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BACKGROUND: There is ambiguity regarding the role of left ventricle wall motion abnormalities (LVWMAs) as a potential cardioembolic source in patients, who satisfy embolic stroke of undetermined source (ESUS) criteria. METHODS AND RESULTS: We analyzed prospectively collected data in 345 acute stroke patients, 185 (53.6%) stroke with atrial fibrillation (SwAF), and 160 (46.4%) stroke with LVWMA. LVWMA were younger (Pâ¯=â¯.003), had significantly higher frequency of stroke risk factors and lower ejection fraction (P < .001). No significant difference was found between the stroke pattern in SwAF and LVWMA except focal cortical, cortical-subcortical lesions were more frequent in LVWMA (Pâ¯=â¯.002). Mean wall motion score index (WMSI) was 1.523 (range 1.05-2.71) without any correlation between the severity of WMSI and multiple strokes (Pâ¯=â¯.976). In subgroup analyses vertical basal WMSI (Pâ¯=â¯.030) and vertical mid cavity WMSI (Pâ¯=â¯.010) was significantly related to branch arterial stroke. LVWMA 94 (65%) patients were on antiplatelet/anticoagulation compared to 47 (52.4%) with atrial fibrillation (AF), with no significant difference in stroke recurrence during 4 years follow-up (Pâ¯=â¯.15). CONCLUSIONS: Patients with LVWMA who satisfy ESUS criteria, have stroke pattern on diffusion-weighted magnetic resonance imaging and risk of stroke recurrence similar to AF-related stroke despite being on appropriate antiplatelet medications. Further studies with anticoagulation therapy may be required in this group of patients to improve the high risk of recurrent stroke.
Assuntos
Fibrilação Atrial/complicações , Embolia Intracraniana/etiologia , Acidente Vascular Cerebral/etiologia , Disfunção Ventricular Esquerda/complicações , Função Ventricular Esquerda , Idoso , Anticoagulantes/uso terapêutico , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/fisiopatologia , Imagem de Difusão por Ressonância Magnética , Feminino , Humanos , Embolia Intracraniana/diagnóstico por imagem , Embolia Intracraniana/prevenção & controle , Masculino , Pessoa de Meia-Idade , Inibidores da Agregação Plaquetária/uso terapêutico , Valor Preditivo dos Testes , Recidiva , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/prevenção & controle , Fatores de Tempo , Resultado do Tratamento , Disfunção Ventricular Esquerda/diagnóstico , Disfunção Ventricular Esquerda/tratamento farmacológico , Disfunção Ventricular Esquerda/fisiopatologiaRESUMO
Purpose: To quantify relevant fundus autofluorescence (FAF) image features cross-sectionally and longitudinally in a large cohort of inherited retinal diseases (IRDs) patients. Design: Retrospective study of imaging data (55-degree blue-FAF on Heidelberg Spectralis) from patients. Participants: Patients with a clinical and molecularly confirmed diagnosis of IRD who have undergone FAF 55-degree imaging at Moorfields Eye Hospital (MEH) and the Royal Liverpool Hospital (RLH) between 2004 and 2019. Methods: Five FAF features of interest were defined: vessels, optic disc, perimacular ring of increased signal (ring), relative hypo-autofluorescence (hypo-AF) and hyper-autofluorescence (hyper-AF). Features were manually annotated by six graders in a subset of patients based on a defined grading protocol to produce segmentation masks to train an AI model, AIRDetect, which was then applied to the entire imaging dataset. Main Outcome Measures: Quantitative FAF imaging features including area in mm 2 and vessel metrics, were analysed cross-sectionally by gene and age, and longitudinally to determine rate of progression. AIRDetect feature segmentation and detection were validated with Dice score and precision/recall, respectively. Results: A total of 45,749 FAF images from 3,606 IRD patients from MEH covering 170 genes were automatically segmented using AIRDetect. Model-grader Dice scores for disc, hypo-AF, hyper-AF, ring and vessels were respectively 0.86, 0.72, 0.69, 0.68 and 0.65. The five genes with the largest hypo-AF areas were CHM , ABCC6 , ABCA4 , RDH12 , and RPE65 , with mean per-patient areas of 41.5, 30.0, 21.9, 21.4, and 15.1 mm 2 . The five genes with the largest hyper-AF areas were BEST1 , CDH23 , RDH12 , MYO7A , and NR2E3 , with mean areas of 0.49, 0.45, 0.44, 0.39, and 0.34 mm 2 respectively. The five genes with largest ring areas were CDH23 , NR2E3 , CRX , EYS and MYO7A, with mean areas of 3.63, 3.32, 2.84, 2.39, and 2.16 mm 2 . Vessel density was found to be highest in EFEMP1 , BEST1 , TIMP3 , RS1 , and PRPH2 (10.6%, 10.3%, 9.8%, 9.7%, 8.9%) and was lower in Retinitis Pigmentosa (RP) and Leber Congenital Amaurosis genes. Longitudinal analysis of decreasing ring area in four RP genes ( RPGR, USH2A, RHO, EYS ) found EYS to be the fastest progressor at -0.18 mm 2 /year. Conclusions: We have conducted the first large-scale cross-sectional and longitudinal quantitative analysis of FAF features across a diverse range of IRDs using a novel AI approach.
