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1.
J Mech Behav Biomed Mater ; 104: 103632, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32174391

RESUMO

This study investigates the effect of needle tip geometry on the needle deflection and tissue sampling length in biopsy. Advances in medical imaging have allowed the identification of suspicious cancerous lesions which then require needle biopsy for tissue sampling and subsequent confirmatory pathological analysis. Precise needle insertion and adequate tissue sampling are essential for accurate cancer diagnosis and individualized treatment decisions. However, the single-bevel needles in current hand-held biopsy devices often deflect significantly during needle insertion, causing variance in the targeted and actual locations of the sampled tissue. This variance can lead to inaccurate sampling and false-negative results. There is also a limited understanding of factors affecting the tissue sampling length which is a critical component of accurate cancer diagnosis. This study compares the needle deflection and tissue sampling length between the existing single-bevel and exploratory multi-bevel needle tip geometries. A coupled Eulerian-Lagrangian finite element analysis was applied to understand the needle-tissue interaction during needle insertion. The needle deflection and tissue sampling length were experimentally studied using tissue-mimicking phantoms and ex-vivo tissue, respectively. This study reveals that the tissue separation location at the needle tip affects both needle deflection and tissue sampling length. By varying the tissue separation location and creating a multi-bevel needle tip geometry, the bending moments induced by the insertion forces can be altered to reduce the needle deflection. However, the tissue separation location also affects the tissue contact inside the needle groove, potentially reducing the tissue sampling length. A multi-bevel needle tip geometry with the tissue separation point below the needle groove face may reduce the needle deflection while maintaining a long tissue sampling length. Results from this study can guide needle tip design to enable the precise needle deployment and adequate tissue sampling for the needle biopsy procedures.

2.
Mol Cancer Res ; 18(5): 774-786, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32029440

RESUMO

Capicua (CIC) is a transcriptional repressor that counteracts activation of genes in response to receptor tyrosine kinase (RTK)/Ras/ERK signaling. Following activation of RTK, ERK enters the nucleus and serine-phosphorylates CIC, releasing it from its targets to permit gene expression. We recently showed that ERK triggers ubiquitin-mediated degradation of CIC in glioblastoma (GBM). In this study, we examined whether another important downstream effector of RTK/EGFR, the non-RTK c-Src, affects CIC repressor function in GBM. We found that c-Src binds and tyrosine-phosphorylates CIC on residue 1455 to promote nuclear export of CIC. On the other hand, CIC-mutant allele (CIC-Y1455F), that escapes c-Src-mediated tyrosine phosphorylation, remains localized to the nucleus and retains strong repressor function against CIC targets, the oncogenic transcription factors ETV1 and ETV5. Furthermore, we show that the orally available Src family kinase inhibitor, dasatinib, which prevents EGF-mediated tyrosine phosphorylation of CIC and attenuates elevated ETV1 and ETV5 levels, reduces viability of GBM cells and glioma stem cells (GSC), but not of their control cells with undetectable c-Src activity. In fact, GBM cells and GSC expressing the tyrosine-defective CIC mutant (Y1455F) lose sensitivity to dasatinib, further endorsing the effect of dasatinib on Src-mediated tyrosine phosphorylation of CIC. These findings elucidate important mechanisms of CIC regulation and provide the rationale to target c-Src alongside ERK pathway inhibitors as a way to fully restore CIC tumor suppressor function in neoplasms such as GBM. IMPLICATIONS: c-Src tyrosine-phosphorylates CIC exports to cytoplasm and inactivates its repressor function in GBM.

