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1.
EMBO J ; 41(15): e110300, 2022 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-35758142

RESUMO

The intrinsic apoptosis pathway, regulated by the BCL-2 protein family, is essential for embryonic development. Using mice lacking all known apoptosis effectors, BAX, BAK and BOK, we have previously defined the processes during development that require apoptosis. Rare Bok-/- Bax-/- Bak-/- triple knockout (TKO) mice developed to adulthood and several tissues that were thought to require apoptosis during development appeared normal. This raises the question if all apoptosis had been abolished in the TKO mice or if other BCL-2 family members could act as effectors of apoptosis. Here, we investigated the role of BID, generally considered to link the extrinsic and intrinsic apoptosis pathways, acting as a BH3-only protein initiating apoptosis upstream of BAX and BAK. We found that Bok-/- Bax-/- Bak-/- Bid-/- quadruple knockout (QKO) mice have additional developmental anomalies compared to TKO mice, consistent with a role of BID, not only upstream but also in parallel to BAX, BAK and BOK. Mitochondrial experiments identified a small cytochrome c-releasing activity of full-length BID. Collectively, these findings suggest a new effector role for BID in the intrinsic apoptosis pathway.


Assuntos
Proteína Agonista de Morte Celular de Domínio Interatuante com BH3 , Proteínas Proto-Oncogênicas c-bcl-2 , Proteína Killer-Antagonista Homóloga a bcl-2 , Animais , Camundongos , Apoptose , Proteína Killer-Antagonista Homóloga a bcl-2/genética , Proteína Killer-Antagonista Homóloga a bcl-2/metabolismo , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo , Proteína Agonista de Morte Celular de Domínio Interatuante com BH3/genética , Proteína Agonista de Morte Celular de Domínio Interatuante com BH3/metabolismo , Desenvolvimento Embrionário/genética , Camundongos Knockout , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo
2.
Cell ; 140(1): 74-87, 2010 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-20074521

RESUMO

We report that eight heterozygous missense mutations in TUBB3, encoding the neuron-specific beta-tubulin isotype III, result in a spectrum of human nervous system disorders that we now call the TUBB3 syndromes. Each mutation causes the ocular motility disorder CFEOM3, whereas some also result in intellectual and behavioral impairments, facial paralysis, and/or later-onset axonal sensorimotor polyneuropathy. Neuroimaging reveals a spectrum of abnormalities including hypoplasia of oculomotor nerves and dysgenesis of the corpus callosum, anterior commissure, and corticospinal tracts. A knock-in disease mouse model reveals axon guidance defects without evidence of cortical cell migration abnormalities. We show that the disease-associated mutations can impair tubulin heterodimer formation in vitro, although folded mutant heterodimers can still polymerize into microtubules. Modeling each mutation in yeast tubulin demonstrates that all alter dynamic instability whereas a subset disrupts the interaction of microtubules with kinesin motors. These findings demonstrate that normal TUBB3 is required for axon guidance and maintenance in mammals.


Assuntos
Tubulina (Proteína)/metabolismo , Sequência de Aminoácidos , Animais , Axônios/metabolismo , Encéfalo/embriologia , Encéfalo/metabolismo , Sobrevivência Celular , Criança , Deficiências do Desenvolvimento , Feminino , Humanos , Cinesinas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microtúbulos/metabolismo , Modelos Moleculares , Dados de Sequência Molecular , Mutação de Sentido Incorreto , Transporte Proteico , Tubulina (Proteína)/química , Tubulina (Proteína)/genética
3.
Can J Neurol Sci ; 51(1): 117-121, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36710572

RESUMO

Dr. Sharpe was a leading eye movement researcher who had also been the editor of this journal. We wish to mark the 10th anniversary of his death by providing a sense of what he had achieved through some examples of his research.


