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1.
Physiol Meas ; 44(3)2023 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-36753767

RESUMO

Objective.Children with heart failure have higher rates of emergency department utilization, health care expenditure, and hospitalization. Therefore, a need exists for a simple, non-invasive, and inexpensive method of screening for left ventricular (LV) dysfunction. We recently demonstrated the practicality and reliability of a wireless smartphone-based handheld device in capturing carotid pressure waveforms and deriving cardiovascular intrinsic frequencies (IFs) in children with normal LV function. Our goal in this study was to demonstrate that an IF-based machine learning method (IF-ML) applied to noninvasive carotid pressure waveforms can distinguish between normal and abnormal LV ejection fraction (LVEF) in pediatric patients.Approach. Fifty patients ages 0 to 21 years underwent LVEF measurement by echocardiogram or cardiac magnetic resonance imaging. On the same day, patients had carotid waveforms recorded using Vivio. The exclusion criterion was known vascular disease that would interfere with obtaining a carotid artery pulse. We adopted a hybrid IF- Machine Learning (IF-ML) method by applying physiologically relevant IF parameters as inputs to Decision Tree classifiers. The threshold for low LVEF was chosen as <50%.Main results.The proposed IF-ML method was able to detect an abnormal LVEF with an accuracy of 92% (sensitivity = 100%, specificity = 89%, area under the curve (AUC) = 0.95). Consistent with previous clinical studies, the IF parameterω1was elevated among patients with reduced LVEF.Significance.A hybrid IF-ML method applied on a carotid waveform recorded by a hand-held smartphone-based device can differentiate between normal and abnormal LV systolic function in children with normal cardiac anatomy.


Assuntos
Smartphone , Disfunção Ventricular Esquerda , Humanos , Criança , Recém-Nascido , Lactente , Pré-Escolar , Adolescente , Adulto Jovem , Adulto , Reprodutibilidade dos Testes , Disfunção Ventricular Esquerda/diagnóstico , Função Ventricular Esquerda , Volume Sistólico , Artérias Carótidas/diagnóstico por imagem
2.
PLoS One ; 16(6): e0252233, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34077449

RESUMO

Tumor angiogenesis is critical for the growth and progression of cancer. As such, angiostasis is a treatment modality for cancer with potential utility for multiple types of cancer and fewer side effects. However, clinical success of angiostatic monotherapies has been moderate, at best, causing angiostatic treatments to lose their early luster. Previous studies demonstrated compensatory mechanisms that drive tumor vascularization despite the use of angiostatic monotherapies, as well as the potential for combination angiostatic therapies to overcome these compensatory mechanisms. We screened clinically approved angiostatics to identify specific combinations that confer potent inhibition of tumor-induced angiogenesis. We used a novel modification of the ex ovo chick chorioallantoic membrane (CAM) model that combined confocal and automated analyses to quantify tumor angiogenesis induced by glioblastoma tumor onplants. This model is advantageous due to its low cost and moderate throughput capabilities, while maintaining complex in vivo cellular interactions that are difficult to replicate in vitro. After screening multiple combinations, we determined that glioblastoma-induced angiogenesis was significantly reduced using a combination of bevacizumab (Avastin®) and temsirolimus (Torisel®) at doses below those where neither monotherapy demonstrated activity. These preliminary results were verified extensively, with this combination therapy effective even at concentrations further reduced 10-fold with a CI value of 2.42E-5, demonstrating high levels of synergy. Thus, combining bevacizumab and temsirolimus has great potential to increase the efficacy of angiostatic therapy and lower required dosing for improved clinical success and reduced side effects in glioblastoma patients.