3.
Pancreatology ; 20(1): 125-131, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31706821

RESUMO

BACKGROUND: The risk of pancreatic ductal adenocarcinoma (PDAC) is increased in patients with diabetes mellitus (DM), particularly in those with new-onset DM. However, the impact of DM on outcomes following pancreatic surgery is not fully understood. We sought to explore the effects of DM on post-resection outcomes in patients undergoing either upfront resection or following neoadjuvant treatment (NAT). METHODS: Resections for PDAC between 2007 and 2016 were identified from a prospectively-maintained database. Data on demographics, pathology, and perioperative outcomes were compared between patients with or without DM. Survival analysis was performed using Kaplan-Meier curves and adjusted for confounders by a Cox-proportional hazards model. RESULTS: 662 patients were identified, of whom 277 (41.8%) had DM. Diabetics were more likely to be male, had higher BMI, and higher ASA-scores. At pathology, DM was associated with larger tumors (30 vs. 26 mm; p = 0.041), higher rates of lymph-node involvement (69% vs. 59%; p = 0.031) and perineural invasion (88% vs. 82%; p = 0.026). Despite having similar rates of complications, diabetics experienced higher 30-day mortality (3.2% vs. 0.8%; p = 0.019). Median overall survival was worse in diabetic patients (18 vs. 34 months; p < 0.001); this effect was more pronounced in patients with NAT (18 vs. 54 months; p < 0.001). At multivariate analysis, DM was confirmed as an independent predictor of post-resection survival. CONCLUSION: DM is a common comorbidity in PDAC and is associated with unfavorable pathology, as well as worse postoperative and oncologic outcomes. The blunted effect on survival is more pronounced in patients who undergo resection following NAT.

4.
Nat Commun ; 10(1): 661, 2019 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-30737375

RESUMO

Capicua (CIC) is a transcriptional repressor that counteracts activation of genes downstream of receptor tyrosine kinase (RTK)/Ras/ERK signaling. It is well-established that tumorigenesis, especially in glioblastoma (GBM), is attributed to hyperactive RTK/Ras/ERK signaling. While CIC is mutated in other tumors, here we show that CIC has a tumor suppressive function in GBM through an alternative mechanism. We find that CIC protein levels are negligible in GBM due to continuous proteasome-mediated degradation, which is mediated by the E3 ligase PJA1 and show that this occurs through binding of CIC to its DNA target and phosphorylation on residue S173. PJA1 knockdown increased CIC stability and extended survival using in-vivo models of GBM. Deletion of the ERK binding site resulted in stabilization of CIC and increased therapeutic efficacy of ERK inhibition in GBM models. Our results provide a rationale to target CIC degradation in Ras/ERK-driven tumors, including GBM, to increase efficacy of ERK inhibitors.


Assuntos
Glioblastoma/metabolismo , Glioblastoma/patologia , Proteínas Repressoras/metabolismo , Animais , Carcinogênese/metabolismo , Carcinogênese/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Proliferação de Células/fisiologia , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Drosophila , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/genética , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Células HEK293 , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação , Proteínas Repressoras/genética , Transdução de Sinais/genética , Transdução de Sinais/fisiologia
5.
Cell Rep ; 22(12): 3115-3125, 2018 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-29562168

RESUMO

Genetic instability of the mitochondrial genome (mtDNA) plays an important role in human aging and disease. Thus far, it has proven difficult to develop successful treatment strategies for diseases that are caused by mtDNA instability. To address this issue, we developed a model of mtDNA disease in the nematode C. elegans, an animal model that can rapidly be screened for genes and biological pathways that reduce mitochondrial pathology. These worms recapitulate all the major hallmarks of mtDNA disease in humans, including increased mtDNA instability, loss of respiration, reduced neuromuscular function, and a shortened lifespan. We found that these phenotypes could be rescued by intervening in numerous biological pathways, including IGF-1/insulin signaling, mitophagy, and the mitochondrial unfolded protein response, suggesting that it may be possible to ameliorate mtDNA disease through multiple molecular mechanisms.


