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BACKGROUND: The increasing prevalence of atrial fibrillation (AF) and chronic kidney diseases highlights the need for a deeper comprehension of the molecular mechanisms linking them. Mutations in PKD1, the gene encoding Polycystin-1 (PKD1 or PC1), account for 85% of autosomal dominant polycystic kidney disease (ADPKD) cases. This disease often includes cardiac complications such as AF. In cardiomyocytes, PC1 deletion reduces hypertrophic response to pressure overload but promotes baseline ventricular dysfunction, while deletion in fibroblasts ameliorates post-myocardial infarction fibrosis. Despite its known cardiac impact, the role of PC1 in atrial cardiomyocytes and arrhythmias is less understood. Here, we sought to investigate the role of PC1 in AF. METHODS: We used intracardiac programmed stimulation and optical mapping to evaluate AF inducibility in two mouse models, Pkd1 R3277C, which recapitulates human ADPKD progression, and cardiomyocyte-specific Pkd1 deletion, and their respective controls. Isolated adult mouse atrial cardiomyocytes, human iPSC-derived atrial cardiomyocytes (hiPSC-aCM), and HL-1 cells served as in vitro cellular models. Molecular mechanisms were evaluated using optical mapping and molecular and biochemical approaches. RESULTS: Loss-of-function PC1 mutations significantly increased AF susceptibility in vivo and facilitated local reentry in ex vivo left atrial appendages. Comprehensive in vitro experiments supported a direct effect of PC1 in atrial cardiomyocytes. PC1-deficient monolayers exhibited increased arrhythmic events, escalating into reentrant spiral waves post-tachypacing. Transcriptomics analysis revealed PC1-dependent regulation of DNA repair, with PC1 deficiency leading to increased DNA damage under stress. PARP1 inhibitors or nicotinamide riboside, which counteract DNA damage-related metabolic consequences, reduced in vitro arrhythmias PC1-deficient monolayers. Overexpression of the C-terminus of PC1 had the opposite effects in DNA repair genes, suggesting its regulatory effects in atrial cardiomyocytes through retinoblastoma/E2F. Analyses of human atrial tissue from non-ADPKD patients showed reduced levels of mature PC1, suggesting a broader relevance of impaired PC1 in AF. CONCLUSIONS: Impaired PC1 increases in vivo AF inducibility under programmed electrical stimulation and promotes in vitro arrhythmias in hiPSC-aCM and HL-1 cells. Our findings indicate that PC1 protects against DNA damage to reduce AF susceptibility.
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ABSTRACT: Fiedler, MJ, Triplett, NT, Hamilton, KC, Needle, AR, and van Werkhoven, H. The effect of different weight plate widths (bumper vs. standard) on the biomechanics of the bench press. J Strength Cond Res 38(4): e143-e149, 2024-Anecdotal evidence suggests that bumper plates impact lifts in powerlifting and weightlifting differently than standard cast iron plates, but whether biomechanical differences exist between lifts using bumper versus standard plates has not been investigated. Eleven resistance-trained subjects performed the bench press at 70, 80, and 90% of their 1 repetition maximum (1RM) while being blinded to whether they were lifting with bumper or standard plates. Motion data were captured by an 8-camera motion capture system, and electromyography (EMG) data were recorded for the anterior deltoid, pectoralis major, and triceps brachii. Repeated-measures analysis of variances showed a significant main weight effect for time under tension (p < 0.001), total work (p < 0.001), and muscle activity through EMG (across all muscles; p < 0.001) and a significant weight × joint interaction effect for average joint moment (p < 0.001) and peak joint moment (p < 0.001). However, there were no significant differences observed between the different weight plates for any of the measures. The main finding of the study suggests that there are no biomechanical differences between using bumper plates compared with standard plates during the bench press lift.
