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It is unclear how improvements in peripheral motor function in children with spinal muscular atrophy (SMA), treated with nusinersen, translate into clinically significant respiratory/sleep outcomes. A retrospective chart review of SMA children at the Sydney Children's Hospital Network was undertaken looking at 2 years before and after receiving their first dose of nusinersen. Polysomnography (PSG), spirometry and clinical data were collected and analysed using paired and unpaired t-tests for PSG parameters and generalised estimating equations for longitudinal lung function data. Forty-eight children (10 Type 1, 23 Type 2, 15 Type 3) at mean age 6.98 yrs (SD 5.25) for nusinersen initiation were included. There was a statistically significant improvement in oxygen nadir during sleep in individuals post nusinersen (mean of 87.9% to 92.3% (95%CI 1.24 - 7.63, p = 0.01)). Based on clinical and PSG findings, 6/21 patients (5 Type 2, 1 Type 3) ceased nocturnal NIV post nusinersen. Non-significant improvements were demonstrated in mean slope for FVC% predicted, FVC Z-score and mean FVC% predicted. Within 2 years of commencing nusinersen, stabilisation of respiratory outcomes occurred. Whilst some of the SMA type 2/3 cohort ceased NIV, there were no statistically significant improvements lung function and most PSG parameters.
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Atrofia Muscular Espinal , Atrofias Musculares Espinales de la Infancia , Humanos , Niño , Estudios Retrospectivos , Atrofia Muscular Espinal/tratamiento farmacológico , Oligonucleótidos/uso terapéutico , Atrofias Musculares Espinales de la Infancia/complicaciones , Atrofias Musculares Espinales de la Infancia/tratamiento farmacológico , SueñoRESUMEN
BACKGROUND: Photodynamic therapy (PDT) is used to treat cutaneous cancers. It may induce cell death through direct and indirect means, including apoptosis, inflammation and certain immune mechanisms, with the depth of penetration as a potential modifying factor. OBJECTIVES: To examine the pathways of apoptosis in the intralesional PDT of basal cell carcinoma (BCC) and intraepidermal squamous cell carcinoma (Bowen's disease). METHODS: Sixteen patients with superficial or nodular BCC and Bowen's disease were treated with intralesional aminolevulinic acid-PDT. Biopsies were taken at baseline and 24 h post-PDT, and sections were examined by immunohistochemistry for the expression of markers of apoptosis, such as caspase 3, involved in the intrinsic apoptotic pathway, granzyme B, a caspase-independent apoptotic mediator, and the proapoptotic markers BAX and BAK. RESULTS: Apoptotic cells stained with TUNEL showed statistically significant staining at 24 h post PDT (p < 0.01 in both BCC and Bowen's lesions). Caspase 3 (p < 0.01 in BCC and p < 0.05 in Bowen's) and granzyme B (p < 0.01 in BCC and p < 0.01 in Bowen's) were significantly increased at 24 h post-PDT. BAX expression was apparently increased compared to baseline in Bowen's lesions at 24 h post-PDT, whereas Bak was upregulated both in BCC and Bowen's disease at baseline and at 24 h post-PDT. CONCLUSION: Intralesional PDT induces apoptosis in BCC and Bowen's disease via common and alternative apoptotic pathways involving granzyme B. Proapoptotic factors Bak in both BCC and Bowen and Bax in Bowen's disease appear to increase by intralesional PDT at 24 h.
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Enfermedad de Bowen , Carcinoma Basocelular , Fotoquimioterapia , Neoplasias Cutáneas , Humanos , Enfermedad de Bowen/tratamiento farmacológico , Fármacos Fotosensibilizantes/uso terapéutico , Caspasa 3/uso terapéutico , Granzimas/uso terapéutico , Proteína X Asociada a bcl-2/uso terapéutico , Carcinoma Basocelular/tratamiento farmacológico , Neoplasias Cutáneas/tratamiento farmacológico , Ácido Aminolevulínico/uso terapéutico , ApoptosisRESUMEN
Dual language management has been proposed as the reason for bilingual children's sometimes enhanced executive functioning (EF). We sought to identify the directionality of the relation between language proficiency and EF, using measures of receptive vocabulary, inhibitory control, and cognitive flexibility. Data were collected twice, a year apart, on 35- to 66.8-month-old bilingual (n = 41, M = 49.19 months) and monolingual preschool children (n = 37, M = 47.82 months). The longitudinal results revealed that while the monolingual children's vocabulary at Time 1 predicted EF at Time 2, EF at Time 1 did not predict vocabulary at Time 2. In contrast, for bilingual children the relation was not present at all. The results were similar after the one-time analyses. The absence of relations between EF and language in bilinguals, while present in monolinguals, challenges the current conceptualization of the EF advantage in bilinguals, and emphasizes the need for more research on the development of bilingual children.
