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BACKGROUND: Cutaneous neurofibromas (cNF) are considered one of the highest burdens of neurofibromatosis type 1 (NF1). To date, no medical treatment can cure cNF or prevent their development. In that context, there is an urgent need to prepare and standardize the methodology of future trials targeting cNF. OBJECTIVES: The objective was to develop a core outcome domain set suitable for all clinical trials targeting NF1-associated cNF. METHODS: The validated approach of this work consisted of a three-phase methodology: (i) generating the domains [systematic literature review (SLR) and qualitative studies]; (ii) agreeing (three-round international e-Delphi consensus process and working groups); and (iii) voting. RESULTS: (i) The SLR and the qualitative studies (three types of focus groups and a French e-survey with 234 participants) resulted in a preliminary list of 31 candidate items and their corresponding definitions. (ii) A total of 229 individuals from 29 countries participated in the first round of the e-Delphi process: 71 patients, relatives or representatives (31.0%), 130 healthcare professionals (HCPs, 56.8%) and 28 researchers, representatives of a drug regulatory authority, industry or pharmaceutical company representatives or journal editors (12.2%). The overall participation rate was 74%. After round 2, five candidate items were excluded. Between rounds 2 and 3, international workshops were held to better understand the disagreements among stakeholders. This phase led to the identification of 19 items as outcome subdomains. (iii) The items were fused to create four outcome domains ('clinical assessment', 'daily life impact', 'patient satisfaction' and 'perception of health') and prioritized. The seven items that did not reach consensus were marked for the research agenda. The final core outcome domain set reached 100% of the votes of the steering committee members. CONCLUSIONS: Although numerous outcomes can be explored in studies related to cNF in NF1, the present study offers four outcome domains that should be reported in all trial studies, agreed on by international patients, relatives and representatives of patients; HCPs; researchers, representatives of drug regulatory authorities or pharmaceutical companies and journal editors. The next step will include the development of a set of core outcome measurement instruments to further standardize how these outcomes should be assessed.
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Neurofibroma , Neurofibromatosis 1 , Neoplasias Cutáneas , Humanos , Técnica Delphi , Proyectos de InvestigaciónRESUMEN
BACKGROUND: Cutaneous neurofibromas (cNFs) are a major cause of disfigurement in patients with Neurofibromatosis Type 1 (NF1). However, clinical trials investigating cNF treatments lack standardised outcome measures to objectively evaluate changes in cNF size and appearance. 3D imaging has been proposed as an objective standardised outcome measure however various systems exist with different features that affect useability in clinical settings. The aim of this study was to compare the accuracy, precision, feasibility, reliability and accessibility of three imaging systems. MATERIALS AND METHODS: We compared the Vectra-H1, LifeViz-Micro and Cherry-Imaging systems. A total of 58 cNFs from 13 participants with NF1 were selected for imaging and analysis. The primary endpoint was accuracy as measured by comparison of measurements between imaging systems. Secondary endpoints included reliability between two operators, precision as measured with the average coefficient of variation, feasibility as determined by time to capture and analyse an image and accessibility as determined by cost. RESULTS: There was no significant difference in accuracy between the three devices for length or surface area measurements (p > 0.05), and reliability and precision were similar. Volume measurements demonstrated the most variability compared to other measurements; LifeViz-Micro demonstrated the least measurement variability for surface area and image capture and analysis were fastest with LifeViz-Micro. LifeViz-Micro was better for imaging smaller number of cNFs (1-3), Vectra-H1 better for larger areas and Cherry for uneven surfaces. CONCLUSIONS: All systems demonstrated excellent reliability but possess distinct advantages and limitations. Surface area is the most consistent and reliable parameter for measuring cNF size in clinical trials.