Assuntos
Neurologia , Oftalmologia , Humanos , Masculino , Oftalmologia/história
4.
Nurs Res ; 73(4): 270-277, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38498851

RESUMO

BACKGROUND: The incidence of type 2 diabetes (T2DM) among U.S. adults has been rising annually, with a higher incidence rate in Black and Hispanic adults than in Whites. The American Heart Association (AHA) has defined cardiovascular health according to the achievement of seven health behaviors (smoking, body mass index [BMI], physical activity, diet) and health factors (total cholesterol, blood pressure, fasting glucose). Optimal cardiovascular health has been associated with a lower risk of cardiovascular disease, and awareness of this risk may influence healthy behaviors. OBJECTIVES: This study aimed to assess cardiovascular health in a sample of Black and Hispanic adults (age: 18-40 years) with T2DM and explore the barriers and facilitators to diabetes self-management and cardiovascular health. METHODS: This was an explanatory sequential mixed-method design. The study staff recruited adults with T2DM for the quantitative data followed by qualitative interviews with a subsample of participants using maximum variation sampling. The seven indices of cardiovascular health as defined by the AHA's "Life's Simple 7" were assessed: health behaviors (smoking, BMI, physical activity, diet) and health factors (total cholesterol, blood pressure, A1C). Qualitative interviews were conducted to explore their results as well as the effects of the pandemic on diabetes self-management. Qualitative and quantitative data were integrated into the final analysis phase. RESULTS: The majority of the sample was female, with 63% identifying as Black and 47% as Hispanic. The factor with the lowest achievement of ideal levels was BMI, followed by a healthy diet. Less than half achieved ideal levels of blood pressure or physical activity. Themes that emerged from the qualitative data included the impact of social support, the effects of the pandemic on their lives, and educating themselves about T2DM. DISCUSSION: Achievement of ideal cardiovascular health factors varied, but the achievement of several health factors may be interrelated. Intervening on even one factor while providing social support may improve other areas of cardiovascular health in this population.


Assuntos
Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Hispânico ou Latino , Adolescente , Adulto , Feminino , Humanos , Masculino , Adulto Jovem , Negro ou Afro-Americano/estatística & dados numéricos , Negro ou Afro-Americano/psicologia , Doenças Cardiovasculares/prevenção & controle , Doenças Cardiovasculares/etnologia , Diabetes Mellitus Tipo 2/etnologia , Diabetes Mellitus Tipo 2/psicologia , Diabetes Mellitus Tipo 2/epidemiologia , Comportamentos Relacionados com a Saúde/etnologia , Hispânico ou Latino/estatística & dados numéricos , Hispânico ou Latino/psicologia , Estados Unidos/epidemiologia
5.
J Pediatr ; 241: 212-220.e2, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34687692

RESUMO

OBJECTIVE: To test the association of material deprivation and the utilization of vision care services for young children. STUDY DESIGN: We conducted a population-based, repeated measures cohort study using linked health and administrative datasets. All children born in Ontario in 2010 eligible for provincial health insurance were followed from birth until their seventh birthday. The main exposure was neighborhood-level material deprivation quintile, a proxy for socioeconomic status. The primary outcome was receipt of a comprehensive eye examination (not to include a vision screening) by age 7 years from an eye care professional, or family physician. RESULTS: Of 128 091 children included, female children represented 48.7% of the cohort, 74.4% lived in major urban areas, and 16.2% lived in families receiving income assistance. Only 65% (n = 82 833) had at least 1 comprehensive eye examination, with the lowest uptake (56.9%; n = 31 911) in the most deprived and the highest uptake (70.5%; n =19 860) in the least deprived quintiles. After adjusting for clinical and demographic variables, children living in the least materially deprived quintile had a higher odds of receiving a comprehensive eye examination (aOR 1.43; 95% CI 1.36, 1.51) compared with children in the most materially deprived areas. CONCLUSIONS: Uptake of comprehensive eye examinations is poor, especially for children living in the most materially deprived neighborhoods. Strategies to improve uptake and reduce inequities are warranted.


Assuntos
Utilização de Instalações e Serviços/economia , Acessibilidade aos Serviços de Saúde/economia , Disparidades em Assistência à Saúde/economia , Classe Social , Transtornos da Visão/diagnóstico , Testes Visuais/economia , Criança , Pré-Escolar , Utilização de Instalações e Serviços/estatística & dados numéricos , Feminino , Acessibilidade aos Serviços de Saúde/estatística & dados numéricos , Disparidades em Assistência à Saúde/estatística & dados numéricos , Humanos , Lactente , Estudos Longitudinais , Masculino , Ontário , Testes Visuais/estatística & dados numéricos
6.
Nurs Res ; 71(3): 218-226, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35067645