Assuntos
Caenorhabditis elegans/metabolismo , DNA Mitocondrial/genética , Mitocôndrias/metabolismo , Animais , Progressão da Doença , Camundongos , Modelos Animais
6.
Sci Adv ; 3(10): e1701484, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-29062891

RESUMO

Accurate transcription is required for the faithful expression of genetic information. To understand the molecular mechanisms that control the fidelity of transcription, we used novel sequencing technology to provide the first comprehensive analysis of the fidelity of transcription in eukaryotic cells. Our results demonstrate that transcription errors can occur in any gene, at any location, and affect every aspect of protein structure and function. In addition, we show that multiple proteins safeguard the fidelity of transcription and provide evidence suggesting that errors that evade these layers of RNA quality control profoundly affect the physiology of living cells. Together, these observations demonstrate that there is an inherent limit to the faithful expression of the genome and suggest that the impact of mutagenesis on cellular health and fitness is substantially greater than currently appreciated.


Assuntos
Células Eucarióticas/metabolismo , Mutagênese , Transcrição Genética , Regiões 3' não Traduzidas , Biologia Computacional/métodos , RNA Polimerases Dirigidas por DNA/química , RNA Polimerases Dirigidas por DNA/metabolismo , Perfilação da Expressão Gênica , Mutação , Taxa de Mutação , Degradação do RNAm Mediada por Códon sem Sentido , Subunidades Proteicas , Transcriptoma , Leveduras/genética , Leveduras/metabolismo
7.
Pediatrics ; 139(2)2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28093465

RESUMO

BACKGROUND AND OBJECTIVES: Little is known of the long-term, including school, outcomes of children diagnosed with Neonatal abstinence syndrome (NAS) (International Statistical Classification of Disease and Related Problems [10th Edition], Australian Modification, P96.1). METHODS: Linked analysis of health and curriculum-based test data for all children born in the state of New South Wales (NSW), Australia, between 2000 and 2006. Children with NAS (n = 2234) were compared with a control group matched for gestation, socioeconomic status, and gender (n = 4330, control) and with other NSW children (n = 598 265, population) for results on the National Assessment Program: Literacy and Numeracy, in grades 3, 5, and 7. RESULTS: Mean test scores (range 0-1000) for children with NAS were significantly lower in grade 3 (359 vs control: 410 vs population: 421). The deficit was progressive. By grade 7, children with NAS scored lower than other children in grade 5. The risk of not meeting minimum standards was independently associated with NAS (adjusted odds ratio [aOR], 2.5; 95% confidence interval [CI], 2.2-2.7), indigenous status (aOR, 2.2; 95% CI, 2.2-2.3), male gender (aOR, 1.3; 95% CI, 1.3-1.4), and low parental education (aOR, 1.5; 95% CI, 1.1-1.6), with all Ps < .001. CONCLUSIONS: A neonatal diagnostic code of NAS is strongly associated with poor and deteriorating school performance. Parental education may decrease the risk of failure. Children with NAS and their families must be identified early and provided with support to minimize the consequences of poor educational outcomes.


Assuntos
Avaliação Educacional , Síndrome de Abstinência Neonatal/diagnóstico , Adolescente , Criança , Pré-Escolar , Estudos Transversais , Currículo , Feminino , Humanos , Lactente , Recém-Nascido , Estudos Longitudinais , Síndrome de Abstinência Neonatal/epidemiologia , New South Wales , Gravidez , Pontuação de Propensão
8.
Nat Immunol ; 17(8): 922-9, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27270400

RESUMO

Deficiency in mevalonate kinase (MVK) causes systemic inflammation. However, the molecular mechanisms linking the mevalonate pathway to inflammation remain obscure. Geranylgeranyl pyrophosphate, a non-sterol intermediate of the mevalonate pathway, is the substrate for protein geranylgeranylation, a protein post-translational modification that is catalyzed by protein geranylgeranyl transferase I (GGTase I). Pyrin is an innate immune sensor that forms an active inflammasome in response to bacterial toxins. Mutations in MEFV (encoding human PYRIN) result in autoinflammatory familial Mediterranean fever syndrome. We found that protein geranylgeranylation enabled Toll-like receptor (TLR)-induced activation of phosphatidylinositol-3-OH kinase (PI(3)K) by promoting the interaction between the small GTPase Kras and the PI(3)K catalytic subunit p110δ. Macrophages that were deficient in GGTase I or p110δ exhibited constitutive release of interleukin 1ß that was dependent on MEFV but independent of the NLRP3, AIM2 and NLRC4 inflammasomes. In the absence of protein geranylgeranylation, compromised PI(3)K activity allows an unchecked TLR-induced inflammatory responses and constitutive activation of the Pyrin inflammasome.