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Imagenología Tridimensional , Neurofibromatosis 1 , Neoplasias Cutáneas , Humanos , Neurofibromatosis 1/diagnóstico por imagen , Neurofibromatosis 1/patología , Neurofibromatosis 1/complicaciones , Reproducibilidad de los Resultados , Imagenología Tridimensional/métodos , Femenino , Neoplasias Cutáneas/diagnóstico por imagen , Neoplasias Cutáneas/patología , Masculino , Adulto , Neurofibroma/diagnóstico por imagen , Neurofibroma/patología , Adulto Joven , Diseño de Equipo , Adolescente , Sensibilidad y Especificidad , Estudios de Factibilidad , Persona de Mediana Edad , Análisis de Falla de Equipo , Dermoscopía/métodos , Dermoscopía/instrumentaciónRESUMEN
BACKGROUND: As exposure to UV radiation is the primary modifiable environmental risk factor associated with skin cancer, it remains the principal focus of most prevention strategies. Numerous sun protection campaigns have been implemented worldwide; however, their impact on the actual incidence and mortality rates of skin cancer seems to be limited. To create successful skin cancer prevention campaigns, it is important to have a comprehensive understanding of individuals' attitudes and behaviours regarding sun protection. The aim of the current study was to determine and report on the prevalence of self-reported attitudes, knowledge and behaviours regarding two of the major sun protection recommendations-avoidance of sun exposure and use of sunscreens-in an international representative sample across five continents. METHODS: This cross-sectional study was conducted in 20 countries using a web-based online survey. FINDINGS: A total of 50,552 individuals, comprising 25,388 men (50.22%) and 25,164 women (49.78%), participated in the survey. Among them, 83.2% reported having been voluntarily exposed to the sun (for sun-basking reasons) at least once in the last 12 months, and 47.96% acknowledged being exposed to the sun between the hours of 10 AM and 4 PM. The primary reason for non-adherence was that these hours were the most convenient times (32.28%). Only 24.05% reported applying sunscreen every 2 h when outdoors. Forgetfulness was the primary reason as provided by 27.79% of participants. Males and older age groups were less likely to adopt sun-protective behaviours around the world. Forgetfulness and the challenges posed by time constraints seem to be the biggest barriers to proper adherence. INTERPRETATION: These findings should prompt the collaboration with health authorities and the manufacturers to enhance adherence by setting reasonable sunscreen prices and creating formulations that make their application less burdensome.
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BACKGROUND: In 2015, a major achievement in vitiligo research was the development of an internationally agreed upon core outcome domain set for randomized clinical trials (RCTs). Three outcomes were identified as being essential: repigmentation, side-effects/harms and maintenance of gained repigmentation. Four items were further recommended for inclusion. The following recommendations then followed: repigmentation should be assessed by measuring the percentage of repigmentation in quartiles (0-25%, 26-50%, 51-79%, 80-100%) and cosmetic acceptability of the results should be assessed using the Vitiligo Noticeability Scale. OBJECTIVES: The primary objective of this study was to assess uptake of the core outcome domain set for RCTs in vitiligo. Secondary objectives were to update the systematic review on outcomes reported in vitiligo RCTs, and to assess whether repigmentation and cosmetic acceptability of the results were measured using the above-mentioned recommended scales. METHODS: We searched PubMed, Cochrane Library (CENTRAL and Systematic Reviews) and ClinicalTrials.gov for vitiligo RCTs between November 2009 and March 2021. Screening and data extraction were independently performed on title and summary by two researchers. All outcomes and outcome measures reported in eligible RCTs were retrieved and collated. RESULTS: In total, 174 RCTs were identified: 62 were published between 2009 and 2015, and 112 were published between 2016 and 2021.Thirty-eight different outcomes were reported. Repigmentation was the primary outcome in 89% of trials (150 of 169). Forty-nine different tools were used to measure repigmentation. Side-effects and harms were reported in 78% of trials (136 of 174). Maintenance of gained repigmentation was reported in only 11% of trials (20 of 174) and duration of follow-up varied greatly from 1 to 14 months. Cosmetic acceptability of the results and cessation of disease activity were assessed in only 2% of trials (four of 174). Quality of life of patients with vitiligo was assessed in 13% of trials (22 of 174). Finally, only 11 of 112 RCTs (10%) published between 2016 and 2021 reported all three essential core outcome domains (repigmentation, side-effects and maintenance of gained repigmentation) and none of the trials reported both essential and recommended core outcome domains. CONCLUSIONS: Efforts are still needed to close the gap between set recommendations and RCT outcome reporting.