RESUMO

BACKGROUND: Improving the recruitment and retention of underrepresented groups in all research areas is essential for health equity. However, achieving and retaining diverse samples is challenging. Barriers to recruitment and retention of diverse participants include socioeconomic and cultural factors and practical challenges (e.g., time and travel commitments). OBJECTIVES: The purpose of this article is to describe the successful recruitment and retention strategies used by two related studies within a P20 center funded by the National Institute of Nursing Research focused on precision health research in diverse populations with multiple chronic conditions, including metabolic syndrome. METHODS: To address the complexity, biodiversity, and effect of metabolic syndrome and multiple chronic conditions, we developed culturally appropriate, multipronged recruitment and retention strategies for a pilot intervention study and a longitudinal observational pilot study within our P20 center. The following are the underlying principles that guided the recruitment and retention strategies: (a) flexibility, (b) active listening and bidirectional conversations, and (c) innovative problem solving. RESULTS: The intervention study (Pilot 1) enrolled 49 participants. The longitudinal observational study (Pilot 2) enrolled 45 participants. Women and racial/ethnic minorities were significantly represented in both. In Pilot 1, most of the participants completed the intervention and all phases of data collection. In Pilot 2, most participants completed all phases of data collection and chose to provide biorepository specimens. DISCUSSION: We developed a recruitment and retention plan building on standard strategies for a general medical population. Our real-world experiences informed the adaption of these strategies to facilitate the participation of individuals who often do not participate in research-specifically, women and racial/ethnic populations. Our experience across two pilot studies suggests that recruiting diverse populations should build flexibility in the research plan at the outset.


Assuntos
Síndrome Metabólica , Múltiplas Afecções Crônicas , Etnicidade , Feminino , Humanos , Seleção de Pacientes , Grupos Raciais
7.
CMAJ ; 192(29): E822-E831, 2020 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-32690557

RESUMO

BACKGROUND: Visual problems can negatively affect visual development and learning but often go undetected. We assessed the feasibility of scaling up a school-based screening program to identify and treat kindergarten children with visual problems. METHODS: We conducted a prospective cohort study offering vision screening to junior (JK) and senior kindergarten (SK) children attending 43 schools in 15 Ontario communities. Screening comprised photoscreeners and tests of visual acuity, stereoacuity and eye alignment. Children who failed any test were referred for a comprehensive eye examination, with treatment as needed (e.g., glasses). RESULTS: Using a passive consent model, 89% of children were screened compared with 62% using an active consent model (p < 0.001). Referral rates to an optometrist varied across schools (mean referral rate for children in JK 53%, range 25%-83%; mean referral rate for children in SK 34%, range 12%-61%). Among 4811 children who were screened, a visual problem was detected in 516 (10.7%), including 164 (3.4%) with amblyopia and 324 (6.7%) with clinically significant refractive errors. For 347 (67.2%) of the children with a visual problem, this was their first eye examination. Rescreening in Year 2 did not lead to detection of additional problems among children who passed screening in Year 1. Regardless of location (child's school or optometrist's office), 1563 (68.9%) of children attended the follow-up optometry examination. Most of the children who were surveyed (291 of 322, 90.4%) indicated that they enjoyed vision screening. INTERPRETATION: Many children in Ontario with a visual problem were not being identified by the status quo in 2015-2017. We found that in-school vision screening with follow-up eye examinations is an effective strategy for identifying at-risk children and placing them in eye care before grade 1.


Assuntos
Serviços de Saúde Escolar/organização & administração , Transtornos da Visão/diagnóstico , Seleção Visual/organização & administração , Acuidade Visual , Ambliopia/diagnóstico , Criança , Pré-Escolar , Estudos de Viabilidade , Humanos , Masculino , Ontário , Estudos Prospectivos , Erros de Refração/diagnóstico
8.
J Radiol Nurs ; 39(3): 164-167, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32837391

RESUMO

When severe acute respiratory syndrome (SARS) hit Singapore in 2003, we began to formulate rigorous protocols and reconfigure our facilities to prevent in-hospital transmission. This became the foundation of our practices in COVID-19. However, some adaptations were made to suit the current needs of the department, and technology has been used for communication. This article describes the preparation and response of nursing in the radiology department in Singapore in SARS and coronavirus 2019 (COVID-19) outbreak. Protocols and measures taken during SARS and COVID-19 outbreak are described. Stringent infection control and prevention measures, detailed standard operating protocols for handling SARS and COVID-19 patients coming for radiological examinations and interventions, team segregation, safe distancing, efficient communication, and rigorous staff surveillance are paramount to ensure patient and staff safety. Our SARS experience has shaped our preparations and response toward the COVID-19 pandemic. To date, there have been zero health care worker transmissions in the department. The crisis has also enhanced the cohesiveness among staff because of the camaraderie and shared experience. The response and measures taken by the radiology department in a large acute care teaching hospital could be practiced in other similar health care settings.

