR were surveyed at our hospital Dermatology Department between 2010 and 2021. A survey was also done on six patients who received TNF antagonist therapy for Crohn's disease, rheumatoid arthritis, ankylosing spondylitis, and hidradenitis suppurativa and were referred to our department due to PR. Additionally, Sanger sequencing analysis was performed for all exons and flanking introns of IL36RN (interleukin 36 receptor antagonist), CARD14 (caspase recruitment domain-containing protein 14), and AP1S3 (adaptor-related protein complex 1 subunit sigma 3). The clinical assessment of the 14 patients demonstrated an average age at PR onset of 48.4 years, a male : female ratio of 5:9, and a mean administration period until onset of 9.2 months. The clinical types of PR were plaque psoriasis, PPP, GPP, pustulosis, acne, ACH, hair loss, and exacerbation of arthralgia. Histopathology revealed psoriasiform dermatitis in three patients. One patient continued TNF antagonist therapy. All of the patients with psoriasis and GPP had dental infections, suggesting that focal infection may be a risk factor of the development of PR following TNF antagonist therapy. Gene analysis demonstrated CARD14 gene variants associated with RA, CD, AS, or PPP in four patients. In addition, all of the patients with ACH and PPP experienced PR, suggesting that these diseases may predispose patients to PR to TNF antagonist therapy.
Asunto(s)
Artritis Reumatoide , Enfermedad de Crohn , Psoriasis , Espondilitis Anquilosante , Proteínas Adaptadoras de Señalización CARD , Femenino , Guanilato Ciclasa , Humanos , Interleucinas , Masculino , Proteínas de la Membrana , Psoriasis/inducido químicamente , Psoriasis/tratamiento farmacológico , Psoriasis/genética , Inhibidores del Factor de Necrosis Tumoral , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
Palmoplantar pustulosis (PPP) is a chronic dermatitis characterized by sterile intra-epidermal pustules associated with erythema and scales on the palms and soles. Tumor necrosis factor (TNF)-α/interleukin (IL)-23/IL-17 inflammatory pathway may be involved in the pathogenesis of PPP, and the skin lesions manifest the enhanced expression of IL-8 in keratinocytes and increased levels of antimicrobial peptide cathelicidin, leucine leucine-37 in vesicles/pustules. Some PPP patients are associated with arthro-osteitis, called pustulotic arthro-osteitis (PAO). Dietary habits may modulate the pathogenesis of PPP, however, have not been investigated in PPP patients. We evaluated dietary habits in adult Japanese PPP patients, using a validated, brief-type self-administered diet history questionnaire, and compared their results to those of age- and sex-matched healthy controls. The results in PPP patients with PAO were compared to those in the patients without. Japanese PPP patients showed higher body mass indices (BMIs), higher intakes of pulses and sugar/sweeteners, and lower intake of vitamin A, compared to those of healthy controls. The bivariate and multivariable logistic regression analysis showed that PPP was associated with high BMI, high intake of pulses, and low intake of vitamin A. The sodium intake and BMI were positively correlated with palmoplantar pustulosis area and severity index (PPPASI). The linear multivariate regression analysis revealed that sodium intake and BMI were predictors of PPPASI. The age and sodium intake in the patients with PAO were lower than those in the patients without. The bivariate and multivariable logistic regression analysis showed that PAO was negatively associated with age and sodium intake. This is the first study showing the dietary habits in patients with PPP. Further studies should clarify if the dietary intervention to correct the BMI and sodium intake will alter the progress of PPP.
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Osteítis , Psoriasis , Enfermedades Cutáneas Vesiculoampollosas , Adulto , Conducta Alimentaria , Humanos , Japón/epidemiologíaAsunto(s)
Productos Biológicos/efectos adversos , Dermatomicosis/epidemiología , Susceptibilidad a Enfermedades/inducido químicamente , Interleucina-17/antagonistas & inhibidores , Psoriasis/tratamiento farmacológico , Adulto , Anciano , Productos Biológicos/administración & dosificación , Dermatomicosis/inmunología , Susceptibilidad a Enfermedades/inmunología , Femenino , Humanos , Incidencia , Interleucina-17/metabolismo , Masculino , Persona de Mediana Edad , Psoriasis/diagnóstico , Psoriasis/inmunología , Estudios Retrospectivos , Factores de Riesgo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunologíaRESUMEN
Changes in gene regulation underlie much of phenotypic evolution1. However, our understanding of the potential for regulatory evolution is biased, because most evidence comes from either natural variation or limited experimental perturbations2. Using an automated robotics pipeline, we surveyed an unbiased mutation library for a developmental enhancer in Drosophila melanogaster. We found that almost all mutations altered gene expression and that parameters of gene expression-levels, location, and state-were convolved. The widespread pleiotropic effects of most mutations may constrain the evolvability of developmental enhancers. Consistent with these observations, comparisons of diverse Drosophila larvae revealed apparent biases in the phenotypes influenced by the enhancer. Developmental enhancers may encode a higher density of regulatory information than has been appreciated previously, imposing constraints on regulatory evolution.