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Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Vitíligo , Humanos , Evaluación de Resultado en la Atención de Salud , Calidad de Vida , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del Tratamiento , Vitíligo/diagnósticoRESUMEN
Atopic dermatitis is a chronic, relapsing and inflammatory skin disease. The impact of atopic dermatitis on the partners living with patients has been poorly investigated. The objective of this study was to evaluate the impact of atopic dermatitis in the daily lives of adult patients and to assess the burden of the disease on their partners. A population-based study was conducted on a representative sample of the general population of French adults aged 18 years of age using stratified, proportional sampling with a replacement design. Data were collected on 1,266 atopic dermatitis patient-partner dyads (mean age of patients 41.6 years, 723 (57.1%) women). The mean age of partners was 41.8 years. Patient burden, measured by the Atopic Dermatitis Burden Scale for Adults (ABS-A) score, was closely related to the objective atopic dermatitis severity: the mean score in the mild group (29.5) was significantly lower than in the moderate (43.9) and severe groups (48.6) (p < 0.0001). Partner burden, measured by the EczemaPartner score, was highly related to atopic dermatitis severity (p < 0.0001). Daytime sleepiness, measured by the Epworth Sleepiness Scale, showed a mean score of 9.24 in patients and 9.01 in their partners, indicating impaired sleep. Atopic dermatitis was found to decrease sexual desire in 39% and 26% of partners and patients respectively.
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Dermatitis Atópica , Adulto , Humanos , Femenino , Adolescente , Masculino , Dermatitis Atópica/diagnóstico , Dermatitis Atópica/epidemiología , Calidad de Vida , Índice de Severidad de la Enfermedad , Libido , PacientesRESUMEN
BACKGROUND: Childhood exposure to ultraviolet radiation (UVR) plays an important role in the development of keratinocyte carcinomas and melanomas. Therefore, sun protective measures ought to be implemented during early childhood. Young children are largely dependent upon adult care providers in order to achieve proper sun protection. OBJECTIVES: To develop effective photoprotection in children, it is necessary to understand caregivers' attitudes and knowledge about UVR exposure. This study aimed to explore the variables associated with sun protective behaviour in parents and grandparents during summer vacations. METHODS: A multinational, cross-sectional study was conducted using a web-based online survey with a representative sample of parents and grandparents of children aged ≤ 12â years, who cared for their children/grandchildren for at least 2 weeks during the summer of 2021, in five countries (France, Germany, Spain, Italy and the USA). Multiple correspondence analysis (MCA) was used to explore in an unbiased way the possible relationships among all the variables and to identify specific profiles. RESULTS: A total of 6190 adult participants responded to the questionnaire: 5104 parents (average age 42.0â years, 54.3% women) and 1086 grandparents (average age 64.2â years, 55.5% women). MCA allowed discrimination of two groups of respondents based on their answers: a profile with 'unprotected sun exposure habits' vs. those with 'protective sun exposure habits'. Parents fell in closer proximity to the 'unprotected sun exposure habits', and 'sunburn reported in youngest child'. Grandparents adopted more cautious behaviours than parents. Nevertheless, grandparents fell in proximity to 'having exposed the grandchild to the sun between 11â h and 17.00 h', 'not using an umbrella' and 'not using sunglasses'. CONCLUSIONS: Although grandparents appear to adopt more cautious behaviours than parents, many gaps in proper sun protection behaviour were observed in both groups of caregivers.
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Neoplasias Cutáneas , Quemadura Solar , Adulto , Niño , Humanos , Preescolar , Femenino , Persona de Mediana Edad , Masculino , Rayos Ultravioleta/efectos adversos , Protectores Solares/uso terapéutico , Cuidadores , Estudios Transversales , Conocimientos, Actitudes y Práctica en Salud , Quemadura Solar/prevención & control , Hábitos , Neoplasias Cutáneas/prevención & control , Neoplasias Cutáneas/tratamiento farmacológico , Ropa de ProtecciónRESUMEN
INTRODUCTION AND OBJECTIVES: Inherited epidermolysis bullosa (EB) is a heterogeneous group of genodermatoses characterized by localized or generalized skin and/or mucosal fragility. The objective of this work was to evaluate in France the burden of disease and out-of-pocket (OOP) expenditures for families with a child affected by EB. MATERIAL AND METHODS: A digital questionnaire was built and distributed to parents of children with EB in partnership with the patients' association DEBRA France. The questionnaire collected clinical and socioeconomic characteristics including the estimated amount of money caregivers had to pay out of their own pockets. The burden of caregivers was assessed using the validated Epidermolysis Bullosa Burden of Disease (EB-BoD) tool. Linear univariate regression models were conducted to search for factors associated with higher burden and higher OOP. RESULTS: Between October and December 2021, 77 parents answered the questionnaire. The responder was the child's mother in 77% (n = 59) of cases. Parents represented 40 girls and 37 boys with a mean age of 7.5 years and with different EB types and disease severity. The mean BE-BOD score was 63.9 ± 20.2. The mean score observed in children with severe EB was 69.0 ± 21 versus 59.0 ± 18.6 for moderate/mild. Similarly, the mean BE-BOD scores observed in parents performing daily wound care were 67.9 ± 19.6. All parents (100%) reported OOP expenses. The mean annual OOP cost was 4129 ± 4321. Linear regression demonstrated that for each one-point increase in the EB-BoD score, OOP expense increases by 91.1 euros (35.1-147) p = 0.002. CONCLUSION: EB places a considerable burden on families' daily lives. This burden is closely associated with OOP expenditures to manage EB which were on average 20 times higher compared with the French population.
