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OBJECTIVE: To derive childhood-onset SLE (cSLE) specific remission definitions for future treat-to-target (T2T) trials, observational studies, and clinical practice. METHODS: The cSLE International T2T Task Force conducted Delphi surveys exploring paediatric perspectives on adult-onset SLE remission targets. A modified nominal group technique was used to discuss, refine, and agree on the cSLE remission target criteria. RESULTS: The Task Force proposed two definitions of remission: 'cSLE clinical remission on steroids (cCR)' and 'cSLE clinical remission off steroids (cCR-0)'. The common criteria are: (1) Clinical-SLEDAI-2 K = 0; (2) PGA score < 0.5 (0-3 scale); (4) stable antimalarials, immunosuppressive, and biologic therapy (changes due to side-effects, adherence, weight, or when building up to target dose allowed). Criterion (3) in cCR is the prednisolone dose ≤0.1 mg/kg/day (maximum 5 mg/day), whereas in cCR-0 it is zero. CONCLUSIONS: cSLE definitions of remission have been proposed, maintaining sufficient alignment with the adult-SLE definition to facilitate life-course research.
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Consenso , Lupus Eritematoso Sistémico , Inducción de Remisión , Humanos , Lupus Eritematoso Sistémico/tratamiento farmacológico , Lupus Eritematoso Sistémico/diagnóstico , Niño , Inmunosupresores/uso terapéutico , Edad de Inicio , Técnica Delphi , Comités ConsultivosRESUMEN
OBJECTIVE: Chronic nonbacterial osteomyelitis (CNO) is an autoinflammatory bone disorder that predominantly affects children and young people. The pathophysiology and molecular mechanisms of CNO remain poorly understood, and diagnostic criteria and biomarkers are lacking. As a result, treatment is empiric and follows personal experience, case series and expert consensus plans. METHODS: A survey was designed to gain insight on clinician and patient experiences of diagnosing and treating CNO and to collate opinions on research priorities. A version containing 24 questions was circulated among international expert clinicians and clinical academics (27 contacted, 21 responses). An equivalent questionnaire containing 20 questions was shared to explore the experience and priorities of CNO patients and family members (93 responses). RESULTS: Responses were used to select topics for four moderated roundtable discussions at the "International Conference on CNO and autoinflammatory bone disease" (Liverpool, United Kingdom, May 25-26th, 2022). The group identified deciphering the pathophysiology of CNO to be the highest priority, followed by clinical trials, necessary outcome measures and classification criteria. Surprisingly, mental wellbeing scored behind these items. CONCLUSIONS: Agreement exists among clinicians, academics, patients and families that deciphering the pathophysiology of CNO is of highest priority to inform clinical trials that will allow for the approval of medications for the treatment of CNO by regulatory agencies.
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Osteomielitis , Adolescente , Niño , Humanos , Enfermedades Óseas , Consenso , Osteomielitis/diagnóstico , Osteomielitis/terapiaRESUMEN
Roadside concentrations of harmful pollutants such as NOx are highly variable in both space and time. This is rarely considered when assessing pedestrian and cyclist exposures. We aim to fully describe the spatio-temporal variability of exposures of pedestrians and cyclists travelling along a road at high resolution. We evaluate the value added of high spatio-temporal resolution compared to high spatial resolution only. We also compare high resolution vehicle emissions modelling to using a constant volume source. We highlight conditions of peak exposures, and discuss implications for health impact assessments. Using the large eddy simulation code Fluidity we simulate NOx concentrations at a resolution of 2 m and 1 s along a 350 m road segment in a complex real-world street geometry including an intersection and bus stops. We then simulate pedestrian and cyclist journeys for different routes and departure times. For the high spatio-temporal method, the standard deviation in 1 s concentration experienced by pedestrians (50.9 µg.m-3) is nearly three times greater than that predicted by the high-spatial only (17.5 µg.m-3) or constant volume source (17.6 µg.m-3) methods. This exposure is characterised by low concentrations punctuated by short duration, peak exposures which elevate the mean exposure and are not captured by the other two methods. We also find that the mean exposure of cyclists on the road (31.8 µg.m-3) is significantly greater than that of cyclists on a roadside path (25.6 µg.m-3) and that of pedestrians on a sidewalk (17.6 µg.m-3). We conclude that ignoring high resolution temporal air pollution variability experienced at the breathing time scale can lead to a mischaracterization of pedestrian and cyclist exposures, and therefore also potentially the harm caused. High resolution methods reveal that peaks, and hence mean exposures, can be meaningfully reduced by avoiding hyper-local hotspots such as bus stops and junctions.