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Drosophila melanogaster/crecimiento & desarrollo , Drosophila melanogaster/genética , Elementos de Facilitación Genéticos/genética , Regulación del Desarrollo de la Expresión Génica/genética , Animales , Secuencia de Bases , Sitios de Unión , Proteínas de Drosophila/genética , Evolución Molecular , Proteínas de Homeodominio/genética , Larva/genética , Larva/crecimiento & desarrollo , Mutación , Fenotipo , Factores de Transcripción/genéticaRESUMEN
Eukaryotic transcription factors (TFs) form complexes with various partner proteins to recognize their genomic target sites. Yet, how the DNA sequence determines which TF complex forms at any given site is poorly understood. Here, we demonstrate that high-throughput in vitro DNA binding assays coupled with unbiased computational analysis provide unprecedented insight into how different DNA sequences select distinct compositions and configurations of homeodomain TF complexes. Using inferred knowledge about minor groove width readout, we design targeted protein mutations that destabilize homeodomain binding both in vitro and in vivo in a complex-specific manner. By performing parallel systematic evolution of ligands by exponential enrichment sequencing (SELEX-seq), chromatin immunoprecipitation sequencing (ChIP-seq), RNA sequencing (RNA-seq), and Hi-C assays, we not only classify the majority of in vivo binding events in terms of complex composition but also infer complex-specific functions by perturbing the gene regulatory network controlled by a single complex.
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ADN/química , Proteínas de Drosophila/metabolismo , Regulación de la Expresión Génica , Proteínas de Homeodominio/metabolismo , Factores de Transcripción/metabolismo , Animales , Secuencia de Bases , Sitios de Unión , ADN/metabolismo , Proteínas de Drosophila/química , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Proteínas de Homeodominio/química , Proteínas de Homeodominio/genética , Mutación , Conformación de Ácido Nucleico , Unión Proteica , Factores de Transcripción/química , Factores de Transcripción/genéticaAsunto(s)
Anafilaxia , Dulces/efectos adversos , Colágeno/efectos adversos , Proteínas de Peces/administración & dosificación , Hipersensibilidad a los Alimentos/sangre , Adulto , Anafilaxia/sangre , Anafilaxia/etiología , Anafilaxia/patología , Femenino , Hipersensibilidad a los Alimentos/patología , HumanosRESUMEN
[Purpose] The purpose of this study was to identify the factors influencing change in life-space mobility after total knee arthroplasty (TKA) in patients with severe knee osteoarthritis (knee OA). [Participants and Methods] Overall, 58 primary unilateral TKA recipients (9 males and 49 females; age ± SD 74.6 ± 6.5â years) were enrolled. We evaluated Life-Space Assessment (LSA) scores, knee extensor strength, Timed Up and Go test (TUG), one-leg standing time (OLS), Western Ontario and McMaster Universities osteoarthritis Index, and physical activity self-efficacy (SE) before surgery and at 3 months post-operation. [Results] Life space mobility significantly expanded 3 months after surgery compared with preoperative baseline. Preoperatively, walking SE and knee extensor muscle strength on the operative side were found to have strong correlation with LSA scores, while stairs SE and knee extensor muscle strength of the operative side were correlated at 3 months post-operation. [Conclusion] These findings suggest that to expand the life-space mobility of TKA recipients, it is important to enhance self-efficacy for general physical activity in addition to strengthening the quadriceps muscles.
RESUMEN
Pustulotic arthro-osteitis, occasionally complicated with palmoplantar pustulosis, affects patients' activities of daily living. Granulocyte and monocyte adsorption apheresis selectively removes activated granulocytes and monocytes by means of extracorporeal circulation. Although the efficacy of granulocyte and monocyte adsorption apheresis in the treatment of generalized pustular psoriasis has been proved, very few reports have assessed its efficacy in the treatment of palmoplantar pustulosis and pustulotic arthro-osteitis. Ten pustulotic arthro-osteitis patients with five palmoplantar skin manifestations were treated with weekly granulocyte and monocyte adsorption apheresis over 5 weeks. Skin manifestations were assessed using palmoplantar pustulosis area and severity index, and joint symptoms were assessed using a visual analog scale of joint pain, tender joint count, swollen joint count and C-reactive protein immediately before, after and at the 3-month follow up of the five granulocyte and monocyte adsorption apheresis sessions. Two out of five patients with skin manifestations achieved more than 50% improvement in their score (remarkably improved). However, in two patients, deterioration was noted, in one of whom the skin manifestations remained unchanged at the 3-month follow up. In five out of the 10 patients, the joint symptoms were assessed as better than improved at the 3-month follow up. No deterioration was noted at the 3-month follow up. In three patients, reduction or cessation of medication for arthralgia was possible. We concluded that granulocyte and monocyte adsorption apheresis is a therapeutic option to consider when pustulotic arthro-osteitis is recalcitrant to conventional therapy.