9.
Exp Eye Res ; 183: 68-75, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-29758189

RESUMO

Amblyopia is a common developmental sensory disorder that has been extensively and systematically investigated as a unisensory visual impairment. However, its effects are increasingly recognized to extend beyond vision to the multisensory domain. Indeed, amblyopia is associated with altered cross-modal interactions in audiovisual temporal perception, audiovisual spatial perception, and audiovisual speech perception. Furthermore, although the visual impairment in amblyopia is typically unilateral, the multisensory abnormalities tend to persist even when viewing with both eyes. Knowledge of the extent and mechanisms of the audiovisual impairments in amblyopia, however, remains in its infancy. This work aims to review our current understanding of audiovisual processing and integration deficits in amblyopia, and considers the possible mechanisms underlying these abnormalities.


Assuntos
Ambliopia/fisiopatologia , Percepção Auditiva/fisiologia , Limiar Sensorial/fisiologia , Percepção Visual/fisiologia , Humanos
10.
Neural Plast ; 2019: 6817839, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31281344

RESUMO

Amblyopia is a neurodevelopmental visual disorder arising from decorrelated binocular experience during the critical periods of development. The hallmark of amblyopia is reduced visual acuity and impairment in binocular vision. The consequences of amblyopia on various sensory and perceptual functions have been studied extensively over the past 50 years. Historically, relatively fewer studies examined the impact of amblyopia on visuomotor behaviours; however, research in this area has flourished over the past 10 years. Therefore, the aim of this review paper is to provide a comprehensive review of current knowledge about the effects of amblyopia on eye movements, upper limb reaching and grasping movements, as well as balance and gait. Accumulating evidence indicates that amblyopia is associated with considerable deficits in visuomotor behaviour during amblyopic eye viewing, as well as adaptations in behaviour during binocular and fellow eye viewing in adults and children. Importantly, due to amblyopia heterogeneity, visuomotor development in children and motor skill performance in adults may be significantly influenced by the etiology and clinical features, such as visual acuity and stereoacuity. Studies with larger cohorts of children and adults are needed to disentangle the unique contribution of these clinical characteristics to the development and performance of visuomotor behaviours.


Assuntos
Adaptação Fisiológica/fisiologia , Ambliopia/fisiopatologia , Ambliopia/psicologia , Desempenho Psicomotor/fisiologia , Acuidade Visual/fisiologia , Ambliopia/diagnóstico , Animais , Marcha/fisiologia , Humanos , Visão Binocular/fisiologia
11.
J Vis ; 18(4): 17, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29710307

RESUMO

Amblyopia is a neurodevelopmental disorder defined as a reduction in visual acuity that cannot be corrected by optical means. It has been associated with low-level deficits. However, research has demonstrated a link between amblyopia and visual attention deficits in counting, tracking, and identifying objects. Visual search is a useful tool for assessing visual attention but has not been well studied in amblyopia. Here, we assessed the extent of visual search deficits in amblyopia using feature and conjunction search tasks. We compared the performance of participants with amblyopia (n = 10) to those of controls (n = 12) on both feature and conjunction search tasks using Gabor patch stimuli, varying spatial bandwidth and orientation. To account for the low-level deficits inherent in amblyopia, we measured individual contrast and crowding thresholds and monitored eye movements. The display elements were then presented at suprathreshold levels to ensure that visibility was equalized across groups. There was no performance difference between groups on feature search, indicating that our experimental design controlled successfully for low-level amblyopia deficits. In contrast, during conjunction search, median reaction times and reaction time slopes were significantly larger in participants with amblyopia compared with controls. Amblyopia differentially affects performance on conjunction visual search, a more difficult task that requires feature binding and possibly the involvement of higher-level attention processes. Deficits in visual search may affect day-to-day functioning in people with amblyopia.