Assuntos
Inibidores da Angiogênese/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Membrana Corioalantoide/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Sinergismo Farmacológico , Glioblastoma/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Animais , Bevacizumab/administração & dosagem , Galinhas , Membrana Corioalantoide/patologia , Glioblastoma/irrigação sanguínea , Glioblastoma/patologia , Humanos , Neovascularização Patológica/patologia , Ratos , Sirolimo/administração & dosagem , Sirolimo/análogos & derivados , Células Tumorais Cultivadas
3.
JCI Insight ; 5(12)2020 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-32437334

RESUMO

Abnormal subretinal neovascularization is a characteristic of vision-threatening retinal diseases, including macular telangiectasia (MacTel) and retinal angiomatous proliferation (RAP). Subretinal neovascular tufts and photoreceptor dysfunction are observed in very-low-density lipoprotein receptor (Vldlr-/-) mutant mice. These changes mirror those observed in patients with MacTel and RAP, but the pathogenesis is largely unknown. In this study, we show that retinal microglia were closely associated with retinal neovascular tufts in Vldlr-/- mice and retinal tissue from patients with MacTel; ablation of microglia/macrophages dramatically prevented formation of retinal neovascular tufts and improved neuronal function, as assessed by electroretinography. Vldlr-/- mice with retinal pigmented epithelium-specific (RPE-specific) Vegfa had greatly reduced subretinal infiltration of microglia/macrophages, subsequently reducing neovascular tufts. These findings highlight the contribution of microglia/macrophages to the pathogenesis of neovascularization, provide valuable clues regarding potential causative cellular mechanisms for subretinal neovascularization in patients with MacTel and RAP and suggest that targeting microglia activation may be a therapeutic option in these diseases.


Assuntos
Degeneração Macular/patologia , Microglia/patologia , Neovascularização Retiniana/patologia , Epitélio Pigmentado da Retina/patologia , Animais , Modelos Animais de Doenças , Camundongos Knockout , Neovascularização Patológica/patologia , Retina/patologia , Vasos Retinianos/patologia
4.
J Neurotrauma ; 36(8): 1343-1351, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30343622

RESUMO

This prospective controlled observational cohort study assessed the performance of a novel panel of serum microRNA (miRNA) biomarkers on indicators of concussion, subconcussive impacts, and neurocognitive function in collegiate football players over the playing season. Male collegiate student football athletes participating in a Division I Football Bowl Subdivision of the National Collegiate Athletic Association (NCAA) were enrolled. There were a total of 53 participants included in the study, 30 non-athlete control subjects and 23 male collegiate student football athletes. Neurocognitive assessments and blood samples were taken within the week before the athletic season began and within the week after the last game of the season and measured for a panel of pre-selected miRNA biomarkers. All the athletes had elevated levels of circulating miRNAs at the beginning of the season compared with control subjects (p < 0.001). Athletes with the lowest standard assessment of concussion (SAC) scores at the beginning of the season had the highest levels of miRNAs. The area under the curve (AUC) for predicting pre-season SAC scores were miR-195 (0.90), miR-20a (0.89), miR-151-5p (0.86), miR-505* (0.85), miR-9-3p (0.77), and miR-362-3p (0.76). In athletes with declining neurocognitive function over the season, concentrations of miRNAs increased over same period. There were significant negative correlations with miR-505* (p = 0.011), miR-30d (p = 0.007), miR-92 (p = 0.033), and (p = 0.008). The miRNAs correlating with balance problems were miR-505* (p = 0.007), miR-30d (p = 0.028), and miR-151-5p (p = 0.023). Those correlating with poor reaction times were miR-20a (0.043), miR-505* (p = 0.049), miR-30d (p = 0.031), miR-92 (p = 0.015), and miR-151-5p (p = 0.044). Select miRNAs were associated with baseline concussion assessments at the beginning of the season and with neurocognitive changes from pre to post-season in collegiate football players. Should these findings be replicated in a larger cohort of athletes, these markers could potentially serve as measures of neurocognitive status in athletes at risk for concussion and subconcussive injuries.