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Artritis Psoriásica/terapia , Leucaféresis , Osteítis/terapia , Adulto , Anciano , Artritis Psoriásica/complicaciones , Femenino , Granulocitos , Humanos , Masculino , Persona de Mediana Edad , Monocitos , Osteítis/etiología , Estudios RetrospectivosAsunto(s)
Eliminación de Componentes Sanguíneos , Granulocitos , Monocitos , Psoriasis/genética , Psoriasis/terapia , Adulto , Anciano , Proteínas Adaptadoras de Señalización CARD/genética , Femenino , Guanilato Ciclasa/genética , Humanos , Interleucinas/deficiencia , Interleucinas/genética , Masculino , Proteínas de la Membrana/genética , Persona de Mediana Edad , Resultado del Tratamiento , Proteínas de Transporte Vesicular/genéticaRESUMEN
Regarding appropriate timings of discontinuation and resumption of biologics for psoriasis patients before and after elective surgeries, an international consensus has yet to be reached. The Japanese Dermatological Association of Guideline and Safety Manual for the use of Biologic Agents in Psoriasis 2013 states that infliximab (IFX) and adalimumab (ADA) should be withheld at least 4 and 2 weeks, respectively, before surgery and can be restarted as neither postoperative infection nor delayed wound healing is recognized. We experienced three generalized pustular psoriasis (GPP) patients and one plaque-type psoriasis patient undergoing surgeries during tumor necrosis factor (TNF)-α blocker therapy. Three GPP cases experienced uneventful post-surgical course. One psoriasis vulgaris patient on IFX had a wound healing delay with deterioration of psoriatic plaques which was restored by restarting IFX. The timing of suspension and resumption of TNF-α blockers in all cases were determined following the Japanese guideline.
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Psoriasis/cirugía , Psoriasis/terapia , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Adalimumab/administración & dosificación , Adulto , Femenino , Humanos , Infliximab/administración & dosificación , Masculino , Persona de Mediana Edad , Atención Perioperativa , Guías de Práctica Clínica como AsuntoRESUMEN
BACKGROUND: Vitamin D3 ointment and corticosteroid ointment are both used for the treatment of palmoplantar pustulosis (PPP). However, to date there is no systematic study of the efficacy of combination therapy for the treatment of PPP. OBJECTIVE: We compared the efficacy of a topical combination therapy with vitamin D3 and a topical corticosteroid with that of topical corticosteroid alone in the treatment of PPP. METHOD: We evaluated left-right comparison study of the efficacy of a combination therapy consisting of maxacalcitol ointment and betamethasone butyrate propionate ointment (BBP), and monotherapy with BBP alone in 27 patients with PPP for 8 weeks. RESULTS: The improvement in the symptom (erythema, pustules/vesicles, hyperkeratosis/scales) scores was high for the combination therapy. In particular, the improvement rate for pustules/vesicles at week 8 after the combination therapy was significantly higher than for the monotherapy (p < 0.05). CONCLUSION: This combination regimen demonstrated that not only topical corticosteroids, but also topical vitamin D3 ointment, is useful for the treatment of PPP.
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Calcitriol/análogos & derivados , Fármacos Dermatológicos/uso terapéutico , Glucocorticoides/uso terapéutico , Psoriasis/tratamiento farmacológico , Administración Tópica , Adulto , Anciano , Calcitriol/uso terapéutico , Quimioterapia Combinada , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pomadas , Estudios Prospectivos , Enfermedades Cutáneas Vesiculoampollosas/tratamiento farmacológico , Resultado del TratamientoRESUMEN
Protein-DNA binding is mediated by the recognition of the chemical signatures of the DNA bases and the 3D shape of the DNA molecule. Because DNA shape is a consequence of sequence, it is difficult to dissociate these modes of recognition. Here, we tease them apart in the context of Hox-DNA binding by mutating residues that, in a co-crystal structure, only recognize DNA shape. Complexes made with these mutants lose the preference to bind sequences with specific DNA shape features. Introducing shape-recognizing residues from one Hox protein to another swapped binding specificities in vitro and gene regulation in vivo. Statistical machine learning revealed that the accuracy of binding specificity predictions improves by adding shape features to a model that only depends on sequence, and feature selection identified shape features important for recognition. Thus, shape readout is a direct and independent component of binding site selection by Hox proteins.