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Cuidadores , Epidermólisis Ampollosa , Niño , Masculino , Femenino , Humanos , Gastos en Salud , Encuestas y Cuestionarios , FranciaRESUMEN
BACKGROUND: The skin plays an important role in establishing interpersonal relationships, and thus visible skin disorders, which have a significant impact on physical appearance, influence other people's behaviours and attitudes. OBJECTIVE: To develop and validate a dermatologic-specific questionnaire to evaluate stigmatization in individuals with visible skin conditions. METHODS: Items were generated by a verbatim report based on qualitative interviews with patients with various dermatologic conditions. Subsequently, a study was implemented for psychometric analysis. A dermatology-specific stigmatization questionnaire (PUSH-D) was refined via item reduction according to inter-question correlations, consensus among experts and exploratory factor analysis. Internal consistency was determined by calculating Cronbach's α. Concurrent validity was determined by calculating the correlation between PUSH-D and the Dermatology Life Quality Index (DLQI) and the Rosenberg Self-Esteem Scale (RSES). RESULTS: From a primary list of 22 items, PUSH-D was reduced to a 17-item questionnaire, covering two pertinent dimensions based on the exploratory factor analysis. Construct validity was demonstrated, and PUSH-D showed good internal consistency (Cronbach's α = 0.9). PUSH-D correlated strongly with the DLQI 0.72 (p < 0.001) and moderately with the RSES 0.49 (p < 0.001). CONCLUSION: PUSH-D allows a comprehensive view of the degree of stigmatization in visible skin disorders, as well as the comparability of stigmatization levels across various skin conditions.
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Dermatología , Estereotipo , Humanos , Calidad de Vida , Dermatología/métodos , Encuestas y Cuestionarios , Psicometría , Reproducibilidad de los ResultadosRESUMEN
PURPOSE OF REVIEW: An early understanding of the role of the Ras/Raf/MEK/ERK signalling pathway in regulating cell proliferation has set the stage for the development of several potent and selective MEK inhibitors (MEKi). MEKi represent promising therapies for RAS-driven neoplasias and RASopathies associated with increased Ras/MAPK activity. RECENT FINDINGS: Neurofibromatosis 1 (NF1) is a prototypic RASopathy in which early-phase clinical trials with MEKi have been successful in the treatment of plexiform neurofibromas (pNF) and low-grade gliomas (LGGs). The phase 2 trial (SPRINT) of selumetinib in pNF resulted in at least 20% reduction in the size of pNF from baseline in 71% of patients and was associated with clinically meaningful improvements. On the basis of this trial, selumetinib (Koselugo) received FDA approval for children 2 years of age and older with inoperable, symptomatic pNF. The phase 2 trial of selumetinib in LGG resulted in 40% partial response and 96% of patients had 2 years of progression-free survival. SUMMARY: Given the potential of MEK inhibition as an effective and overall well tolerated medical treatment, the use of targeted agents in the NF1 population is likely to increase considerably. Future work on non-NF1 RASopathies should focus on developing preclinical models and defining endpoints for measurement of efficacy in order to conduct clinical trials.
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Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidores , Neurofibroma Plexiforme/tratamiento farmacológico , Neurofibromatosis 1/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Animales , Ensayos Clínicos Fase II como Asunto , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Neurofibroma Plexiforme/enzimología , Neurofibroma Plexiforme/metabolismo , Neurofibromatosis 1/enzimología , Neurofibromatosis 1/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Ensayos Clínicos Controlados Aleatorios como Asunto , Proteínas ras/metabolismoRESUMEN
Vitiligo, a common depigmenting skin disorder, has an estimated prevalence of 0.5-2% of the population worldwide. The disease is characterized by the selective loss of melanocytes which results in typical nonscaly, chalky-white macules. In recent years, considerable progress has been made in our understanding of the pathogenesis of vitiligo which is now clearly classified as an autoimmune disease. Vitiligo is often dismissed as a cosmetic problem, although its effects can be psychologically devastating, often with a considerable burden on daily life. In 2011, an international consensus classified segmental vitiligo separately from all other forms of vitiligo, and the term vitiligo was defined to designate all forms of nonsegmental vitiligo. This review summarizes the current knowledge on vitiligo and attempts to give an overview of the future in vitiligo treatment.