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Contaminantes Atmosféricos , Contaminación del Aire , Contaminantes Ambientales , Contaminantes Atmosféricos/análisis , Monitoreo del Ambiente/métodos , Contaminación del Aire/análisis , Emisiones de Vehículos/análisis , Material Particulado/análisisRESUMEN
Chronic nonbacterial osteomyelitis (CNO) is an autoinflammatory bone disease that primarily affects children and adolescents. CNO is associated with pain, bone swelling, deformity, and fractures. Its pathophysiology is characterized by increased inflammasome assembly and imbalanced expression of cytokines. Treatment is currently based on personal experience, case series and resulting expert recommendations. Randomized controlled trials (RCTs) have not been initiated because of the rarity of CNO, expired patent protection of some medications, and the absence of agreed outcome measures. An international group of fourteen CNO experts and two patient/parent representatives was assembled to generate consensus to inform and conduct future RCTs. The exercise delivered consensus inclusion and exclusion criteria, patent protected (excludes TNF inhibitors) treatments of immediate interest (biological DMARDs targeting IL-1 and IL-17), primary (improvement of pain; physician global assessment) and secondary endpoints (improved MRI; improved PedCNO score which includes physician and patient global scores) for future RCTs in CNO.
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Antirreumáticos , Osteomielitis , Niño , Adolescente , Humanos , Consenso , Citocinas , Antirreumáticos/uso terapéutico , Osteomielitis/tratamiento farmacológico , Dolor/complicaciones , Dolor/tratamiento farmacológico , Enfermedad CrónicaRESUMEN
OBJECTIVE: To achieve a consensus-based definition of Low Disease Activity (LDA) for use in cSLE trials. METHODS: The International cSLE T2T Task Force, comprising of paediatric rheumatologists/nephrologists, and adult rheumatologists undertook a series of Delphi surveys/consensus meetings to discuss, refine, and vote upon cSLE LDA criteria. RESULTS: The Task Force agreed that LDA should be based upon the adult-SLE Lupus Low Disease Activity State definition (LLDAS), with modifications to make it applicable to cSLE (cLLDAS). They agreed upon five cLLDAS criteria: (1) SLE Disease Activity Index (SLEDAI)-2 K ≤4, with no activity in major organ systems; (2) no new features of lupus disease activity compared with the last assessment; (3) Physician Global Assessment score of ≤1 (0-3 scale); (4) prednisolone dose of ≤0.15 mg/kg/day, 7.5 mg/day/maximum; while on (5) stable antimalarials, immunosuppressives, and biologics. CONCLUSIONS: A cSLE-appropriate definition of cLLDAS has been generated, maintaining alignment with the adult-SLE definition to promote life-course research.
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Inmunosupresores , Lupus Eritematoso Sistémico , Adulto , Niño , Humanos , Índice de Severidad de la Enfermedad , Inmunosupresores/uso terapéutico , Prednisolona , Consenso , Lupus Eritematoso Sistémico/diagnóstico , Lupus Eritematoso Sistémico/tratamiento farmacológicoRESUMEN
BACKGROUND: For many children and young people (CYP) with paediatric rheumatic conditions, glucocorticoid medications and their associated side-effects have a substantial impact on disease experience. Whilst there are physician-rated measures of glucocorticoid toxicity, no parallel patient reported measure has been developed to date for CYP with rheumatic disease. This manuscript describes a series of public patient involvement (PPI) events to inform the development of a future paediatric glucocorticoid-associated patient reported outcome measure (PROM). METHODS: One large group PPI event was advertised to CYP with experience of glucocorticoid medication use and their parents through clinicians, charities and existing PPI groups. This featured education on the team's research into glucocorticoid medication and interactive polls/structured discussion to help participants share their experiences. Further engagement was sought for PPI group work to co-develop future glucocorticoid studies, including development of a glucocorticoid associated PROM. Quantitative and qualitative feedback was collected from online questionnaires. The initiative was held virtually due to the Covid-19 pandemic. RESULTS: Nine families (n = 15) including 6 CYP joined the large group PPI event. Online pre-attendance and post-attendance questionnaires showed improvement in mean self-reported confidence [1 = not at all confident, 5 = very confident] in the following: what steroid medications are (pre = 3.9, post = 4.8), steroid side effects (pre = 3.8, post = 4.6), patient-reported outcome measures (pre = 2.0, post = 4.5), available research on steroids (pre = 2.2, post = 3.5). Five families (n = 7) were involved in a monthly PPI group who worked alongside the research team to identify priorities in glucocorticoid research, produce age-appropriate study materials, identify barriers to study participation (e.g. accessibility & convenience) and recommend appropriate modalities for dissemination. The participants found discussing shared experiences and learning about research to be the most enjoyable aspects of the initiative. CONCLUSIONS: This PPI initiative provided a valuable forum for families, including young children, to share their perspectives. Here, the authors explore the effective use of PPI in a virtual setting and provide a unique case study for the involvement of CYP in PROM development. The monthly PPI group also identified a need for the development of a new PROM related to glucocorticoid medication use and provided unique insights into how such a study could be structured.