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ADN/química , ADN/metabolismo , Proteínas de Drosophila/química , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Factores de Transcripción/química , Factores de Transcripción/metabolismo , Secuencia de Aminoácidos , Animales , Cristalografía por Rayos X , Proteínas de Homeodominio/química , Proteínas de Homeodominio/metabolismo , Datos de Secuencia Molecular , Conformación de Ácido Nucleico , Unión Proteica , Alineación de SecuenciaRESUMEN
DNA binding specificities of transcription factors (TFs) are a key component of gene regulatory processes. Underlying mechanisms that explain the highly specific binding of TFs to their genomic target sites are poorly understood. A better understanding of TF-DNA binding requires the ability to quantitatively model TF binding to accessible DNA as its basic step, before additional in vivo components can be considered. Traditionally, these models were built based on nucleotide sequence. Here, we integrated 3D DNA shape information derived with a high-throughput approach into the modeling of TF binding specificities. Using support vector regression, we trained quantitative models of TF binding specificity based on protein binding microarray (PBM) data for 68 mammalian TFs. The evaluation of our models included cross-validation on specific PBM array designs, testing across different PBM array designs, and using PBM-trained models to predict relative binding affinities derived from in vitro selection combined with deep sequencing (SELEX-seq). Our results showed that shape-augmented models compared favorably to sequence-based models. Although both k-mer and DNA shape features can encode interdependencies between nucleotide positions of the binding site, using DNA shape features reduced the dimensionality of the feature space. In addition, analyzing the feature weights of DNA shape-augmented models uncovered TF family-specific structural readout mechanisms that were not revealed by the DNA sequence. As such, this work combines knowledge from structural biology and genomics, and suggests a new path toward understanding TF binding and genome function.
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ADN/química , ADN/metabolismo , Conformación de Ácido Nucleico , Factores de Transcripción/metabolismo , Algoritmos , Animales , Secuencia de Bases , Sitios de Unión/genética , Biología Computacional/métodos , ADN/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Cinética , Ratones , Modelos Genéticos , Análisis por Matrices de Proteínas , Unión Proteica , Factores de Transcripción/genéticaRESUMEN
In animals, Hox transcription factors define regional identity in distinct anatomical domains. How Hox genes encode this specificity is a paradox, because different Hox proteins bind with high affinity in vitro to similar DNA sequences. Here, we demonstrate that the Hox protein Ultrabithorax (Ubx) in complex with its cofactor Extradenticle (Exd) bound specifically to clusters of very low affinity sites in enhancers of the shavenbaby gene of Drosophila. These low affinity sites conferred specificity for Ubx binding in vivo, but multiple clustered sites were required for robust expression when embryos developed in variable environments. Although most individual Ubx binding sites are not evolutionarily conserved, the overall enhancer architecture-clusters of low affinity binding sites-is maintained and required for enhancer function. Natural selection therefore works at the level of the enhancer, requiring a particular density of low affinity Ubx sites to confer both specific and robust expression.
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Proteínas de Unión al ADN/genética , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Elementos de Facilitación Genéticos , Proteínas de Homeodominio/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Animales , Secuencia de Bases , Drosophila melanogaster/genética , Embrión no Mamífero/metabolismo , Regulación de la Expresión Génica , Datos de Secuencia Molecular , Unión Proteica , Alineación de SecuenciaRESUMEN
The closely related members of the Hox family of homeodomain transcription factors have similar DNA-binding preferences as monomers, yet carry out distinct functions in vivo. Transcription factors often bind DNA as multiprotein complexes, raising the possibility that complex formation might modify their DNA-binding specificities. To test this hypothesis we developed a new experimental and computational platform, termed SELEX-seq, to characterize DNA-binding specificities of Hox-based multiprotein complexes. We found that complex formation with the same cofactor reveals latent specificities that are not observed for monomeric Hox factors. The findings from this in vitro platform are consistent with in vivo data, and the "latent specificity" concept serves as a precedent for how the specificities of similar transcription factors might be distinguished in vivo. Importantly, the SELEX-seq platform is flexible and can be used to determine the relative affinities to any DNA sequence for any transcription factor or multiprotein complex.