Assuntos
Ambliopia/fisiopatologia , Transtornos da Percepção/fisiopatologia , Percepção Visual/fisiologia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Limiar Sensorial , Análise e Desempenho de Tarefas , Visão Binocular/fisiologia , Acuidade Visual , Adulto Jovem
12.
Paediatr Child Health ; 23(3): e33-e39, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29769813

RESUMO

OBJECTIVES: Early intervention is critical to prevent treatable causes of vision loss in children. The objectives of the current study are: (1) to assess how well primary care physicians in Ontario follow the vision screening guidelines for children as recommended by the Canadian Paediatric Society and the Rourke Baby Record and (2) to identify barriers to vision screening in the primary care setting. DESIGN: Cross-sectional survey. METHODS: A 19-question survey was mailed out to 1000 randomly selected family physicians (family MDs), 1000 general practitioners (GPs) and 1000 paediatricians in Ontario as listed in the 2013 Canadian Medical Directory. RESULTS: A total of 719 completed surveys were included in the analysis (449 from family MDs/GPs and 270 from paediatricians). Vision screening was reported to be performed by 65% of family MDs/GPs and 52% of general paediatricians at every well child visit. While red reflex was reported to be checked by 94% of all physicians in children under 3, it was only performed by 25% of respondents for children over 3. Thirty seven percent of all physicians reported never performing a visual acuity test in any age group. When asked about the obstacles preventing them from performing vision screening, lack of training (family MDs/GPs: 50%, paediatricians: 42%), time constraints (family MDs/GPs: 42%; paediatricians: 40%) and inadequate reimbursement (family MDs/GPs: 17%; paediatricians: 15%) were the most commonly cited reasons. CONCLUSIONS: Strategies to improve vision screening are necessary given that early intervention is crucial to prevent treatable causes of vision loss in children.

13.
Healthc Q ; 20(4): 48-53, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29595428

RESUMO

One of the key challenges to healthcare organizations is the development of relevant and accurate cost information. In this paper, we used time-driven activity-based costing (TDABC) method to calculate the costs of treating individual patients with specific medical conditions over their full cycle of care. We discussed how TDABC provides a critical, systematic and data-driven approach to estimate costs accurately and dynamically, as well as its potential to enable structural and rational cost reduction to bring about a sustainable healthcare system.


Assuntos
Custos de Cuidados de Saúde , Oftalmologia/economia , Ambulatório Hospitalar/economia , Avaliação de Processos em Cuidados de Saúde/métodos , Criança , Custos e Análise de Custo , Hospitais Pediátricos , Humanos , Ontário , Oftalmologia/organização & administração , Estudos de Casos Organizacionais , Ambulatório Hospitalar/organização & administração , Fatores de Tempo
14.
Mol Cell Neurosci ; 65: 125-34, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25752731

RESUMO

Neurotrophic factors have been intensively studied as potential therapeutic agents for promoting neural regeneration and functional recovery after nerve injury. Artemin is a member of the glial cell line-derived neurotrophic factor (GDNF) family of ligands (GFLs) that forms a signalling complex with GFRα3 and the tyrosine kinase Ret. Systemic administration of artemin in rodents is reported to facilitate regeneration of primary sensory neurons following axotomy, improve recovery of sensory function, and reduce sensory hypersensitivity that is a cause of pain. However, the biological mechanisms that underlie these effects are mostly unknown. This study has investigated the biological significance of the colocalisation of GFRα3 with TrkA (neurotrophin receptor for nerve growth factor [NGF]) in the peptidergic type of unmyelinated (C-fibre) sensory neurons in rat dorsal root ganglia (DRG). In vitro neurite outgrowth assays were used to study the effects of artemin and NGF by comparing DRG neurons that were previously uninjured, or were axotomised in vivo by transecting a visceral or somatic peripheral nerve. We found that artemin could facilitate neurite initiation but in comparison to NGF had low efficacy for facilitating neurite elongation and branching. This low efficacy was not increased when a preconditioning in vivo nerve injury was used to induce a pro-regenerative state. Neurite initiation was unaffected by artemin when PI3 kinase and Src family kinase signalling were blocked, but NGF had a reduced effect.


Assuntos
Fator de Crescimento Neural/farmacologia , Proteínas do Tecido Nervoso/farmacologia , Neuritos/efeitos dos fármacos , Traumatismos dos Nervos Periféricos/metabolismo , Células Receptoras Sensoriais/metabolismo , Animais , Células Cultivadas , Feminino , Gânglios Espinais/citologia , Receptores de Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Humanos , Masculino , Regeneração Nervosa , Neuritos/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor trkA/metabolismo , Células Receptoras Sensoriais/efeitos dos fármacos , Células Receptoras Sensoriais/fisiologia
15.
Healthc Q ; 19(1): 36-41, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27133606