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A widely hypothesized but complex transition from widespread fluvial activity to predominantly aeolian processes is inferred on Mars based on remote sensing data observations of ancient landforms. However, the lack of analysis of in situ martian fluvial deposits hinders our understanding of the flow regime nature and sustainability of the martian fluvial activity and the hunt for ancient life. Studying analogs from arid zones on Earth is fundamental to quantitatively understanding geomorphic processes and climate drivers that might have dominated during early Mars. Here we investigate the formation and preservation of fluvial depositional systems in the eastern Sahara, where the largest arid region on Earth hosts important repositories of past climatic changes. The fluvial systems are composed of well-preserved single-thread sinuous to branching ridges and fan-shaped deposits interpreted as deltas. The systems' configuration and sedimentary content suggest that ephemeral rivers carved these landforms by sequential intermittent episodes of erosion and deposition active for 10-100s years over â¼10,000 years during the late Quaternary. Subsequently, these landforms were sculpted by a marginal role of rainfall and aeolian processes with minimum erosion rates of 1.1 ± 0.2 mm/yr, supplying â¼96 ± 24 × 1010 m3 of disaggregated sediment to adjacent aeolian dunes. Our results imply that similar martian fluvial systems preserving single-thread, short distance source-to-sink courses may have formed due to transient drainage networks active over short durations. Altogether, this study adds to the growing recognition of the complexity of interpreting climate history from orbital images of landforms.
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The plant Golgi apparatus is responsible for the processing of proteins received from the endoplasmic reticulum (ER) and their distribution to multiple destinations within the cell. Golgi matrix components, such as golgins, have been identified and suggested to function as putative tethering factors to mediate the physical connections between Golgi bodies and the ER network. Golgins are proteins anchored to the Golgi membrane by the C-terminus either through transmembrane domains or interaction with small regulatory GTPases. The golgin N-terminus contains long coiled-coil domains, which consist of a number of α-helices wrapped around each other to form a structure similar to a rope being made from several strands, reaching into the cytoplasm. In animal cells, golgins are also implicated in specific recognition of cargo at the Golgi.Here, we investigate the plant golgin Atgolgin-84A for its subcellular localization and potential role as a tethering factor at the ER-Golgi interface. For this, fluorescent fusions of Atgolgin-84A and an Atgolgin-84A truncation lacking the coiled-coil domains (Atgolgin-84AΔ1-557) were transiently expressed in tobacco leaf epidermal cells and imaged using high-resolution confocal microscopy. We show that Atgolgin-84A localizes to a pre-cis-Golgi compartment that is also labelled by one of the COPII proteins as well as by the tether protein AtCASP. Upon overexpression of Atgolgin-84A or its deletion mutant, transport between the ER and Golgi bodies is impaired and cargo proteins are redirected to the vacuole. LAY DESCRIPTION: The Golgi apparatus is a specialised compartment found in mammalian and plant cells. It is the post office of the cell and packages proteins into small membrane boxes for transport to their destination in the cell. The plant Golgi apparatus consist of many separate Golgi bodies and is responsible for the processing of proteins received from the endoplasmic reticulum (ER) and their distribution to multiple destinations within the cell. Specialised proteins called golgins have been suggested to tether Golgi bodies and the ER. Here we investigate the plant golgin Atgolgin-84A for its exact within the Golgi body and its potential role as a tethering factor at the ER-Golgi interface. For this, we have fused Atgolgin-84A with a fluorescent protein from jellyfish and we are producing this combination in tobacco leaf cells. This allows us to see the protein using laser microscopy. We show that Atgolgin-84A localises to a compartment between the ER and Golgi that is also labelled by the tether protein AtCASP. When Atgolgin-84A is produced in high amounts in the cell, transport between the ER and Golgi bodies is inhibited and proteins are redirected to the vacuole.