Assuntos
Alquil e Aril Transferases/metabolismo , Febre Familiar do Mediterrâneo/metabolismo , Inflamassomos/metabolismo , Macrófagos/fisiologia , Mutação/genética , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Pirina/genética , Alquil e Aril Transferases/genética , Animais , Células Cultivadas , Febre Familiar do Mediterrâneo/genética , Humanos , Imunidade Inata , Interleucina-1beta/metabolismo , Camundongos Endogâmicos C57BL , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Fosfatos de Poli-Isoprenil/metabolismo , Processamento de Proteína Pós-Traducional , Transdução de Sinais , Receptores Toll-Like/metabolismo
9.
Age Ageing ; 45(2): 274-80, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26822196

RESUMO

BACKGROUND AND OBJECTIVE: C-reactive protein (CRP) is a widely used cardiovascular risk marker, but questions remain about its role in the disability process in old age. This study examines the associations between CRP levels and physical performance in old age in different societies. METHODS: data were collected during the baseline survey of IMIAS in 2012 in Kingston (Canada), Saint-Hyacinthe (Canada), Manizales (Colombia) and Natal (Brazil). Approximately 200 men and 200 women aged 65-74 were recruited at each site. CRP was assessed using a high sensitivity assay and categorised as low (<1 mg/l), moderate (1-3 mg/l), high (3-10 mg/l) and very high (≥10 mg/l). Participants were interviewed at home; blood pressure, weight and height were measured. Physical function was assessed with the Short Physical Performance Battery (SPPB) and hand grip strength. Data were analysed using descriptive statistics, bivariate analysis (χ²) and linear or logistic regression. RESULTS: CRP was significantly associated with low hand grip strength and poor physical performance in bivariate analyses. Hand grip strength association with CRP disappeared after adjustment by socioeconomic factors and health behaviours. The odds of poor physical function was OR = 2.67 [95% CI 1.43-4.99] comparing the highest and lowest CRP categories after adjustment by relevant covariates. The three SPPB components were assessed separately. Graded associations between low CRP and faster gait speed and shorter time to rise from a chair were observed in adjusted models. Association between impaired balance and CRP was attenuated after adjustment by relevant covariates, OR = 1.15 [0.65-2.04]. CONCLUSIONS: CRP could be a possible pathway from inflammation to physical decline in older populations.


Assuntos
Envelhecimento/sangue , Proteína C-Reativa/análise , Nível de Saúde , Mediadores da Inflamação/sangue , Aptidão Física , Fatores Etários , Idoso , Biomarcadores/sangue , Brasil , Canadá , Distribuição de Qui-Quadrado , Colômbia , Estudos Transversais , Avaliação da Deficiência , Feminino , Avaliação Geriátrica , Força da Mão , Inquéritos Epidemiológicos , Humanos , Modelos Lineares , Modelos Logísticos , Masculino , Análise Multivariada , Razão de Chances , Fatores de Risco
10.
BMC Geriatr ; 15: 102, 2015 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-26286183