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A large body of research in developmental psychology has been devoted to the ongoing debate over which aspects of language are fundamental to false belief understanding (FBU). A key proposal from de Villiers and colleagues proposes the essential role of complementation syntax in FBU development. The current study, using scalp electroencephalography (EEG), addressed one opposing hypothesis purporting that complementation is redundant to FBU by characterizing the electrophysiological correlates of FBU and complementation syntax in school-age children. Time-frequency decomposition showed robust parieto-occipital low beta (12-16 Hz) power reduction in the belief versus complementation conditions. This divergence was also supported by event-related potentials (ERPs), with parieto-occipital late slow waves around 600 to 900 ms distinguishing belief and complementation conditions. The false belief condition generated the lowest behavioral response accuracy, suggesting that it is the most challenging condition. Together, the current findings provide evidence showing that complementation is not redundant to FBU.
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Ondas Encefálicas/fisiología , Corteza Cerebral/fisiología , Desarrollo Infantil/fisiología , Comprensión/fisiología , Potenciales Evocados/fisiología , Lenguaje , Niño , Femenino , Humanos , MasculinoRESUMEN
OBJECTIVE: In the context of increasing numbers of childhood cancer survivors (CCS), this study aimed to enhance understanding of the biophysical basis for long term chemotherapy induced peripheral neuropathy from different chemotherapy agents in CCS. METHODS: Detailed cross-sectional neurophysiological examination, using median nerve axonal excitability studies, alongside clinical assessments, in 103 long term CCS (10.5 ± 0.6 years post-treatment). RESULTS: Cisplatin treated CCS (n = 16) demonstrated multiple sensory axonal excitability changes including increased threshold (P < 0.05), alterations in depolarising and hyperpolarising threshold electrotonus (P < 0.05) and reduction in resting and minimum IV slope (P < 0.01). Vincristine treated CCS (n = 73) were comparable to controls, except for prolonged distal motor latency (P = 0.001). No differences were seen in the non-neurotoxic chemotherapy group (n = 14). Abnormalities were more evident in the cisplatin subgroup with greater clinical neuropathy manifestations. CONCLUSION: Persistent long term changes in axonal biophysical properties vary with different chemotherapy agents, most evident after cisplatin exposure. Longitudinal studies of nerve function during chemotherapy treatment are required to further evaluate these differences and their mechanistic basis. SIGNIFICANCE: This study provides a unique biophysical perspective for persistent cisplatin related neurotoxicity in children, previously under recognised.