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Proteínas de Arabidopsis/metabolismo , Arabidopsis/metabolismo , Retículo Endoplásmico/metabolismo , Aparato de Golgi/metabolismo , Proteínas de la Matriz de Golgi/metabolismo , Arabidopsis/química , Arabidopsis/ultraestructura , Proteínas de Arabidopsis/análisis , Proteínas de Arabidopsis/química , Brefeldino A/farmacología , Retículo Endoplásmico/ultraestructura , Aparato de Golgi/química , Aparato de Golgi/ultraestructura , Proteínas de la Matriz de Golgi/análisis , Proteínas de la Matriz de Golgi/química , Dominios Proteicos , Transporte de ProteínasAsunto(s)
Esclerodermia Localizada , Niño , Enfermedad Crónica , Estudios de Cohortes , Humanos , RecurrenciaRESUMEN
OBJECTIVES: Monogenic autoinflammatory disorders (AID) and primary immunodeficiencies can present early in life with features that may be mistaken for Behçet's disease (BD). We aimed to retrospectively describe the clinical and laboratory features of 11 paediatric cases referred for suspected BD who turned out to have an alternative, monogenic disease mimicking BD. METHODS: Retrospective, paediatric BD specialist multicentre case series. Next generation sequencing (NGS) or conventional candidate gene screening approaches were utilized, facilitated in some cases by functional assays. RESULTS: Eleven children referred with suspected BD underwent genetic screening because of atypical BD features, and/or presentation before age 5 years. Eight patients (73%) were Caucasian, two were Pakistani and one was Turkish; 55% were female. A positive family history of BD was reported in 54% cases. The median age of disease onset was 0.6 (range 0.2-2.3) years. All had systemic inflammation and oral ulceration; 5/11 had genital ulceration; 3/11 had ocular involvement; and 9/11 had cutaneous manifestations. Nine/11 had known disease-causing genetic mutations in: TNFAIP3 (n = 2), WDR1 (n = 2), NCF1, AP1S3, LYN, MEFV and GLA. The remaining two cases each had novel variants in STAT1 and TNFRSF1A. CONCLUSION: Rare monogenic diseases can mimic BD, particularly when presenting early in life. These observations are now informing a strategy to explore screening for genetic mimics of BD in a UK cohort of children and adults to better understand the proportion of UK BD patients who may in fact have an underlying monogenetic diagnosis.
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Síndrome de Behçet/diagnóstico , Edad de Inicio , Síndrome de Behçet/genética , Niño , Preescolar , Diagnóstico Diferencial , Femenino , Predisposición Genética a la Enfermedad , Pruebas Genéticas/métodos , Enfermedades Autoinflamatorias Hereditarias/diagnóstico , Enfermedades Autoinflamatorias Hereditarias/genética , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Masculino , Mutación , Estudios RetrospectivosAsunto(s)
Estrógenos/metabolismo , Melanosis/etiología , Melanosomas/efectos de la radiación , Rayos Ultravioleta/efectos adversos , Técnicas de Cultivo de Célula , Células Cultivadas , Humanos , Melanosomas/metabolismo , Melanosomas/ultraestructura , Microscopía Electrónica , Proyectos Piloto , Progesterona/metabolismo , Piel/citología , Piel/efectos de la radiación , Piel/ultraestructuraAsunto(s)
Lupus Eritematoso Sistémico/complicaciones , Lupus Eritematoso Sistémico/diagnóstico , Miastenia Gravis/complicaciones , Miastenia Gravis/diagnóstico , Adolescente , Niño , Femenino , Humanos , Incidencia , Lupus Eritematoso Sistémico/tratamiento farmacológico , Lupus Eritematoso Sistémico/epidemiología , Miastenia Gravis/tratamiento farmacológico , Miastenia Gravis/epidemiologíaRESUMEN
The paper presents a novel method for numerically modelling fluid-structure interactions. The method consists of solving the fluid-dynamics equations on an extended domain, where the computational mesh covers both fluid and solid structures. The fluid and solid velocities are relaxed to one another through a penalty force. The latter acts on a thin shell surrounding the solid structures. Additionally, the shell is represented on the extended domain by a non-zero shell-concentration field, which is obtained by conservatively mapping the shell mesh onto the extended mesh. The paper outlines the theory underpinning this novel method, referred to as the immersed-shell approach. It also shows how the coupling between a fluid- and a structural-dynamics solver is achieved. At this stage, results are shown for cases of fundamental interest.