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Vitíligo , Humanos , Estrés Oxidativo , Calidad de Vida , Vitíligo/diagnóstico , Vitíligo/epidemiología , Vitíligo/etiología , Vitíligo/terapiaRESUMEN
Formation of neutrophil extracellular traps has been implicated in autoimmunity. However, the presence and clinical relevance of neutrophil extracellular traps in immune-complex-mediated cutaneous small and medium vessel vasculitides has not been investigated. This study retrospectively analysed 72 patients with histology-proven hypersensitivity vasculitis (n = 21), IgA vasculitis (n = 22), urticarial vasculitis (n = 22), erythema elevatum diutinum (n = 3) and polyarteritis nodosa (n = 4). Neutrophil extracellular traps were detected in hypersensitivity vasculitis, IgA vasculitis, urticarial vasculitis and erythema elevatum diutinum, but not in polyarteritis nodosa lesions. Neutrophil extracellular traps were found around inflamed vessels, and their formation was highest early after the onset of vasculitis and decreased progressively thereafter. Neutrophil extracellular traps were strongly correlated with the histological severity of vasculitis and the production of reactive oxygen species. Both hypersensitivity vasculitis and IgA vasculitis showed significantly more neutrophil extracellular traps than did urticarial vasculitis, independent of the histological severity and duration of vasculitis. These results provide evidence on the implication of neutrophil extracellular traps in the early phases of immune-complex-mediated small vessel vasculitis.
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Trampas Extracelulares , Vasculitis Leucocitoclástica Cutánea , Vasculitis , Humanos , Especies Reactivas de Oxígeno , Estudios Retrospectivos , PielRESUMEN
BACKGROUND: Many physiological processes are influenced by nicotinic acetylcholine receptors (nAChR), ranging from neuromuscular and parasympathetic signaling to modulation of the reward system and long-term memory. Due to the complexity of the nAChR family and variable evolutionary rates among its members, their evolution in vertebrates has been difficult to resolve. In order to understand how and when the nAChR genes arose, we have used a broad approach of analyses combining sequence-based phylogeny, chromosomal synteny and intron positions. RESULTS: Our analyses suggest that there were ten subunit genes present in the vertebrate predecessor. The two basal vertebrate tetraploidizations (1R and 2R) then expanded this set to 19 genes. Three of these have been lost in mammals, resulting in 16 members today. None of the ten ancestral genes have kept all four copies after 2R. Following 2R, two of the ancestral genes became triplicates, five of them became pairs, and three seem to have remained single genes. One triplet consists of CHRNA7, CHRNA8 and the previously undescribed CHRNA11, of which the two latter have been lost in mammals but are still present in lizards and ray-finned fishes. The other triplet consists of CHRNB2, CHRNB4 and CHRNB5, the latter of which has also been lost in mammals. In ray-finned fish the neuromuscular subunit gene CHRNB1 underwent a local gene duplication generating CHRNB1.2. The third tetraploidization in the predecessor of teleosts (3R) expanded the repertoire to a total of 31 genes, of which 27 remain in zebrafish. These evolutionary relationships are supported by the exon-intron organization of the genes. CONCLUSION: The tetraploidizations explain all gene duplication events in vertebrates except two. This indicates that the genome doublings have had a substantial impact on the complexity of this gene family leading to a very large number of members that have existed for hundreds of millions of years.