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Potenciales de Acción/fisiología , Antineoplásicos/efectos adversos , Cisplatino/efectos adversos , Nervio Mediano/fisiopatología , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Vincristina/efectos adversos , Adolescente , Supervivientes de Cáncer , Niño , Estudios Transversales , Femenino , Humanos , Masculino , Neoplasias/tratamiento farmacológico , Enfermedades del Sistema Nervioso Periférico/fisiopatologíaRESUMEN
MSTO1 encodes a cytosolic mitochondrial fusion protein, misato homolog 1 or MSTO1. While the full genotype-phenotype spectrum remains to be explored, pathogenic variants in MSTO1 have recently been reported in a small number of patients presenting with a phenotype of cerebellar ataxia, congenital muscle involvement with histologic findings ranging from myopathic to dystrophic and pigmentary retinopathy. The proposed underlying pathogenic mechanism of MSTO1-related disease is suggestive of impaired mitochondrial fusion secondary to a loss of function of MSTO1. Disorders of mitochondrial fusion and fission have been shown to also lead to mitochondrial DNA (mtDNA) depletion, linking them to the mtDNA depletion syndromes, a clinically and genetically diverse class of mitochondrial diseases characterized by a reduction of cellular mtDNA content. However, the consequences of pathogenic variants in MSTO1 on mtDNA maintenance remain poorly understood. We present extensive phenotypic and genetic data from 12 independent families, including 15 new patients harbouring a broad array of bi-allelic MSTO1 pathogenic variants, and we provide functional characterization from seven MSTO1-related disease patient fibroblasts. Bi-allelic loss-of-function variants in MSTO1 manifest clinically with a remarkably consistent phenotype of childhood-onset muscular dystrophy, corticospinal tract dysfunction and early-onset non-progressive cerebellar atrophy. MSTO1 protein was not detectable in the cultured fibroblasts of all seven patients evaluated, suggesting that pathogenic variants result in a loss of protein expression and/or affect protein stability. Consistent with impaired mitochondrial fusion, mitochondrial networks in fibroblasts were found to be fragmented. Furthermore, all fibroblasts were found to have depletion of mtDNA ranging from 30 to 70% along with alterations to mtDNA nucleoids. Our data corroborate the role of MSTO1 as a mitochondrial fusion protein and highlight a previously unrecognized link to mtDNA regulation. As impaired mitochondrial fusion is a recognized cause of mtDNA depletion syndromes, this novel link to mtDNA depletion in patient fibroblasts suggests that MSTO1-deficiency should also be considered a mtDNA depletion syndrome. Thus, we provide mechanistic insight into the disease pathogenesis associated with MSTO1 mutations and further define the clinical spectrum and the natural history of MSTO1-related disease.
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Proteínas de Ciclo Celular/genética , Enfermedades Cerebelosas/genética , Proteínas del Citoesqueleto/genética , ADN Mitocondrial , Enfermedades Mitocondriales/genética , Distrofias Musculares/genética , Mutación , Adolescente , Adulto , Atrofia , Células Cultivadas , Enfermedades Cerebelosas/diagnóstico por imagen , Enfermedades Cerebelosas/patología , Enfermedades Cerebelosas/fisiopatología , Niño , Variaciones en el Número de Copia de ADN , Femenino , Fibroblastos/metabolismo , Fibroblastos/patología , Humanos , Masculino , Persona de Mediana Edad , Enfermedades Mitocondriales/diagnóstico por imagen , Enfermedades Mitocondriales/patología , Enfermedades Mitocondriales/fisiopatología , Músculos/patología , Distrofias Musculares/diagnóstico por imagen , Distrofias Musculares/patología , Distrofias Musculares/fisiopatología , Fenotipo , Adulto JovenRESUMEN
Research consistently finds that language and theory of mind are interrelated. The content and qualities of language that specifically predict theory of mind remain under investigation and the question of why language might impact theory of mind development is open. In this chapter we analyze and highlight current findings and theory addressing theory of mind and language. The principal focus is upon typically developing children between ages 2 and 5, a period characterized by extensive development in language and social understanding. We propose that the study of young children's narrative development can inform how and why language and theory of mind are connected. False belief understanding and narrative comprehension share many similarities and this association provides a promising avenue for future work.
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Desarrollo Infantil , Lenguaje , Narración , Teoría de la Mente , Preescolar , HumanosRESUMEN
False belief understanding (FBU) enables people to consider conflicting beliefs about the same situation. While language has been demonstrated to be a correlate of FBU, there is still controversy about the extent to which a specific aspect of language, complementation syntax, is a necessary condition for FBU. The present study tested an important notion from the debate proposing that complementation syntax task is redundant to FBU measures. Specifically, we examined electrophysiological correlates of false belief, false complementation, and their respective true conditions in adults using electroencephalography (EEG), focusing on indices of oscillatory brain activity and large-scale connectivity. The results showed strong modulation of parieto-occipital alpha (8-12 Hz) and beta (13-20 Hz) power by the experimental manipulations, with heightened sustained alpha power reflective of effortful internal processing observed in the false compared to the true conditions and reliable beta power reductions sensitive to mentalizing and/or syntactic demands in the belief versus the complementation conditions. In addition, higher coupling between parieto-occipital regions and widespread frontal sites in the beta band was found for the false-belief condition selectively. The result of divergence in beta oscillatory activity and in connectivity between false belief and false complementation does not support the redundancy hypothesis.