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BACKGROUND: Polymorphisms of NLR (nucleotide-binding domain and leucine rich repeat containing) family, pyrin domain containing protein 1 (NLRP1) have been found in patients with vitiligo/nonsegmental vitiligo (NSV), and increased NLRP1 expression has been detected in the leading edge of lesional skin biopsies. OBJECTIVES: To evaluate the presence and intensity of NLRP1 immunostaining in lesional and perilesional skin of patients with vitiligo/NSV and to search for possible correlations between NLRP1 and interleukin (IL)-1ß expression, lymphocytic infiltrates and disease activity. METHODS: Of 14 consecutive vitiligo/NSV patients, eight had active disease [Vitiligo European Task Force (VETF) spreading score +1 to +5], one patient had stable disease and five patients had regressive disease (VETF spreading score -1 to -3). We performed immunostaining for NLRP1, B and T lymphocytes, IL-1ß and kallikrein 7 on lesional and perilesional vitiligo skin. RESULTS: NLRP1 and IL-1ß immunostaining in perilesional vitiligo/NSV skin was significantly associated with progressive disease (P = 0·009 and 0·04, respectively) and performed better than the simple detection of lymphocytic infiltrates. CONCLUSIONS: Our findings suggest that markers of the NLRP1 inflammasome could be a useful test for assessing disease activity in addition to the detection of inflammatory infiltrates in the progressing margins of vitiligo/NSV lesions.
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Inflamasomas/metabolismo , Vitíligo/diagnóstico , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Adolescente , Adulto , Anciano , Proteínas Reguladoras de la Apoptosis/metabolismo , Biomarcadores/metabolismo , Estudios de Casos y Controles , Progresión de la Enfermedad , Femenino , Humanos , Inmunohistoquímica , Interleucina-1beta/metabolismo , Calicreínas/metabolismo , Linfocitos/fisiología , Masculino , Persona de Mediana Edad , Proteínas NLRRESUMEN
Exposure to electromagnetic radiations (EMR) produced by mobile phone concerns half the world's population and raises the problem of their impact on human health. In this study, we looked at the effects of mobile phone exposure (GSM basic, 900 MHz, SAR 2 mW g(-1) , 6 h) on a model of pigmented skin. We have analysed the expression and localization of various markers of keratinocyte and melanocyte differentiation 2, 6, 18 and 24 h after EMR exposure of reconstructed epidermis containing either only keratinocytes or a combination of keratinocytes and melanocytes grown on dead de-epidermized dermis, using histology, immunohistochemistry and Western blot. No changes were found in epidermal architecture, localization of epidermal markers, presence of apoptotic cells and the induction of p53 in both types of epidermis (with or without melanocytes) after exposure to EMR. In pigmented reconstructs, no change in the location and dendricity of melanocytes and in melanin transfer to neighbouring keratinocytes was detected after EMR exposure. Loricrin, cytokeratin 14 were significantly decreased at 6 h. The level of all markers increased at 24 h as compared to 6 h post-EMR exposure, associated with a significant decrease of the 20S proteasome activity. Our data indicate that exposure to 900 MHz frequency induces a transient alteration of epidermal homoeostasis, which may alter the protective capacity of the skin against external factors. Presence or absence of melanocytes did not modify the behaviour of reconstructs after EMR exposure.
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Teléfono Celular , Campos Electromagnéticos , Epidermis/fisiopatología , Homeostasis , Modelos Biológicos , Pigmentación de la Piel , Apoptosis , Diferenciación Celular , Proliferación Celular , Células Cultivadas , Humanos , InmunoquímicaRESUMEN
Research into the use of unstructured mesh methods in oceanography has been growing steadily over the past decade. The advantages of this approach for domain representation and non-uniform resolution are clear. However, a number of issues remain, in particular those related to the computational cost of models produced using unstructured mesh methods compared with their structured mesh counterparts. Mesh adaptivity represents an important means to improve the competitiveness of unstructured mesh models, where high resolution is only used when and where necessary. In this paper, an optimization-based approach to mesh adaptivity is described where emphasis is placed on capturing anisotropic solution characteristics. Comparisons are made between the results obtained with uniform isotropic resolution, isotropic adaptive resolution and fully anisotropic adaptive resolution.