RESUMO

BACKGROUND: Recent studies suggest potential associations between childhood adversity and chronic inflammation at older ages. Our aim is to compare associations between childhood health, social and economic adversity and high sensitivity C-reactive protein (hsCRP) in populations of older adults living in different countries. METHODS: We used the 2012 baseline data (n = 1340) from the International Mobility in Aging Study (IMIAS) of community-dwelling people aged 65-74 years in Natal (Brazil), Manizales (Colombia) and Canada (Kingston, Ontario; Saint-Hyacinthe, Quebec). Multiple linear and Poisson regressions with robust covariance were fitted to examine the associations between early life health, social, and economic adversity and hsCRP, controlling for age, sex, financial strain, marital status, physical activity, smoking and chronic conditions both in the Canadian and in the Latin American samples. RESULTS: Participants from Canadian cities have less adverse childhood conditions and better childhood self-reported health. Inflammation was lower in the Canadian cities than in Manizales and Natal. Significant associations were found between hsCRP and childhood social adversity in the Canadian but not in the Latin American samples. Among Canadian older adults, the fully-adjusted mean hsCRP was 2.2 (95% CI 1.7; 2.8) among those with none or one childhood social adversity compared with 2.8 (95% CI 2.1; 3.8) for those with two or more childhood social adversities (p = 0.053). Similarly, the prevalence of hsCRP > 3 mg/dL was 40% higher among those with higher childhood social adversity but after adjustment by health behaviors and chronic conditions the association was attenuated. No associations were observed between hsCRP and childhood poor health or childhood economic adversity. CONCLUSIONS: Inflammation was higher in older participants living in the Latin American cities compared with their Canadian counterparts. Childhood social adversity, not childhood economic adversity or poor health during childhood, was an independent predictor of chronic inflammation in old age in the Canadian sample. Selective survival could possibly explain the lack of association between social adversity and hsCRP in the Latin American samples.


Assuntos
Envelhecimento/fisiologia , Saúde da Criança/estatística & dados numéricos , Inflamação , Idoso , Brasil/epidemiologia , Proteína C-Reativa/análise , Canadá/epidemiologia , Causalidade , Criança , Doença Crônica , Efeito de Coortes , Colômbia/epidemiologia , Estudos Transversais , Feminino , Humanos , Inflamação/sangue , Inflamação/etnologia , Inflamação/fisiopatologia , Masculino , Prevalência , Fatores Socioeconômicos
11.
Microbiol Spectr ; 2(1): OH-0015-2012, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26082109

RESUMO

The emergence of infectious diseases, caused by novel pathogens or the spread of existing ones to new populations and regions, represents a continuous threat to humans and other species. The early detection of emerging human, animal, and plant diseases is critical to preventing the spread of infection and protecting the health of our species and environment. Today, more than 75% of emerging infectious diseases are estimated to be zoonotic and capable of crossing species barriers and diminishing food supplies. Traditionally, surveillance of diseases has relied on a hierarchy of health professionals that can be costly to build and maintain, leading to a delay or interruption in reporting. However, Internet-based surveillance systems bring another dimension to epidemiology by utilizing technology to collect, organize, and disseminate information in a more timely manner. Partially and fully automated systems allow for earlier detection of disease outbreaks by searching for information from both formal sources (e.g., World Health Organization and government ministry reports) and informal sources (e.g., blogs, online media sources, and social networks). Web-based applications display disparate information online or disperse it through e-mail to subscribers or the general public. Web-based early warning systems, such as ProMED-mail, the Global Public Health Intelligence Network (GPHIN), and Health Map, have been able to recognize emerging infectious diseases earlier than traditional surveillance systems. These systems, which are continuing to evolve, are now widely utilized by individuals, humanitarian organizations, and government health ministries.


Assuntos
Doenças Transmissíveis Emergentes/epidemiologia , Doenças Transmissíveis Emergentes/veterinária , Monitoramento Epidemiológico , Internet , Doenças das Plantas , Animais , Saúde Global , Humanos
12.
PLoS One ; 7(12): e51156, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23236444