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Músculo Esquelético , Treinamento Resistido , Humanos , Fenômenos Biomecânicos , Músculo Esquelético/fisiologia , Músculos Peitorais/fisiologia , Eletromiografia , Levantamento de Peso/fisiologia , Força Muscular/fisiologiaRESUMO
Heart failure (HF) remains a leading cause of death worldwide, with increasing prevalence and burden. Despite extensive research, a cure for HF remains elusive. Traditionally, the study of HF's pathogenesis and therapies has relied heavily on animal experimentation. However, these models have limitations in recapitulating the full spectrum of human HF, resulting in challenges for clinical translation. To address this translational gap, research employing human cells, especially cardiomyocytes derived from human-induced pluripotent stem cells (hiPSC-CMs), offers a promising solution. These cells facilitate the study of human genetic and molecular mechanisms driving cardiomyocyte dysfunction and pave the way for research tailored to individual patients. Further, engineered heart tissues combine hiPSC-CMs, other cell types, and scaffold-based approaches to improve cardiomyocyte maturation. Their tridimensional architecture, complemented with mechanical, chemical, and electrical cues, offers a more physiologically relevant environment. This review explores the advantages and limitations of conventional and innovative methods used to study HF pathogenesis, with a primary focus on ischemic HF due to its relative ease of modeling and clinical relevance. We emphasize the importance of a collaborative approach that integrates insights obtained in animal and hiPSC-CMs-based models, along with rigorous clinical research, to dissect the mechanistic underpinnings of human HF. Such an approach could improve our understanding of this disease and lead to more effective treatments.
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Insuficiência Cardíaca , Células-Tronco Pluripotentes Induzidas , Animais , Humanos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Insuficiência Cardíaca/terapia , Insuficiência Cardíaca/metabolismoRESUMO
The aim of this systematic review was to perform qualitative and quantitative analysis on the toxic effects of chloroquine (CQ) and hydroxychloroquine (HCQ) on skeletal muscles. We designed the study according to PRISMA guidelines. Studies for qualitative and quantitative analyses were selected according to the following inclusion criteria: English language; size of sample (> 5 patients), adult (> age of 18) patients, treated with CQ/HCQ for inflammatory diseases, and presenting and not presenting with toxic effects on skeletal muscles. We collected data published from 1990 to April 2020 using PubMed, Cochrane Library, EMBASE, and SciELO. Risk of bias for observational studies was assessed regarding the ROBIN-I scale. Studies with less than five patients (case reports) were selected for an additional qualitative analysis. We used the software Comprehensive Meta-Analysis at the confidence level of 0.05. We identified 23 studies for qualitative analysis (17 case-reports), and five studies were eligible for quantitative analysis. From case reports, 21 patients presented muscle weakness and confirmatory biopsy for CQ/HCQ induced myopathy. From observational studies, 37 patients out of 1,367 patients from five studies presented muscle weakness related to the use of CQ/HCQ, and 252 patients presented elevated levels of muscle enzymes (aldolase, creatine phosphokinase, and lactate dehydrogenase). Four studies presented data on 34 patients with confirmatory biopsy for drug-induced myopathy. No study presented randomized samples. The chronic use of CQ/HCQ may be a risk for drug-induced myopathy. There is substantiated need for proper randomized trials and controlled prospective studies needed to assess the clinical and subclinical stages of CQ/HCQ -induced muscle myopathy.
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Hidroxicloroquina/toxicidade , Debilidade Muscular/etiologia , Músculo Esquelético/efeitos dos fármacos , Adulto , Idoso , Creatina Quinase/metabolismo , Frutose-Bifosfato Aldolase/metabolismo , Humanos , Hidroxicloroquina/administração & dosagem , Hidroxicloroquina/efeitos adversos , L-Lactato Desidrogenase/metabolismo , Pessoa de Meia-Idade , Debilidade Muscular/epidemiologia , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Estudos Observacionais como AssuntoRESUMO
Volumetric muscle loss injuries overwhelm the endogenous regenerative capacity of skeletal muscle, and the associated oxidative damage can delay regeneration and prolong recovery. This study aimed to investigate the effect of silicon-ions on C2C12 skeletal muscle cells under normal and excessive oxidative stress conditions to gain insights into its role on myogenesis during the early stages of muscle regeneration. In vitro studies indicated that 0.1 mM Si-ions into cell culture media significantly increased cell viability, proliferation, migration, and myotube formation compared to control. Additionally, MyoG, MyoD, Neurturin, and GABA expression were significantly increased with addition of 0.1, 0.5, and 1.0 mM of Si-ion for 1 and 5 days of C2C12 myoblast differentiation. Furthermore, 0.1-2.0 mM Si-ions attenuated the toxic effects of H2O2 within 24 h resulting in increased cell viability and differentiation. Addition of 1.0 mM of Si-ions significantly aid cell recovery and protected from the toxic effect of 0.4 mM H2O2 on cell migration. These results suggest that ionic silicon may have a potential effect in unfavorable situations where reactive oxygen species is predominant affecting cell viability, proliferation, migration, and differentiation. Furthermore, this study provides a guide for designing Si-containing biomaterials with desirable Si-ion release for skeletal muscle regeneration.