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Evolución Molecular , Receptores Nicotínicos/genética , Vertebrados/genética , Animales , Secuencia de Bases , Cromosomas/genética , Exones/genética , Duplicación de Gen , Humanos , Intrones/genética , Funciones de Verosimilitud , Filogenia , Poliploidía , Subunidades de Proteína/genética , Sintenía/genética , Factores de TiempoRESUMEN
Congenital Hemidysplasia with Ichthyosiform nevus and Limb Defects (CHILD syndrome) is a rare X-linked dominant genodermatosis caused by mutations in the NAD(P) dependent steroid dehydrogenase-like protein gene. Its defect leads to accumulation of toxic metabolic intermediates upstream from the pathway block and to the deficiency of bulk cholesterol, probably leading to altered keratinocyte membrane function, resulting in the phenotype seen in CHILD syndrome. Symptomatic treatment using emollients and retinoids to reduce scaling has long been used until recently, whereby new therapeutic means based on the pathogenesis-targeted therapy have been developed. We subsequently chose to use the same pathogenesis-based therapy using a 2% cholesterol and 2% lovastatin cream with or without glycolic acid in two of our patients. Improvement in CHILD skin lesions was seen as early as 4 weeks after initiation. The addition of glycolic acid helped improve the penetrance of the cholesterol and lovastatin cream into the thick waxy scales. Our study confirms the efficacy of the pathogenesis-targeted therapy and introduces the possibility of modifying its formula by adding glycolic acid in order to improve the treatment.
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Anomalías Múltiples/diagnóstico , Anomalías Múltiples/genética , Enfermedades Genéticas Ligadas al Cromosoma X/diagnóstico , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Eritrodermia Ictiosiforme Congénita/diagnóstico , Eritrodermia Ictiosiforme Congénita/genética , Deformidades Congénitas de las Extremidades/diagnóstico , Deformidades Congénitas de las Extremidades/genética , 3-Hidroxiesteroide Deshidrogenasas/genética , Anomalías Múltiples/terapia , Biopsia , Niño , Colesterol/administración & dosificación , Femenino , Enfermedades Genéticas Ligadas al Cromosoma X/terapia , Humanos , Eritrodermia Ictiosiforme Congénita/terapia , Deformidades Congénitas de las Extremidades/terapia , Lovastatina/administración & dosificación , Mutación , Fenotipo , Piel/patología , Resultado del TratamientoRESUMEN
Orf virus (ORFV) is an important pathogen responsible for a highly contagious zoonotic viral infection that threatens those who handle sheep and goats. Orf virus is the prototype of the Parapoxvirus genus, and its resilience in the environment and ability to reinfect its host has contributed to the spread and maintenance of the infection in many species. In healthy humans, the disease usually resolves spontaneously within 3 to 6 weeks. There is no specific treatment and many different approaches such as use of imiquimod, cidofovir, curettage, shave excision, cryotherapy, and electrocautery have all been reported to be successful, without supporting evidence from controlled clinical trials. Throughout its interaction with the different hosts, ORFV has evolved a strategy for immune evasion via the development of an array of virulence factors. The interaction of ORFV with the immune system has been the subject of research for decades. Whole inactivated ORFV has been used as a type of immunomodulating drug; a so called paramunity inducer proposed as both a preventative and a therapeutic immunomodulator across various species. Additional research on the remarkable strategies underlying ORFV infection could lead to improved understanding of skin immunity.
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Ectima Contagioso/patología , Ectima Contagioso/terapia , Zoonosis/patología , Zoonosis/terapia , Animales , Cabras , Interacciones Huésped-Patógeno , Humanos , Enfermedades Profesionales/patología , Enfermedades Profesionales/terapia , Virus del Orf/fisiología , Ovinos , Piel/inmunología , Piel/virologíaRESUMEN
Recently, de novo mutations in the gene KCNA2, causing either a dominant-negative loss-of-function or a gain-of-function of the voltage-gated K+ channel Kv1.2, were described to cause a new molecular entity within the epileptic encephalopathies. Here, we report a cohort of 23 patients (eight previously described) with epileptic encephalopathy carrying either novel or known KCNA2 mutations, with the aim to detail the clinical phenotype associated with each of them, to characterize the functional effects of the newly identified mutations, and to assess genotype-phenotype associations. We identified five novel and confirmed six known mutations, three of which recurred in three, five and seven patients, respectively. Ten mutations were missense and one was a truncation mutation; de novo occurrence could be shown in 20 patients. Functional studies using a Xenopus oocyte two-microelectrode voltage clamp system revealed mutations with only loss-of-function effects (mostly dominant-negative current amplitude reduction) in eight patients or only gain-of-function effects (hyperpolarizing shift of voltage-dependent activation, increased amplitude) in nine patients. In six patients, the gain-of-function was diminished by an additional loss-of-function (gain-and loss-of-function) due to a hyperpolarizing shift of voltage-dependent activation combined with either decreased amplitudes or an additional hyperpolarizing shift of the inactivation curve. These electrophysiological findings correlated with distinct phenotypic features. The main differences were (i) predominant focal (loss-of-function) versus generalized (gain-of-function) seizures and corresponding epileptic discharges with prominent sleep activation in most cases with loss-of-function mutations; (ii) more severe epilepsy, developmental problems and ataxia, and atrophy of the cerebellum or even the whole brain in about half of the patients with gain-of-function mutations; and (iii) most severe early-onset phenotypes, occasionally with neonatal onset epilepsy and developmental impairment, as well as generalized and focal seizures and EEG abnormalities for patients with gain- and loss-of-function mutations. Our study thus indicates well represented genotype-phenotype associations between three subgroups of patients with KCNA2 encephalopathy according to the electrophysiological features of the mutations.