RESUMO

A dearth of information obscures the true scale of the global illegal trade in wildlife. Herein, we introduce an automated web crawling surveillance system developed to monitor reports on illegally traded wildlife. A resource for enforcement officials as well as the general public, the freely available website, http://www.healthmap.org/wildlifetrade, provides a customizable visualization of worldwide reports on interceptions of illegally traded wildlife and wildlife products. From August 1, 2010 to July 31, 2011, publicly available English language illegal wildlife trade reports from official and unofficial sources were collected and categorized by location and species involved. During this interval, 858 illegal wildlife trade reports were collected from 89 countries. Countries with the highest number of reports included India (n = 146, 15.6%), the United States (n = 143, 15.3%), South Africa (n = 75, 8.0%), China (n = 41, 4.4%), and Vietnam (n = 37, 4.0%). Species reported as traded or poached included elephants (n = 107, 12.5%), rhinoceros (n = 103, 12.0%), tigers (n = 68, 7.9%), leopards (n = 54, 6.3%), and pangolins (n = 45, 5.2%). The use of unofficial data sources, such as online news sites and social networks, to collect information on international wildlife trade augments traditional approaches drawing on official reporting and presents a novel source of intelligence with which to monitor and collect news in support of enforcement against this threat to wildlife conservation worldwide.


Assuntos
Animais Selvagens , Comércio/métodos , Conservação dos Recursos Naturais/métodos , Crime/prevenção & controle , Coleta de Dados/métodos , Internet , Animais , Mineração de Dados/métodos , Mapeamento Geográfico
13.
Clin Exp Optom ; 95(6): 606-14, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22530621

RESUMO

BACKGROUND: Work-related physical discomfort exists within the optometric profession. It is not well understood how optometrists manage this issue in their workplaces. METHOD: An online questionnaire was sent by e-mail to approximately 1,700 Australian optometrists. Participants were asked if they experienced work-related discomfort in any of eight nominated body regions. If so, they were asked to describe specific work tasks, which contribute to their work-related discomfort, and strategies they have adopted to minimise their discomfort. These data were subject to qualitative and quantitative analyses. RESULTS: There was a 25 per cent response rate and 416 optometrists participated in the questionnaire. Work-related physical discomfort was reported by 339 respondents (81 per cent), most commonly with the use of the phoropter (n = 144, 35 per cent) and slitlamp (n = 94, 23 per cent). Males were more likely to report lower back discomfort with phoropter use (Chi-squared, p < 0.01) and ophthalmoscopy (Chi-squared, p < 0.01). To minimise discomfort, optometrists 41 years and older were more likely to report that they adjust their posture (Chi-squared, p < 0.03) and females were more likely to report that they alter their work schedule (Chi-squared, p < 0.05). A recurrent theme expressed by participants was an inability to make changes to improve their comfort due to room and equipment design, poorly maintained equipment, non-supply of suitable equipment or furniture and inherent difficulties within optometric tasks. CONCLUSION: There is a need for all optometrists to have skills to evaluate their own personal risk of discomfort in the consultation room. Owners and managers of optometric practices also need greater awareness of the importance of room and equipment design and maintenance on work-related discomfort. This has implications for the well-being of optometrists, for their productivity and for compliance with health and safety legislation.


Assuntos
Pessoal de Saúde , Necessidades e Demandas de Serviços de Saúde/organização & administração , Mão de Obra em Saúde/estatística & dados numéricos , Optometria , Carga de Trabalho , Adulto , Austrália , Feminino , Humanos , Masculino , Inquéritos e Questionários , Adulto Jovem
14.
J Autism Dev Disord ; 41(2): 185-95, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20556501

RESUMO

The present study explored the relations among lie-telling ability, false belief understanding, and verbal mental age. We found that children with autism spectrum disorder (ASD), like typically developing children, can and do tell antisocial lies (to conceal a transgression) and white lies (in politeness settings). However, children with ASD were less able than typically developing children to cover up their initial lie; that is, children with ASD had difficulty exercising semantic leakage control--the ability to maintain consistency between their initial lie and subsequent statements. Furthermore, unlike in typically developing children, lie-telling ability in children with ASD was not found to be related to their false belief understanding. Future research should examine the underlying processes by which children with ASD tell lies.