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Mapeo Encefálico , Encéfalo/fisiología , Comprensión , Teoría de la Mente/fisiología , Adulto , Electroencefalografía/métodos , Femenino , Humanos , Lenguaje , Masculino , Análisis y Desempeño de Tareas , Adulto JovenRESUMEN
Bilingual preschoolers often perform better than monolingual children on false-belief understanding. It has been hypothesized that this is due to their enhanced executive function skills, although this relationship has rarely been tested or supported. The current longitudinal study tested whether metalinguistic awareness was responsible for this advantage. Further, we examined the contributions of both executive functioning and language ability to false-belief understanding by including multiple measures of both. Seventy-eight children (n = 40 Spanish-English bilingual; age M = 49.29, SD = 7.38 and, n = 38 English monolingual; age M = 47.75, SD = 6.86) were tested. A year later the children were tested again (n = 22 bilingual, n = 25 monolingual). The results indicated that language and executive function (inhibitory control) at time 1 were related to false belief in monolinguals at time 2. In contrast, bilinguals' metalinguistic performance at time 1 was the sole predictor of false belief at time 2. The different linguistic and cognitive profiles of monolinguals and bilinguals may create different pathways for their development of false-belief understanding. A video abstract of this article can be viewed at: https://youtu.be/vILn2gKjFxw.
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Comprensión/fisiología , Función Ejecutiva/fisiología , Lingüística , Multilingüismo , Concienciación/fisiología , Preescolar , Femenino , Humanos , Lenguaje , Estudios Longitudinales , MasculinoRESUMEN
Purpose: Language is related to false-belief (FB) understanding in both typically developing children and children with autism spectrum disorder (ASD). The current study examined the role of complementation and general language in FB understanding. Of interest was whether language plays similar or different roles in the groups' FB performance. Method: Participants were 16 typically developing children (mean age = 5.0 years; mental age = 6.7) and 18 with ASD (mean age = 7.3 years; mental age = 8.3). Children were administered FB and language tasks (say- and think-complements), receptive and expressive vocabulary tests, and relative clauses. Results: When mental age and receptive and expressive vocabulary were used as separate covariates, the typical control group outperformed the children with ASD in FB task performance. Chi-square analyses indicated that passing both complementation tasks was linked to the FB understanding of children with ASD. Children with ASD who passed FB tasks all passed say- and think-complement tasks. However, some children in the control group were able to pass the FB tasks, even if they failed the say- and think-complement tasks. Conclusion: The results indicate that children with ASD relied more on complement understanding to pass FB than typically developing children. Results are discussed regarding the developmental pathways for FB understanding.
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Trastorno del Espectro Autista/psicología , Lenguaje , Procesos Mentales , Análisis de Varianza , Niño , Preescolar , Femenino , Humanos , Masculino , Pruebas NeuropsicológicasAsunto(s)
Luz Solar , Deficiencia de Vitamina D/etnología , Adulto , Anciano , Comprensión , Cultura , Inglaterra/epidemiología , Femenino , Grupos Focales , Conocimientos, Actitudes y Práctica en Salud , Humanos , Masculino , Persona de Mediana Edad , Pakistán/etnología , Satisfacción del Paciente , Factores de Riesgo , Vitamina D/análogos & derivados , Vitamina D/metabolismoRESUMEN
Signal transducer and activator of transcription 5 (STAT5) activation occurs frequently in human progenitor B-cell acute lymphoblastic leukemia (B-ALL). To identify gene alterations that cooperate with STAT5 activation to initiate leukemia, we crossed mice expressing a constitutively active form of STAT5 (Stat5b-CA) with mice in which a mutagenic Sleeping Beauty transposon (T2/Onc) was mobilized only in B cells. Stat5b-CA mice typically do not develop B-ALL (<2% penetrance); in contrast, 89% of Stat5b-CA mice in which the T2/Onc transposon had been mobilized died of B-ALL by 3 months of age. High-throughput sequencing approaches were used to identify genes frequently targeted by the T2/Onc transposon; these included Sos1 (74%), Kdm2a (35%), Jak1 (26%), Bmi1 (19%), Prdm14 or Ncoa2 (13%), Cdkn2a (10%), Ikzf1 (8%), Caap1 (6%) and Klf3 (6%). Collectively, these mutations target three major cellular processes: (i) the Janus kinase/STAT5 pathway (ii) progenitor B-cell differentiation and (iii) the CDKN2A tumor-suppressor pathway. Transposon insertions typically resulted in altered expression of these genes, as well as downstream pathways including STAT5, extracellular signal-regulated kinase (Erk) and p38. Importantly, expression of Sos1 and Kdm2a, and activation of p38, correlated with survival, further underscoring the role these genes and associated pathways have in B-ALL.