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PURPOSE: The possible adverse health effects of low-dose radiation (LDR) exposure constitute a growing concern. Clinically and environmentally relevant exposures occur predominantly under chronic conditions, notwithstanding that most studies of LDR effects have been performed using a single acute exposure. Sex- and tissue-specificity of the LDR-induced changes have not been considered before. We investigated LDR-related expression patterns in muscle, liver and spleen of male and female mice subjected to acute and chronic LDR exposure. Genes involved in oncogenic signaling were of specific interest, as radiation is a well-known carcinogen. MATERIALS AND METHODS: We analyzed the expression pattern of genes coding for growth factors and growth-factor receptors, cytoplasmic serine/threonine protein kinases, G-proteins and nuclear DNA-binding proteins, and other important components of oncogenic signaling. RESULTS: We found sex- and tissue-specific changes in the expression of Ras superfamily members (Nras, Rab2, Rab34, Vav2), protein kinase C (PKC) isoforms (PKCbeta, PKCmu), AP-1 factor components (Jun, JunB and FosB), Wnt signaling pathway members as well as in a variety of other cellular proto-oncogenes and oncogenes. Importantly, Western blot analysis of JunB, PKCmu and Rab2 proteins supported the transcriptomic data. CONCLUSIONS: Substantially different protein levels were observed in all three tissues (muscle, spleen and liver) of acutely and chronically irradiated female and male animals. Based on the obtained data and available literature, we discuss several possible mechanisms that may contribute to radiation-induced carcinogenesis in various tissues of males and females. From our results we could identify the genes that may serve as sex- and tissue-specific biomarkers of the LDR exposure.
Assuntos
Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Fígado/metabolismo , Músculos/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias Induzidas por Radiação/metabolismo , Transdução de Sinais/efeitos da radiação , Baço/metabolismo , Adaptação Fisiológica/efeitos da radiação , Animais , Relação Dose-Resposta à Radiação , Feminino , Fígado/efeitos da radiação , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculos/efeitos da radiação , Especificidade de Órgãos/efeitos da radiação , Doses de Radiação , Baço/efeitos da radiação , Distribuição TecidualRESUMO
The phenoxy herbicides 2,4-D and dicamba are released daily into the environment in large amount. The mechanisms of genotoxicity and mutagenicity of these herbicides are poorly understood, and the available genotoxicity data is controversial. There is a cogent need for a novel genotoxicity monitoring system that could provide both reliable information at the molecular level, and complement existing systems.We employed the transgenic Arabidopsis thaliana 'point mutation' and 'recombination' plants to monitor the genetic effects of the herbicides 2,4-D and dicamba. We found that both herbicides had a significant effect on the frequency of homologous recombination A-->G mutation. Neither herbicides affected the T-->G mutation frequency. Interestingly, these transgenic biomonitoring plants were able to detect the presence of phenoxy herbicides at concentrations that were lower than the guideline levels for Drinking Water Quality. The results of our studies suggest that our transgenic system may be ideal for the evaluation of the genotoxicity of herbicide-contaminated water. Moreover, the unique ability of the plants to detect both double-strand breaks (homologous recombination) and point mutations provides tremendous potential in the study of molecular mechanisms of genotoxicity and mutagenicity of phenoxy herbicides.