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Músculo Esquelético/fisiologia , Mioblastos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Regeneração/efeitos dos fármacos , Silício/farmacologia , Animais , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Íons/química , Íons/farmacologia , Camundongos , Desenvolvimento Muscular/efeitos dos fármacos , Desenvolvimento Muscular/genética , Músculo Esquelético/citologia , Músculo Esquelético/metabolismo , Proteína MyoD/genética , Proteína MyoD/metabolismo , Mioblastos/metabolismo , Mioblastos/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Regeneração/genéticaAssuntos
Previsões , Política de Saúde/tendências , Competição Econômica , Política de Saúde/legislação & jurisprudência , Cobertura do Seguro/legislação & jurisprudência , Pessoas sem Cobertura de Seguro de Saúde/estatística & dados numéricos , Patient Protection and Affordable Care Act/tendências , Sistema de Fonte Pagadora Única/legislação & jurisprudência , Estados UnidosRESUMO
This study explores the potential to reach a circular economy for post-consumer Recycled Polyethylene Terephthalate (rPET) packaging and bottles by using it as a Distributed Recycling for Additive Manufacturing (DRAM) feedstock. Specifically, for the first time, rPET water bottle flake is processed using only an open source toolchain with Fused Particle Fabrication (FPF) or Fused Granular Fabrication (FGF) processing rather than first converting it to filament. In this study, first the impact of granulation, sifting, and heating (and their sequential combination) is quantified on the shape and size distribution of the rPET flakes. Then 3D printing tests were performed on the rPET flake with two different feed systems: an external feeder and feed tube augmented with a motorized auger screw, and an extruder-mounted hopper that enables direct 3D printing. Two Gigabot X machines were used, each with the different feed systems, and one without and the latter with extended part cooling. 3D print settings were optimized based on thermal characterization, and both systems were shown to 3D print rPET directly from shredded water bottles. Mechanical testing showed the importance of isolating rPET from moisture and that geometry was important for uniform extrusion. The mechanical strength of 3D-printed parts with FPF and inconsistent flow is lower than optimized fused filament, but adequate for a wide range of applications. Future work is needed to improve consistency and enable water bottles to be used as a widespread DRAM feedstock.
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The Affordable Care Act required most people to obtain health insurance or pay a tax penalty. Legislation enacted in December 2017 effectively repealed that requirement, starting in 2019. This article reviews recent research on the mandate's effects, concluding that the mandate meaningfully increased insurance coverage, but likely by less than was projected before implementation. These coverage gains are likely to erode as mandate repeal takes hold. Looking ahead, policy makers have many options for expanding insurance coverage without restoring an individual mandate. However, achieving universal coverage without some form of mandatory individual contribution to health insurance would have a very large fiscal cost.