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Linfocitos B/metabolismo , Elementos Transponibles de ADN/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Factor de Transcripción STAT5/genética , Animales , Western Blotting , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Regulación Leucémica de la Expresión Génica , Factor de Transcripción Ikaros/genética , Factor de Transcripción Ikaros/metabolismo , Janus Quinasa 1/genética , Janus Quinasa 1/metabolismo , Histona Demetilasas con Dominio de Jumonji/genética , Histona Demetilasas con Dominio de Jumonji/metabolismo , Estimación de Kaplan-Meier , Ratones Endogámicos C57BL , Ratones Transgénicos , Mutagénesis Insercional , Mutación , Complejo Represivo Polycomb 1/genética , Complejo Represivo Polycomb 1/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patología , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Proteína SOS1/genética , Proteína SOS1/metabolismo , Factor de Transcripción STAT5/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
BACKGROUND: Sun exposure has positive and negative effects on health, yet little is known about the sun exposure behaviour of UK adolescents, including those more prone or less prone to sunburn. OBJECTIVE: To examine sun exposure behaviour of UK white Caucasian adolescents including time spent outdoors, holiday behaviour, use of sunscreen and clothing, with assessment for differences between sun-reactive skin type groups. METHODS: White Caucasian adolescents (12-15 years) attending schools in Greater Manchester completed a two-page questionnaire to assess sun exposure and photoprotective behaviour. RESULTS: A total of 133 adolescents (median age 13.4 years; 39% skin type I/II, 61% skin type III/IV) completed the questionnaire. In summer, adolescents spent significantly longer outdoors at weekends (median 4 h/day, range 0.25-10) than on weekdays (2, 0.25-6; P < 0.0001). When at home in the UK during summer, 44% reported never wearing sunscreen compared to just 1% when on a sunny holiday. Sunscreen use was also greater (frequency/coverage) when on a sunny holiday than at home in the UK summer (P < 0.0001). Adolescents of skin types I/II (easy burning) spent significantly less time outdoors than skin types III/IV (easy tanning) on summer weekends (P < 0.001), summer weekdays (P < 0.05) and on a sunny holiday (P = 0.001). Furthermore, skin types I/II reported greater sunscreen use during summer in the UK and on sunny holiday (both P < 0.01), and wore clothing covering a greater skin area on a sunny holiday (P < 0.01) than skin types III/IV. There was no difference in sun exposure behaviour/protection between males and females. CONCLUSION: The greater sun-protective measures reported by adolescents of sun-reactive skin type group I/II than III/IV suggest those who burn more easily are aware of the greater need to protect their skin. However, use of sunscreen during the UK summer is low and may need more effective promotion in adolescents.