Assuntos
Transtornos Globais do Desenvolvimento Infantil/psicologia , Decepção , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Testes Psicológicos
15.
Optom Vis Sci ; 88(2): 317-26, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21187801

RESUMO

PURPOSE: There are anecdotal reports that optometrists suffer work-related physical discomfort but no published reports to support this. METHODS: An on-line questionnaire was sent by e-mail to ∼1700 Australian optometrists. Participants were asked if they experienced work-related discomfort in any of eight nominated body regions, the type and severity of discomfort, self-reported work-related factors contributing to the discomfort, and demographic and work-related information. RESULTS: Four hundred sixteen optometrists participated in the questionnaire. Work-related physical discomfort was reported by 82% of respondents. The most common sites of discomfort were neck, shoulder, and lower back. Univariate analysis revealed that females are more likely to report discomfort than males (p = 0.001) and more likely to report a higher number of discomfort sites (p = 0.002). Multivariate analysis revealed that females have up to a 6.6× [confidence interval (CI) = 2.2-19.9] greater risk of reporting discomfort in individual body locations compared with males and a higher risk of experiencing severe discomfort (discomfort present for >30 days) [odds ratio (OR) = 3.0, CI = 1.7 to 5.5]. A greater number of eye examinations per day increased the risk of reporting work-related discomfort by up to 5.1× (CI = 2.1 to 12.7). Being self-employed and being older than 40 years both appear to be protective factors for work-related discomfort. The risk of experiencing severe discomfort is increased by performing repetitive tasks (OR = 1.9, CI = 1.2 to 3.1) and by continuing to work while injured (OR = 2.9, CI = 1.6 to 5.2). Eliminating both these factors would reduce the disease load for severe discomfort by 28%. CONCLUSIONS: Females, young optometrists, and those conducting a high number of consultations daily have a higher risk of experiencing work-related physical discomfort. Performing repetitive tasks and continuing to work while injured increases the risk of severe discomfort. The results of this investigation have important implications for the longevity of the optometry workforce.


Assuntos
Pessoal de Saúde , Doenças Musculoesqueléticas/epidemiologia , Doenças Profissionais/epidemiologia , Optometria , Dor/epidemiologia , Adulto , Fatores Etários , Austrália/epidemiologia , Feminino , Humanos , Dor Lombar/epidemiologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Cervicalgia/epidemiologia , Doenças Profissionais/fisiopatologia , Razão de Chances , Dor/fisiopatologia , Prevalência , Fatores de Risco , Índice de Gravidade de Doença , Dor de Ombro/epidemiologia , Inquéritos e Questionários , Adulto Jovem
16.
BMC Med Educ ; 10: 94, 2010 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-21176226

RESUMO

BACKGROUND: Physicians today are increasingly faced with healthcare challenges that require an understanding of global health trends and practices, yet little is known about what constitutes appropriate global health training. METHODS: A literature review was undertaken to identify competencies and educational approaches for teaching global health in medical schools. RESULTS: Using a pre-defined search strategy, 32 articles were identified; 11 articles describing 15 global health competencies for undergraduate medical training were found. The most frequently mentioned competencies included an understanding of: the global burden of disease, travel medicine, healthcare disparities between countries, immigrant health, primary care within diverse cultural settings and skills to better interface with different populations, cultures and healthcare systems. However, no consensus on global health competencies for medical students was apparent. Didactics and experiential learning were the most common educational methods used, mentioned in 12 and 13 articles respectively. Of the 11 articles discussing competencies, 8 linked competencies directly to educational approaches. CONCLUSIONS: This review highlights the imperative to document global health educational competencies and approaches used in medical schools and the need to facilitate greater consensus amongst medical educators on appropriate global health training for future physicians.