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BACKGROUND: Scleroderma skin overexpresses the platelet-derived growth factor receptor beta-subunit (PDGFR-beta) in dermal vessels and PDGFR-beta messenger RNA in cultured fibroblasts. Moreover, increased levels of PDGF and stimulatory autoantibodies to PDGFR have been identified in the serum of scleroderma patients. OBJECTIVE: Imatinib being an inhibitor of tyrosine kinase receptors such as PDGFR, its effect on scleroderma fibroblasts was evaluated in vitro as a preclinical therapeutic step. METHODS: The effect of imatinib on fibroblasts grown from normal or involved/uninvolved scleroderma skin was studied by Western blot and the methyltetrazolium test. The pattern of distribution of PDGFR-beta in scleroderma versus normal skin was studied by immunohistochemistry. RESULTS: In vitro, imatinib inhibited the proliferation of normal dermal and scleroderma fibroblasts at least partly via the inhibition of the phosphorylation of PDGFR. PDGFR-beta was expressed in the epidermis and adnexae in 5 lesional scleroderma biopsies and not in controls. CONCLUSION: This study suggests that imatinib can serve as therapy to limit dermal fibroblast proliferation in scleroderma.
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Fibroblastos/efectos de los fármacos , Piperazinas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/uso terapéutico , Esclerodermia Sistémica/tratamiento farmacológico , Piel/citología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Benzamidas , Western Blotting , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Femenino , Fibroblastos/citología , Fibroblastos/metabolismo , Humanos , Mesilato de Imatinib , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/biosíntesis , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/efectos de los fármacos , Esclerodermia Sistémica/metabolismo , Esclerodermia Sistémica/patología , Piel/efectos de los fármacos , Piel/metabolismo , Resultado del TratamientoRESUMEN
Common generalized vitiligo is an acquired depigmenting disorder characterized by a chronic and progressive loss of melanocytes from the epidermis and hair follicles. We previously proposed a new theory that vitiligo involves the chronic detachment and transepidermal loss of melanocytes caused by autoimmune, neural and impaired redox mechanisms associated with mechanical trauma. In this study, we reconstructed epidermis on dead de-epidermized dermis with normal and/or non-segmental non-lesional vitiligo (NSV) cells and tested catecholamines or sera or hydrogen peroxide. Under unstressed conditions, the number of melanocytes located in the basal layer was significantly lower in reconstructs made with melanocytes from non-lesional NSV skin and normal keratinocytes compared with controls made with autologous normal melanocytes. The number of non-lesional NSV melanocytes was even lower in reconstructs made with keratinocytes from non-lesional NSV skin. Epinephrine and H(2)O(2) could trigger the transepidermal loss of normal and vitiligo melanocytes. Some sera induced melanocyte detachment but without any clear correlation with disease activity in the donors. In conclusion, our results are the first step to obtaining a reproducible melanocytorrhagic model in vitro with some of the stressors investigated. They support the hypothesis that NSV melanocytes have an intrinsic defect, which limits their adhesion in a reconstructed epidermis, with an enhancer effect of the vitiligo keratinocyte milieu.
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Epidermis/metabolismo , Pigmentación de la Piel , Vitíligo/metabolismo , Vitíligo/patología , Dermis/metabolismo , Epinefrina/metabolismo , Humanos , Peróxido de Hidrógeno/metabolismo , Peróxido de Hidrógeno/farmacología , Inmunohistoquímica/métodos , Queratinocitos/metabolismo , Melanocitos/metabolismo , Modelos Biológicos , Modelos Teóricos , Pigmentación , Piel/metabolismo , Factores de TiempoRESUMEN
Reactive oxygen species (ROS) generated by ultraviolet (UV) irradiation are counterbalanced by endogenous antioxidant systems. To test the hypothesis of a novel photoprotective approach, we irradiated epidermis reconstructed with normal human keratinocytes overexpressing sustainably lentivirus-mediated catalase (CAT), copper/zinc superoxide dismutase (CuZnSOD) or manganese superoxide dismutase (MnSOD) enzymes. We found that following UVB irradiation there was a marked decrease in sunburn cell formation, caspase-3 activation and p53 accumulation in human reconstructed epidermis overexpressing CAT. Moreover, UVA-induced hypertrophy and DNA oxidation (8-oxodeoxyguanosine) were decreased by CAT overexpression. These effects were not achieved by overexpression of CuZnSOD or MnSOD. In conclusion, vector-mediated CAT overexpression could be a promising photoprotective tool against deleterious effects of UV irradiation such skin cancer especially in monogenic/polygenic photosensitive disorders characterized by ROS accumulation.