Assuntos
Ácido 2,4-Diclorofenoxiacético/toxicidade , Arabidopsis/efeitos dos fármacos , Dicamba/toxicidade , Mutagênicos/toxicidade , Plantas Geneticamente Modificadas/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Arabidopsis/genética , Monitoramento Ambiental/métodos , Plantas Geneticamente Modificadas/genética , Mutação Puntual , Recombinação Genética , TransgenesRESUMO
Adaptation is a complex process by which populations of organisms respond to long-term environmental stresses by permanent genetic change. Here we present data from the natural "open-field" radiation adaptation experiment after the Chernobyl accident and provide the first evidence of the involvement of epigenetic changes in adaptation of a eukaryote-Scots pine (Pinus silvestris), to chronic radiation exposure. We have evaluated global genome methylation of control and radiation-exposed pine trees using a method based on cleavage by a methylation-sensitive HpaII restriction endonuclease that leaves a 5' guanine overhang and subsequent single nucleotide extension with labeled [3H] dCTP. We have found that genomic DNA of exposed pine trees was considerably hypermethylated. Moreover, hypermethylation appeared to be dependent upon the radiation dose absorbed by the trees. Such hypermethylation may be viewed as a defense strategy of plants that prevents genome instability and reshuffling of the hereditary material, allowing survival in an extreme environment. Further studies are clearly needed to analyze in detail the involvement of DNA methylation and other epigenetic mechanisms in the complex process of radiation stress and adaptive response.
Assuntos
Metilação de DNA/efeitos da radiação , Genoma de Planta , Pinus/genética , Pinus/efeitos da radiação , Tolerância a Radiação , Liberação Nociva de Radioativos , Aclimatação , DNA de Plantas/efeitos da radiação , UcrâniaRESUMO
The biological and genetic effects of chronic low-dose radiation (LDR) exposure and its relationship to carcinogenesis have received a lot of attention in the recent years. For example, radiation-induced genome instability, which is thought to be a precursor of tumorogenesis, was shown to have a transgenerational nature. This indicates a possible involvement of epigenetic mechanisms in LDR-induced genome instability. Genomic DNA methylation is one of the most important epigenetic mechanisms. Existing data on radiation effects on DNA methylation patterns is limited, and no one has specifically studied the effects of the LDR. We report the first study of the effects of whole-body LDR exposure on global genome methylation in muscle and liver tissues of male and female mice. In parallel, we evaluated changes in promoter methylation and expression of the tumor suppressor gene p16(INKa) and DNA repair gene O(6)-methylguanine-DNA methyltransferase (MGMT). We observed different patterns of radiation-induced global genome DNA methylation in the liver and muscle of exposed males and females. We also found sex and tissue-specific differences in p16(INKa) promoter methylation upon LDR exposure. In male liver tissue, p16(INKa) promoter methylation was more pronounced than in female tissue. In contrast, no significant radiation-induced changes in p16(INKa) promoter methylation were noted in the muscle tissue of exposed males and females. Radiation also did not significantly affect methylation status of MGMT promoter. We also observed substantial sex differences in acute and chronic radiation-induced expression of p16(INKa) and MGMT genes. Another important outcome of our study was the fact that chronic low-dose radiation exposure proved to be a more potent inducer of epigenetic effects than the acute exposure. This supports previous findings that chronic exposure leads to greater genome destabilization than acute exposure.
Assuntos
Metilação de DNA , Regulação Neoplásica da Expressão Gênica , Fígado/efeitos da radiação , Músculos/efeitos da radiação , Regiões Promotoras Genéticas , Animais , Inibidor p16 de Quinase Dependente de Ciclina/genética , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , DNA/metabolismo , Reparo do DNA , DNA de Neoplasias/metabolismo , Relação Dose-Resposta à Radiação , Feminino , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculos/metabolismo , O(6)-Metilguanina-DNA Metiltransferase/genética , O(6)-Metilguanina-DNA Metiltransferase/metabolismo , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Irradiação Corporal TotalRESUMO
Herbicides, such as atrazine, are extensively used in agriculture in order to suppress growth of weeds. From the soil they inevitably find their way to water supplies, leading to human exposure via drinking water. Therefore, it is extremely important to know whether those chemicals pose any hazard to public health. The genotoxicity of atrazine has been a subject of studies in recent years. However, the data that are currently available are inconclusive. There is a need to examine the genotoxicity of low, environmentally relevant concentrations that are currently assumed to be safe. Up to date, studying the genotoxicity of low concentrations of atrazine has constituted a great challenge due to the lack of appropriate, sensitive test systems. In the present work, we used a new sensitive transgenic plant-based system to study the genotoxicity and mutagenicity of atrazine present at minute concentrations in the liquid media. This system gave us an opportunity to monitor the two main types of rearrangements, the frequency of homologous recombination and point mutations, which are indicators of the genotoxicity of atrazine. Atrazine present at low concentrations was found to be a strong inducer of homologous recombination. On the other hand, it did not have a significant influence on the levels of A --> G and T --> G mutations. These results suggest that the transgenic plant-based biomonitoring system is a useful tool for analyzing the genotoxicity of water contaminated by atrazine. In the future this system can be used to study molecular mechanisms of genotoxicity and mutagenicity atrazine and other triazine herbicides.