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Encefalopatías/diagnóstico , Encefalopatías/genética , Epilepsia/diagnóstico , Canal de Potasio Kv.1.2/genética , Animales , Encefalopatías/complicaciones , Epilepsia/complicaciones , Epilepsia/genética , Estudios de Asociación Genética , Mutación , Oocitos/fisiología , Fenotipo , XenopusRESUMEN
A peptide ending with RFamide (Arg-Phe-amide) was discovered independently by three different laboratories in 2003 and named 26RFa or QRFP. In mammals, a longer version of the peptide, 43 amino acids, was identified and found to bind to the orphan G protein-coupled receptor GPR103. We searched the genome database of Branchiostoma floridae (Bfl) for receptor sequences related to those that bind peptides ending with RFa or RYa (including receptors for NPFF, PRLH, GnIH, and NPY). One receptor clustered in phylogenetic analyses with mammalian QRFP receptors. The gene has 3 introns in Bfl and 5 in human, but all intron positions differ, implying that the introns were inserted independently. A QRFP-like peptide consisting of 25 amino acids and ending with RFa was identified in the amphioxus genome. Eight of the ten last amino acids are identical between Bfl and human. The prepro-QRFP gene in Bfl has one intron in the propeptide whereas the human gene lacks introns. The Bfl QRFP peptide was synthesized and the receptor was functionally expressed in human cells. The response was measured as inositol phosphate (IP) turnover. The Bfl QRFP peptide was found to potently stimulate the receptor's ability to induce IP turnover with an EC50 of 0.28nM. Also the human QRFP peptides with 26 and 43 amino acids were found to stimulate the receptor (1.9 and 5.1nM, respectively). Human QRFP with 26 amino acids without the carboxyterminal amide had dramatically lower potency at 1.3µM. Thus, we have identified an amphioxus QRFP-related peptide and a corresponding receptor and shown that they interact to give a functional response.
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Anfioxos/genética , Péptidos/genética , Receptores Acoplados a Proteínas G/genética , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Clonación Molecular , Células HEK293 , Humanos , Péptidos y Proteínas de Señalización Intercelular , Intrones , Datos de Secuencia Molecular , Neuropéptidos , Filogenia , TransfecciónRESUMEN
AIM: The long-term effects of the ketogenic diet, a high fat diet for treating intractable epilepsy, on resting energy expenditure (REE) are unknown. The aim of this study was to evaluate the impact of 15 months of ketogenic diet treatment on growth and REE in children with intractable epilepsy. METHOD: Growth, body composition, and REE were assessed at baseline, 3 months and 15 months in 24 children (14 males, 10 females; mean age 5 y 6 mo [SD 26 mo], range 7 mo-6 y 5 mo), 10 with cerebral palsy [CP]). Fifteen were identified as ketogenic diet responders at 3 months and continued on the ketogenic diet until 15 months. These were compared to 75 healthy children (43 males, 32 females; mean age 6 y 3 mo [SD 21 mo] age range 2-9 y). REE was expressed as percentage predicted, growth as height (HAz) and weight (WAz) z-scores, and body composition as fat and fat free mass (FFM). RESULTS: HAz declined -0.2 and -0.6 from baseline to 3 months and 15 months respectively (p = 0.001), while WAz was unchanged. In ketogenic diet responders, FFM, age and CP diagnosis predicted REE (overall R(2) = 0.76, p<0.001) and REE did not change. REE adjusted for FFM was lower (p<0.01) in children with CP at baseline (mean [standard error], -143[51] kcals/d) and 15 months (-198[53] kcals/d) compared to the healthy children. INTERPRETATION: After 15 months of the ketogenic diet, linear growth status declined while weight status and REE were unchanged. REE remained reduced in children with CP.