Assuntos
Biomarcadores/sangue , Concussão Encefálica/sangue , Futebol Americano/lesões , RNA Mensageiro/sangue , Atletas , Estudos de Coortes , Humanos , Masculino , Estudos Prospectivos , Recuperação de Função Fisiológica/fisiologia , Adulto Jovem
5.
Elife ; 52016 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-26978795

RESUMO

Photoreceptors are the most numerous and metabolically demanding cells in the retina. Their primary nutrient source is the choriocapillaris, and both the choriocapillaris and photoreceptors require trophic and functional support from retinal pigment epithelium (RPE) cells. Defects in RPE, photoreceptors, and the choriocapillaris are characteristic of age-related macular degeneration (AMD), a common vision-threatening disease. RPE dysfunction or death is a primary event in AMD, but the combination(s) of cellular stresses that affect the function and survival of RPE are incompletely understood. Here, using mouse models in which hypoxia can be genetically triggered in RPE, we show that hypoxia-induced metabolic stress alone leads to photoreceptor atrophy. Glucose and lipid metabolism are radically altered in hypoxic RPE cells; these changes impact nutrient availability for the sensory retina and promote progressive photoreceptor degeneration. Understanding the molecular pathways that control these responses may provide important clues about AMD pathogenesis and inform future therapies.


Assuntos
Células Epiteliais/fisiologia , Hipóxia , Degeneração Macular/fisiopatologia , Células Fotorreceptoras/fisiologia , Epitélio Pigmentado da Retina/fisiologia , Estresse Fisiológico , Animais , Modelos Animais de Doenças , Camundongos
6.
Stem Cells Int ; 2016: 8470263, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26880994

RESUMO

Phototransduction is accomplished in the retina by photoreceptor neurons and retinal pigment epithelium (RPE) cells. Photoreceptors rely heavily on the RPE, and death or dysfunction of RPE is characteristic of age-related macular degeneration (AMD), a very common neurodegenerative disease for which no cure exists. RPE replacement is a promising therapeutic intervention for AMD, and large numbers of RPE cells can be generated from pluripotent stem cells. However, questions persist regarding iPSC-derived RPE (iPS-RPE) viability, immunogenicity, and tumorigenesis potential. We showed previously that iPS-RPE prevent photoreceptor atrophy in dystrophic rats up until 24 weeks after implantation. In this follow-up study, we longitudinally monitored the same implanted iPS-RPE, in the same animals. We observed no gross abnormalities in the eyes, livers, spleens, brains, and blood in aging rats with iPSC-RPE grafts. iPS-RPE cells that integrated into the subretinal space outlived the photoreceptors and survived for as long as 2 1/2 years while nonintegrating RPE cells were ingested by host macrophages. Both populations could be distinguished using immunohistochemistry and electron microscopy. iPSC-RPE could be isolated from the grafts and maintained in culture; these cells also phagocytosed isolated photoreceptor outer segments. We conclude that iPS-RPE grafts remain viable and do not induce any obvious associated pathological changes.

7.
J Vis Exp ; (95): 52247, 2015 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-25651341

RESUMO

The conversion of light into electrical impulses occurs in the outer retina and is accomplished largely by rod and cone photoreceptors and retinal pigment epithelium (RPE) cells. RPE provide critical support for photoreceptors and death or dysfunction of RPE cells is characteristic of age-related macular degeneration (AMD), the leading cause of permanent vision loss in people age 55 and older. While no cure for AMD has been identified, implantation of healthy RPE in diseased eyes may prove to be an effective treatment, and large numbers of RPE cells can be readily generated from pluripotent stem cells. Several interesting questions regarding the safety and efficacy of RPE cell delivery can still be examined in animal models, and well-accepted protocols used to inject RPE have been developed. The technique described here has been used by multiple groups in various studies and involves first creating a hole in the eye with a sharp needle. Then a syringe with a blunt needle loaded with cells is inserted through the hole and passed through the vitreous until it gently touches the RPE. Using this injection method, which is relatively simple and requires minimal equipment, we achieve consistent and efficient integration of stem cell-derived RPE cells in between the host RPE that prevents significant amount of photoreceptor degeneration in animal models. While not part of the actual protocol, we also describe how to determine the extent of the trauma induced by the injection, and how to verify that the cells were injected into the subretinal space using in vivo imaging modalities. Finally, the use of this protocol is not limited to RPE cells; it may be used to inject any compound or cell into the subretinal space.