RESUMO

Long patient dwell time (i.e., the time between patients arriving and leaving the clinic) has been a long-standing issue in the eye clinic at The Hospital for Sick Children. By applying the Lean principles of eliminating waste and enhancing flow, we achieved a 26% reduction in the mean patient dwell time over an eight-month period. Importantly, the average time a patient spent with healthcare providers (value-added time) increased from 21% to 31%. In this paper, we summarized our experience by illustrating how an implicit mental model (conscious or unconscious conceptual framework from which we understand the world) pervades in the healthcare system based on deeply held but unexamined assumptions that arise from heuristics (general rules of thumb) and biases; how these assumptions can be tested by objective data; and how we can build a new mental model based on objective findings to improve the healthcare system.


Assuntos
Instituições de Assistência Ambulatorial/organização & administração , Eficiência Organizacional , Oftalmologia/organização & administração , Fluxo de Trabalho , Criança , Hospitais Pediátricos , Humanos , Ontário , Melhoria de Qualidade , Fatores de Tempo
16.
Mol Cell Neurosci ; 63: 132-40, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25461619

RESUMO

Brain-derived neurotrophic factor (BDNF) plays critical roles in the development and maintenance of the central (CNS) and peripheral nervous systems (PNS). BDNF exerts its biological effects via tropomyosin-related kinase B (TrkB) and the p75 neurotrophin receptor (p75NTR). We have recently identified that BDNF promotes CNS myelination via oligodendroglial TrkB receptors. In order to selectively target TrkB to promote CNS myelination, we have used a putative TrkB agonist, a small multicyclic peptide (tricyclic dimeric peptide 6, TDP6) previously described by us that structurally mimics a region of BDNF that binds TrkB. We confirmed that TDP6 acts as a TrkB agonist as it provoked autophosphorylation of TrkB and its downstream signalling effector extracellular related-kinase 1 and 2 (Erk1/2) in primary oligodendrocytes. Using an in vitro myelination assay, we show that TDP6 significantly promotes myelination by oligodendrocytes in vitro, as evidenced by enhanced myelin protein expression and an increased number of myelinated axonal segments. In contrast, a second, structurally distinct BDNF mimetic (cyclo-dPAKKR) that targets p75NTR had no effect upon oligodendrocyte myelination in vitro, despite the fact that cyclo-dPAKKR is a very effective promoter of peripheral (Schwann cell) myelination. The selectivity of TDP6 was further verified by using TrkB-deficient oligodendrocytes, in which TDP6 failed to promote myelination, indicating that the pro-myelinating effect of TDP6 is oligodendroglial TrkB-dependent. Together, our results demonstrate that TDP6 is a novel BDNF mimetic that promotes oligodendrocyte myelination in vitro via targeting TrkB.


Assuntos
Bainha de Mielina/metabolismo , Oligodendroglia/efeitos dos fármacos , Peptidomiméticos/farmacologia , Receptor trkB/agonistas , Animais , Axônios/efeitos dos fármacos , Axônios/metabolismo , Fator Neurotrófico Derivado do Encéfalo/química , Células Cultivadas , Camundongos , Camundongos Endogâmicos C57BL , Bainha de Mielina/genética , Oligodendroglia/metabolismo , Fosforilação , Ratos , Ratos Sprague-Dawley , Receptor trkB/metabolismo
17.
J Neurosci ; 33(11): 4947-57, 2013 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-23486965

RESUMO

The neurotrophin brain-derived neurotrophic factor (BDNF) has been implicated in regulating CNS myelination. BDNF mutant mice exhibit a hypomyelinating phenotype, and BDNF exerts distinct effects upon oligodendroglial proliferation, differentiation, and myelination in vitro. To investigate the precise influence that BDNF exerts in regulating CNS myelination in vivo, we have generated conditional knock-out mice in which TrkB has been deleted specifically in oligodendrocytes. Deletion of TrkB disrupted normal oligodendrocyte myelination, resulting in a significant reduction in myelin protein expression and myelination of CNS white matter tracts during development. Importantly, conditional knock-out mice exhibited normal numbers of mature oligodendrocytes and normal numbers of myelinated axons; however, myelin thickness was significantly reduced during development. These data indicate that while TrkB expression in oligodendrocytes plays no role in the initial contact with axons, it exerts an important influence in subsequent stages to promote myelin ensheathment. The conditional knock-out mice also exhibited an increased density of oligodendrocyte progenitor cells (OPCs) in CNS white matter tracts. Concordant with these results, in vitro analyses using OPCs subjected to TrkB knockdown also revealed increased OPC proliferation. Our data suggested this effect was dependent upon TrkC and p75 expression. Thus, our data demonstrate that TrkB expression in oligodendroglia exerts a direct effect on oligodendrocytes to promote myelination and an indirect effect upon the OPC population, modifying their proliferative potential.