Asunto(s)
Estatura , Peso Corporal , Dieta Cetogénica , Metabolismo Energético , Epilepsia/dietoterapia , Epilepsia/fisiopatología , Tejido Adiposo , Factores de Edad , Composición Corporal , Parálisis Cerebral/complicaciones , Parálisis Cerebral/diagnóstico , Parálisis Cerebral/fisiopatología , Niño , Desarrollo Infantil , Preescolar , Dieta Cetogénica/efectos adversos , Epilepsia/complicaciones , Femenino , Humanos , Lactante , Estudios Longitudinales , Masculino , Descanso , Factores de TiempoRESUMEN
The corticotropin releasing hormone receptors (CRHR) and the arthropod diuretic hormone 44 receptors (DH44R) are structurally and functionally related members of the G protein-coupled receptors (GPCR) of the secretin-like receptor superfamily. We show here that they derive from a bilaterian predecessor. In protostomes, the receptor became DH44R that has been identified and functionally characterised in several arthropods but the gene seems to be absent from nematode genomes. Duplicate DH44R genes (DH44 R1 and DH44R2) have been described in some arthropods resulting from lineage-specific duplications. Recently, CRHR-DH44R-like receptors have been identified in the genomes of some lophotrochozoans (molluscs, which have a lineage-specific gene duplication, and annelids) as well as representatives of early diverging deuterostomes. Vertebrates have previously been reported to have two CRHR receptors that were named CRHR1 and CRHR2. To resolve their origin we have analysed recently assembled genomes from representatives of early vertebrate divergencies including elephant shark, spotted gar and coelacanth. We show here by analysis of synteny conservation that the two CRHR genes arose from a common ancestral gene in the early vertebrate tetraploidizations (2R) approximately 500 million years ago. Subsequently, the teleost-specific tetraploidization (3R) resulted in a duplicate of CRHR1 that has been lost in some teleost lineages. These results help distinguish orthology and paralogy relationships and will allow studies of functional conservation and changes during evolution of the individual members of the receptor family and their multiple native peptide agonists.
Asunto(s)
Hormona Liberadora de Corticotropina/genética , Proteínas de Drosophila/genética , Evolución Molecular , Invertebrados/genética , Receptores de Superficie Celular/genética , Vertebrados/genética , Animales , Secuencia Conservada , Hormona Liberadora de Corticotropina/clasificación , Hormona Liberadora de Corticotropina/metabolismo , Proteínas de Drosophila/clasificación , Proteínas de Drosophila/metabolismo , Humanos , Hormonas de Insectos/genética , Hormonas de Insectos/metabolismo , Invertebrados/metabolismo , Filogenia , Receptores de Superficie Celular/clasificación , Receptores de Superficie Celular/metabolismo , Vertebrados/metabolismoRESUMEN
Malignant peripheral nerve sheath tumors (MPNSTs) are the leading cause of death in patients with neurofibromatosis type 1. They can result from premalignant neurofibromas, including neurofibromas with atypia and atypical neurofibromatous neoplasms of uncertain biologic potential. Some phenotypic characteristics have been described as associated with their development. The aim of this study was to outline our use of whole-body positron emission tomography with 18F-fluorodeoxyglucose/magnetic resonance imaging in adults with neurofibromatosis type 1, especially in the screening of asymptomatic individuals with a higher risk of developing an MPNST, and to study its impact on neurofibroma classification (malignant vs premalignant) and MPNST staging over time. Individuals with neurofibromatosis type 1 who underwent a positron emission tomography with 18F-fluorodeoxyglucose/magnetic resonance imaging between 2017 and 2021 were included, analyzing separately the screened population. Maximum standard uptake value and diffusion-weighted imaging were assessed. Biopsy/surgery confirmed the diagnosis. In all, 345 positron emission tomography with 18F-fluorodeoxyglucose/magnetic resonance imaging were performed in 241 patients, including 149 asymptomatic (62%) but at-risk patients. Eight MPNSTs in 8 screened individuals (5%), 6 neurofibromas with atypia in 4 individuals (3%), and 29 atypical neurofibromatous neoplasms of uncertain biologic potential in 23 individuals (15%) were diagnosed. Over time, the proportion of grade 3 MPNST and the malignant/premalignant ratio in screened individuals significantly decreased (P = .03 and P < .001, respectively). This study emphasizes the diagnostic and screening performances of whole-body positron emission tomography with 18F-fluorodeoxyglucose/magnetic resonance imaging in adults with neurofibromatosis type 1.