Assuntos
Epitélio Pigmentado da Retina/citologia , Epitélio Pigmentado da Retina/transplante , Animais , Modelos Animais de Doenças , Injeções/métodos , Degeneração Macular/terapia , Camundongos , Células Fotorreceptoras , Células-Tronco Pluripotentes , Ratos , Tomografia de Coerência Óptica/métodos
8.
Appl Physiol Nutr Metab ; 38(6): 681-8, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23724887

RESUMO

It has been postulated that fructose-induced triglyceride synthesis is augmented when accompanied by glucose. Chronic elevations could lead to excess fat accumulation in the liver and ectopic fat deposition in muscles, which in turn could contribute to the induction of abnormalities in glucose homeostasis, insulin resistance, and the subsequent development of type 2 diabetes. Our objective was to evaluate the effect of the addition of commonly consumed fructose- and (or) glucose-containing sugars in the usual diet on liver fat content and intramuscular adipose tissue. For 10 weeks, 64 individuals (mean age, 42.16 ± 11.66 years) consumed low-fat milk sweetened with either high-fructose corn syrup (HFCS) or sucrose; the added sugar matched consumption levels of fructose in the 25th, 50th, and 90th percentiles of the population. The fat content of the liver was measured with unenhanced computed tomography imaging, and the fat content of muscle was assessed with magnetic resonance imaging. When the 6 HFCS and sucrose groups were averaged, there was no change over the course of 10 weeks in the fat content of the liver (13.32% ± 10.49% vs. 13.21% ± 10.75%; p > 0.05), vastus lateralis muscle (3.07 ± 0.74 g per 100 mL vs. 3.15 ± 0.84 g per 100 mL; p > 0.05), or gluteus maximus muscle (4.08 ± 1.50 g per 100 mL vs. 4.24 ± 1.42 g per 100 mL; p > 0.05). Group assignment did not affect the result (interaction > 0.05). These data suggest that when fructose is consumed as part of a typical diet in normally consumed sweeteners, such as sucrose or HFCS, ectopic fat storage in the liver or muscles is not promoted.


Assuntos
Frutose , Xarope de Milho Rico em Frutose , Diabetes Mellitus Tipo 2 , Frutose/farmacologia , Humanos , Fígado/efeitos dos fármacos , Obesidade , Sacarose , Edulcorantes , Zea mays
9.
J Clin Invest ; 122(11): 4213-7, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23093773

RESUMO

Current therapies directed at controlling vascular abnormalities in cancers and neovascular eye diseases target VEGF and can slow the progression of these diseases. While the critical role of VEGF in development has been well described, the function of locally synthesized VEGF in the adult eye is incompletely understood. Here, we show that conditionally knocking out Vegfa in adult mouse retinal pigmented epithelial (RPE) cells, which regulate retinal homeostasis, rapidly leads to vision loss and ablation of the choriocapillaris, the major blood supply for the outer retina and photoreceptor cells. This deletion also caused rapid dysfunction of cone photoreceptors, the cells responsible for fine visual acuity and color vision. Furthermore, Vegfa deletion showed significant downregulation of multiple angiogenic genes in both physiological and pathological states, whereas the deletion of the upstream regulatory transcriptional factors HIFs did not affect the physiological expressions of angiogenic genes. These results suggest that endogenous VEGF provides critical trophic support necessary for retinal function. Targeting factors upstream of VEGF, such as HIFs, may be therapeutically advantageous compared with more potent and selective VEGF antagonists, which may have more off-target inhibitory trophic effects.


Assuntos
Cegueira , Proteínas do Olho/metabolismo , Células Fotorreceptoras Retinianas Cones , Epitélio Pigmentado da Retina , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Cegueira/genética , Cegueira/metabolismo , Cegueira/patologia , Proteínas do Olho/genética , Deleção de Genes , Camundongos , Camundongos Transgênicos , Células Fotorreceptoras Retinianas Cones/metabolismo , Células Fotorreceptoras Retinianas Cones/patologia , Epitélio Pigmentado da Retina/metabolismo , Epitélio Pigmentado da Retina/patologia , Fator A de Crescimento do Endotélio Vascular/genética
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