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Conductas Relacionadas con la Salud/etnología , Quemadura Solar/prevención & control , Luz Solar/efectos adversos , Población Blanca , Adolescente , Niño , Femenino , Humanos , Masculino , Ropa de Protección , Estaciones del Año , Quemadura Solar/etiología , Protectores Solares/uso terapéutico , Encuestas y Cuestionarios , Factores de Tiempo , Reino UnidoRESUMEN
BACKGROUND: Animal studies report photodynamic therapy (PDT) to improve healing of excisional wounds; the mechanism is uncertain and equivalent human studies are lacking. OBJECTIVES: To explore the impact of methyl aminolaevulinate (MAL)-PDT on clinical and microscopic parameters of human cutaneous excisional wound healing, examining potential modulation through production of transforming growth factor (TGF)-ß isoforms. METHODS: In 27 healthy older men (60-77 years), a 4-mm punch biopsy wound was created in skin of the upper inner arm and treated with MAL-PDT three times over 5 days. An identical control wound to the contralateral arm was untreated and both wounds left to heal by secondary intention. Wounds were re-excised during the inflammatory phase (7 days, n = 10), matrix remodelling (3 weeks, n = 8) and cosmetic outcome/dermal structure (9 months, n = 9). Production of TGF-ß1, TGF-ß3 and matrix metalloproteinases (MMPs) was assessed by immunohistochemistry alongside microscopic measurement of wound size/area and clinical assessment of wound appearance. RESULTS: MAL-PDT delayed re-epithelialization at 7 days, associated with increased inflammation. However, 3 weeks postwounding, treated wounds were smaller with higher production of MMP-1 (P = 0·01), MMP-9 (P = 0·04) and TGF-ß3 (P = 0·03). TGF-ß1 was lower than control at 7 days and higher at 3 weeks (both P = 0·03). At 9 months, MAL-PDT-treated wounds showed greater, more ordered deposition of collagen I, collagen III and elastin (all P < 0·05). CONCLUSIONS: MAL-PDT increases MMP-1, MMP-9 and TGF-ß3 production during matrix remodelling, ultimately producing scars with improved dermal matrix architecture.
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Ácido Aminolevulínico/análogos & derivados , Metaloproteinasa 1 de la Matriz/biosíntesis , Metaloproteinasa 9 de la Matriz/biosíntesis , Fármacos Fotosensibilizantes/administración & dosificación , Piel/lesiones , Factor de Crecimiento Transformador beta3/biosíntesis , Administración Cutánea , Anciano , Ácido Aminolevulínico/administración & dosificación , Brazo , Voluntarios Sanos , Humanos , Masculino , Fotoquimioterapia/métodos , Repitelización/efectos de los fármacos , Cicatrización de Heridas/efectos de los fármacosRESUMEN
The authors examined the relationship between number of siblings and false belief understanding (FBU) in 94 low-income 4-5-year-olds. Previous research with middle-income children has shown a positive association between number of siblings and FBU. However, it is unclear whether having multiple siblings in low-income families is related to better FBU. Language, specifically vocabulary, was examined as a possible mediator between number of siblings and FBU as several researchers have found that language is causally related to FBU. Contrary to research with middle-income preschoolers, the authors found that number of siblings was negatively related to low-income children's FBU. This relationship was mediated by children's vocabulary skill. Suggestions for why the sibling-FB relationship may differ in low- and middle-income samples are offered.
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Desarrollo Infantil/fisiología , Pobreza/psicología , Hermanos/psicología , Teoría de la Mente/fisiología , Vocabulario , Preescolar , Comprensión/fisiología , Femenino , Humanos , Lenguaje , Pruebas del Lenguaje , Masculino , Encuestas y CuestionariosRESUMEN
BACKGROUND: Topical photodynamic therapy (PDT) is a widely applied treatment for basal cell carcinoma (BCC). PDT-induced immunosuppression leading to reduced antitumour immune responses may be a factor in treatment failure. OBJECTIVES: To examine the impact of topical PDT on leucocyte trafficking following clinical treatment of BCC. METHODS: Superficial BCCs in eight white caucasian patients were treated with methyl aminolaevulinate (MAL)-PDT. Biopsies for immunohistochemical assessment were taken from BCCs pre-PDT, 1 h and 24 h post-PDT and from untreated healthy skin. RESULTS: Treatment of BCC with MAL-PDT produced a rapid neutrophil infiltration, commencing by 1 h and significantly increased at 24 h post-PDT (P < 0·05 compared with baseline). An associated increase in the number of blood vessels expressing E-selectin was observed at 1 h and 24 h post-PDT (both P < 0·05 compared with baseline). In contrast, the number of epidermal Langerhans cells fell sharply by 1 h post-PDT, and remained significantly reduced at 24 h post-PDT (both P < 0·05 compared with baseline). CONCLUSIONS: Reduction of Langerhans cells during clinical treatment of BCC might potentially impact negatively on antitumour responses through reduced activation of tumour-specific effector cells. Investigation of modified PDT protocols with the aim to minimize immunosuppressive effects while maintaining antitumour efficacy is warranted.