Assuntos
Proliferação de Células , Bainha de Mielina/fisiologia , Oligodendroglia/metabolismo , Receptor trkB/metabolismo , Células-Tronco/fisiologia , Fatores Etários , Análise de Variância , Animais , Animais Recém-Nascidos , Proteínas Relacionadas à Autofagia , Diferenciação Celular/genética , Células Cultivadas , Sistema Nervoso Central/crescimento & desenvolvimento , Sistema Nervoso Central/metabolismo , Técnicas de Cocultura , Feminino , Gânglios Espinais/citologia , Gânglios Espinais/metabolismo , Regulação da Expressão Gênica/genética , Proteínas de Fluorescência Verde/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microscopia Eletrônica de Transmissão , Proteína Básica da Mielina/genética , Proteína Básica da Mielina/metabolismo , Bainha de Mielina/ultraestrutura , Oligodendroglia/ultraestrutura , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor de Fator de Crescimento Neural/metabolismo , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptor trkB/genética , Receptor trkC/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Células-Tronco/ultraestrutura , Transfecção
18.
J Neurochem ; 129(4): 614-27, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24484474

RESUMO

Suppressor of cytokine signaling-2 (SOCS2) is a regulator of intracellular responses to growth factors and cytokines. Cultured dorsal root ganglia neurons from neonatal mice with increased or decreased SOCS2 expression were examined for altered responsiveness to nerve growth factor (NGF). In the presence of NGF, SOCS2 over-expression increased neurite length and complexity, whereas loss of SOCS2 reduced neurite outgrowth. Neither loss nor gain of SOCS2 expression altered the relative survival of these cells, suggesting that SOCS2 can discriminate between the differentiation and survival responses to NGF. Interaction studies in 293T cells revealed that SOCS2 immunoprecipitates with TrkA and a juxtamembrane motif of TrkA was required for this interaction. SOCS2 also immunoprecipitated with endogenous TrkA in PC12 Tet-On cells. Over-expression of SOCS2 in PC12 Tet-On cells increased total and surface TrkA expression. In contrast, dorsal root ganglion neurons which over-expressed SOCS2 did not exhibit significant changes in total levels but an increase in surface TrkA was noted. SOCS2-induced neurite outgrowth in PC12 Tet-On cells correlated with increased and prolonged activation of pAKT and pErk1/2 and required an intact SOCS2 SH2 domain and SOCS box domain. This study highlights a novel role for SOCS2 in the regulation of TrkA signaling and biology.


Assuntos
Receptor trkA/biossíntese , Proteínas Supressoras da Sinalização de Citocina/fisiologia , Animais , Membrana Celular/metabolismo , Células Cultivadas , Gânglios Espinais/citologia , Camundongos , Camundongos Endogâmicos C57BL , Fator de Crescimento Neural/fisiologia , Neuritos/ultraestrutura , Neurogênese/fisiologia , Neurônios/metabolismo , Células PC12 , Ratos , Receptor trkA/química , Receptor trkA/genética , Transdução de Sinais/fisiologia , Proteínas Supressoras da Sinalização de Citocina/química
19.
Can J Public Health ; 2024 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-38691337

RESUMO

OBJECTIVE: To assess the effectiveness of a kindergarten vision screening program by randomly assigning schools to receive or not receive vision screening, then following up 1.5 years later. METHODS: Fifty high-needs elementary schools were randomly assigned to participate or not in a vision screening program for children in senior kindergarten (SK; age 5‒6 years). When the children were in Grade 2 (age 6‒7 years), vision screening was conducted at all 50 schools. RESULTS: Contrary to expectations, screened and non-screened schools did not differ in the prevalence of suspected amblyopia in Grade 2 (8.6% vs. 7.5%, p = 0.10), nor prevalence of other visual problems such as astigmatism (45.1% vs. 47.1%, p = 0.51). There was also no difference between screened and non-screened schools in academic outcomes such as the proportion of children below grade level in reading (33% vs. 29%) or math (44% vs. 38%) (p = 0.86). However, more children were wearing glasses in screened than in non-screened schools (10.2% vs. 7.8%, p = 0.05), and more children reported their glasses as missing or broken (8.3% vs. 4.7%, p = 0.01), suggesting that SK screening had identified successfully those in need of glasses. Examination of individual results revealed that 72% of children diagnosed and treated for amblyopia in SK no longer had amblyopia in Grade 2. CONCLUSION: The prevalence of amblyopia and other visual problems was not reduced in Grade 2 by our SK vision screening program, perhaps because of poor treatment compliance and high attrition. The results suggest that a single screening intervention is insufficient to reduce visual problems among young children. However, the data from individuals with amblyopia suggest that continuing vision care and access to glasses benefits children, especially children from lower socioeconomic class.