Assuntos
Competência Clínica , Educação Médica , Saúde Global , Internacionalidade , Consenso , Competência Cultural , Currículo , Humanos , Intercâmbio Educacional Internacional
17.
J Biol Chem ; 280(51): 42454-63, 2005 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-16221665

RESUMO

Notch signaling is a component of a wide variety of developmental processes in many organisms. Notch activity can be modulated by O-fucosylation (mediated by protein O-fucosyltransferase-1) and Fringe, a beta1,3-N-acetylglucosaminyltransferase that modifies O-fucose in the context of epidermal growth factor-like (EGF) repeats. Fringe was initially described in Drosophila, and three mammalian homologues have been identified, Manic fringe, Lunatic fringe, and Radical fringe. Here for the first time we have demonstrated that, similar to Manic and Lunatic, Radical fringe is also a fucose-specific beta1,3-N-acetylglucosaminyltransferase. The fact that three Fringe homologues exist in mammals raises the question of whether and how these enzymes differ. Although Notch contains numerous EGF repeats that are predicted to be modified by O-fucose, previous studies in our laboratory have demonstrated that not all O-fucosylated EGF repeats of Notch are further modified by Fringe, suggesting that the Fringe enzymes can differentiate between them. In this work, we have sought to identify specificity determinants for the recognition of an individual O-fucosylated EGF repeat by the Fringe enzymes. We have also sought to determine differences in the biochemical behavior of the Fringes with regard to their in vitro enzymatic activities. Using both in vivo and in vitro experiments, we have found two amino acids that appear to be important for the recognition of an O-fucosylated EGF repeat by all three mammalian Fringes. These amino acids provide an initial step toward defining sequences that will allow us to predict which O-fucosylated EGF repeats are modified by the Fringes.


Assuntos
Fator de Crescimento Epidérmico/metabolismo , Fucose/metabolismo , Glicosiltransferases/metabolismo , Sequências Repetitivas de Aminoácidos , Sequência de Aminoácidos , Animais , Células CHO , Cricetinae , Glicosiltransferases/química , Dados de Sequência Molecular , Homologia de Sequência de Aminoácidos , Especificidade por Substrato
18.
Mol Cell Biol ; 22(11): 3842-51, 2002 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-11997518

RESUMO

PTEN is mutated at high frequency in many primary human cancers and several familial cancer predisposition disorders. Activation of AKT is a common event in tumors in which the PTEN gene has been inactivated. We previously showed that deletion of the murine Pten gene in embryonic stem (ES) cells led to increased phosphatidylinositol triphosphate (PIP(3)) accumulation, enhanced entry into S phase, and better cell survival. Since PIP(3) controls multiple signaling molecules, it was not clear to what degree the observed phenotypes were due to deregulated AKT activity. In this study, we mutated Akt-1 in Pten(-/-) ES cells to directly assess the role of AKT-1 in PTEN-controlled cellular processes, such as cell proliferation, cell survival, and tumorigenesis in nude mice. We showed that AKT-1 is one of the major downstream effectors of PTEN in ES cells and that activation of AKT-1 is required for both the cell survival and cell proliferation phenotypes observed in Pten(-/-) ES cells. Deletion of Akt-1 partially reverses the aggressive growth of Pten(-/-) ES cells in vivo, suggesting that AKT-1 plays an essential role in PTEN-controlled tumorigenesis.


Assuntos
Neoplasias Experimentais/etiologia , Monoéster Fosfórico Hidrolases/genética , Monoéster Fosfórico Hidrolases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Animais , Divisão Celular , Linhagem Celular , Sobrevivência Celular , Ativação Enzimática , Marcação de Genes , Humanos , Camundongos , Camundongos Knockout , Camundongos Nus , Mitose , Mutação , Neoplasias Experimentais/enzimologia , Neoplasias Experimentais/genética , Neoplasias Experimentais/patologia , PTEN Fosfo-Hidrolase , Fenótipo , Monoéster Fosfórico Hidrolases/deficiência , Proteínas Serina-Treonina Quinases/deficiência , Proteínas Proto-Oncogênicas c-akt , Proteínas Supressoras de Tumor/deficiência
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