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Ácido Aminolevulínico/análogos & derivados , Carcinoma Basocelular/tratamiento farmacológico , Células de Langerhans/patología , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes/administración & dosificación , Neoplasias Cutáneas/tratamiento farmacológico , Administración Cutánea , Anciano , Ácido Aminolevulínico/administración & dosificación , Carcinoma Basocelular/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Infiltración Neutrófila , Neoplasias Cutáneas/etiologíaRESUMEN
BACKGROUND: Topical photodynamic therapy (PDT) elicits a therapeutic response in both skin cancer and immune-mediated skin disorders. While PDT induces direct cell death, host inflammatory and immune responses to PDT may contribute to the therapeutic effects. OBJECTIVES: To examine the impact of topical PDT on leucocyte trafficking and mediators of chemotaxis in healthy human skin. METHODS: Aminolaevulinic acid (ALA)-PDT was performed on the buttock skin of seven healthy volunteers. Biopsies for immunohistochemical assessment were taken 1, 4 and 24 h post-PDT and from untreated contralateral buttock skin (baseline). RESULTS: A significant dermal neutrophilic infiltrate appeared early, peaking at 4 h (P < 0·01) and returning to near baseline by 24 h. Expression of E-selectin was significantly higher at 4 h (P < 0·05) and correlated strongly with neutrophil numbers (r = 0·93). Expression of intercellular adhesion molecule 1 was significantly elevated after 24 h (P < 0·05) with an apparent gradual increase in CD4+ T cells up to this time point. Notably, epidermal Langerhans cells were significantly reduced 24 h post-PDT compared with baseline (P < 0·01) and comprised a significantly larger proportion of cells with migratory rather than dendritic morphology (P < 0·05). The number of epidermal cells expressing tumour necrosis factor-α significantly increased at 4 h (P < 0·05) and remained elevated 24 h post-PDT, whereas no significant change in expression of interleukin (IL)-1ß or IL-8 was seen. CONCLUSIONS: Reduction of Langerhans cells by topical PDT of human skin may play a significant role in PDT-induced local immunosuppression, potentially benefiting the treatment of immune-mediated skin disorders but negatively impacting on antitumour responses. Further exploration according to disease indication/treatment protocol is warranted.
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Ácido Aminolevulínico/farmacología , Células de Langerhans/efectos de los fármacos , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes/farmacología , Piel/citología , Administración Tópica , Adulto , Ácido Aminolevulínico/administración & dosificación , Nalgas , Movimiento Celular/efectos de los fármacos , Citocinas/metabolismo , Selectina E/metabolismo , Femenino , Humanos , Masculino , Neutrófilos/efectos de los fármacos , Fármacos Fotosensibilizantes/administración & dosificación , Piel/efectos de los fármacos , Linfocitos T/efectos de los fármacos , Adulto JovenRESUMEN
UNLABELLED: This study examined the role that mothers' scaffolding plays in the autobiographical memory (AM) and storybook narratives of children with specific language impairment (SLI). Seven 4-5-year-old children and their mothers co-constructed narratives in both contexts. We also compared children's narratives with mothers to their narratives with an experimenter. Narratives were assessed in terms of narrative style (i.e., elaborativeness) and topic control. Mothers' elaborative and repetitive questions during AM and book narratives were related to children's elaborations, whereas mothers' elaborative and repetitive statements were not. Mothers produced more topic-controlling utterances than children in both contexts; however, both mothers and children provided proportionally more information in the book context. Additionally, children were more elaborative with mothers compared to an experimenter. LEARNING OUTCOMES: Readers will be able to: (1) understand the importance of mother-child narratives for both typical and clinical populations; (2) understand how mother-child autobiographical memory and storybook narratives may differ between typical and clinical populations; and (3) consider the implications for designing narrative intervention studies for language impaired children.