RéSUMé: OBJECTIF: Évaluer l'efficacité d'un programme de dépistage visuel à l'école maternelle (EM) en assignant aléatoirement des écoles à participer ou non à un tel programme, puis en faisant un suivi un an et demi après. MéTHODES: Cinquante écoles primaires pour étudiants et étudiantes ayant des besoins importants ont été assignées aléatoirement à participer ou non à un programme de dépistage visuel auprès des enfants fréquentant la maternelle (EM; 5‒6 ans). Lorsque ces enfants étaient en 2e année (6‒7 ans), un dépistage visuel a été effectué dans les 50 écoles. RéSULTATS: Contre toute attente, il n'y a pas eu de différence entre les écoles ayant participé ou non au dépistage dans la prévalence de l'amblyopie présumée en 2e année (8,6 % contre 7,5 %, p = 0,10), ni dans la prévalence d'autres problèmes de vision comme l'astigmatisme (45,1 % contre 47,1 %, p = 0,51). Il n'y a pas eu non plus de différence dans les résultats scolaires des deux groupes d'écoles, comme la proportion d'enfants dont le niveau en lecture (33 % contre 29 %) ou en mathématiques (44 % contre 38 %), p = 0,86, ne correspondait pas à leur année d'étude. Cependant, le nombre d'enfants portant des lunettes était plus élevé dans les écoles ayant participé au dépistage que dans les autres écoles (10,2 % contre 7,8 %, p = 0,05), ainsi que le nombre d'enfants disant avoir perdu ou brisé leurs lunettes (8,3 % contre 4,7 %, p = 0,01), ce qui indique que le dépistage en maternelle a identifié avec succès les enfants ayant besoin de lunettes. L'examen des résultats individuels a révélé que 72 % des enfants diagnostiqués et traités pour l'amblyopie en maternelle ne présentaient plus d'amblyopie en 2e année. CONCLUSION: Notre programme de dépistage visuel à l'école maternelle n'a pas réduit la prévalence de l'amblyopie et d'autres problèmes de vision en 2e année, peut-être en raison du manque d'assiduité au traitement et d'une attrition importante. Les résultats indiquent qu'une seule intervention de dépistage ne suffit pas à réduire les problèmes de vision chez les jeunes enfants. Cependant, les données individuelles des sujets présentant une amblyopie indiquent qu'il est avantageux pour les enfants, et surtout ceux de la classe socioéconomique inférieure, de continuer de recevoir des soins de la vue et d'avoir accès à des lunettes.

20.
J AAPOS ; 28(2): 103850, 2024 04.
Artigo em Inglês | MEDLINE | ID: mdl-38360350

RESUMO

Myelinated retinal nerve fiber layer (RNFL) is a rare structural anomaly that occurs from abnormal myelination extending anterior to the lamina cribrosa. Clinically, myelinated RNFL is characterized as a gray-white lesion with feathered, well-demarcated borders obscuring the retinal vasculature. Myelinated RNFL is typically congenital, benign, and asymptomatic. It is most commonly noted as an incidental finding on ophthalmic examination. However, cases of acquired myelinated RNFL have been reported. We report the case of a patient with neurofibromatosis type 1 and optic pathway glioma with unilateral acquired myelinated RNFL.


Assuntos
Neurofibromatose 1 , Glioma do Nervo Óptico , Criança , Humanos , Neurofibromatose 1/complicações , Neurofibromatose 1/diagnóstico , Células Ganglionares da Retina/patologia , Fibras Nervosas/patologia , Tomografia de Coerência Óptica , Glioma do Nervo Óptico/complicações , Glioma do Nervo Óptico/diagnóstico
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