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Cobertura do Seguro , Patient Protection and Affordable Care Act , Previsões , Humanos , Seguro Saúde , Estados Unidos , Cobertura Universal do Seguro de SaúdeRESUMO
Fused particle fabrication (FPF) (or fused granular fabrication (FGF)) has potential for increasing recycled polymers in 3-D printing. Here, the open source Gigabot X is used to develop a new method to optimize FPF/FGF for recycled materials. Virgin polylactic acid (PLA) pellets and prints were analyzed and were then compared to four recycled polymers including the two most popular printing materials (PLA and acrylonitrile butadiene styrene (ABS)) as well as the two most common waste plastics (polyethylene terephthalate (PET) and polypropylene (PP)). The size characteristics of the various materials were quantified using digital image processing. Then, power and nozzle velocity matrices were used to optimize the print speed, and a print test was used to maximize the output for a two-temperature stage extruder for a given polymer feedstock. ASTM type 4 tensile tests were used to determine the mechanical properties of each plastic when they were printed with a particle drive extruder system and were compared with filament printing. The results showed that the Gigabot X can print materials 6.5× to 13× faster than conventional printers depending on the material, with no significant reduction in the mechanical properties. It was concluded that the Gigabot X and similar FPF/FGF printers can utilize a wide range of recycled polymer materials with minimal post processing.
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Financiamento Governamental/legislação & jurisprudência , Cobertura do Seguro/legislação & jurisprudência , Seguro Saúde/legislação & jurisprudência , Patient Protection and Affordable Care Act/legislação & jurisprudência , Governo Federal , Financiamento da Assistência à Saúde , Cobertura do Seguro/economia , Seguro Saúde/economia , Medicaid/legislação & jurisprudência , Política , Governo Estadual , Estados UnidosAssuntos
Cobertura do Seguro/economia , Seguro Saúde/organização & administração , Patient Protection and Affordable Care Act/organização & administração , Política , Custo Compartilhado de Seguro , Seguro , Seguro Saúde/economia , Seguro Saúde/legislação & jurisprudência , Patient Protection and Affordable Care Act/economia , Patient Protection and Affordable Care Act/legislação & jurisprudência , Governo Estadual , Estados UnidosRESUMO
Stochastic resonance (SR) is a phenomenon whereby the response of a non-linear system to a weak periodic input signal is optimized by the presence of a particular non-zero level of noise. Stochastic resonance using imperceptible stochastic vestibular electrical stimulation, when applied to normal young and elderly subjects, has been shown to significantly improve ocular stabilization reflexes in response to whole-body tilt; improved balance performance during postural disturbances and optimize covariance between the weak input periodic signals introduced via venous blood pressure receptors and the heart rate responses. In our study, 15 subjects stood on a compliant surface with their eyes closed. They were given low-amplitude binaural bipolar stochastic electrical stimulation of the vestibular organs in two frequency ranges of 1-2 and 0-30 Hz over the amplitude range of 0 to ±700 µA. Subjects were instructed to maintain an upright stance during 43-s trials, which consisted of baseline (zero amplitude) and stimulation (non-zero amplitude) periods. Measures of stability of the head and trunk using inertial motion unit sensors attached to these segments and the whole body using a force plate were measured and quantified in the mediolateral plane. Using a multivariate optimization criterion, our results show that the low levels of vestibular stimulation given to the vestibular organs improved balance performance in normal healthy subjects in the range of 5-26% consistent with the stochastic resonance phenomenon. In our study, 8 of 15 and 10 of 15 subjects were responsive for the 1-2- and 0-30-Hz stimulus signals, respectively. The improvement in balance performance did not differ significantly between the stimulations in the two frequency ranges. The amplitude of optimal stimulus for improving balance performance was predominantly in the range of ±100 to ±400 µA. A device based on SR stimulation of the vestibular system might be useful as either a training modality to enhance adaptability or skill acquisition, or as a miniature patch-type stimulator that may be worn by people with disabilities due to aging or disease to improve posture and locomotion function.
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Terapia por Estimulação Elétrica/métodos , Equilíbrio Postural/fisiologia , Doenças Vestibulares/terapia , Vestíbulo do Labirinto/fisiologia , Adulto , Humanos , Recuperação de Função Fisiológica/fisiologia , Processos Estocásticos , Resultado do Tratamento , Doenças Vestibulares/fisiopatologiaRESUMO
We propose a technique to estimate functional limits of stability (LOS) during bipedal stance using a controlled, low speed, voluntary leaning protocol requiring feet to remain in contact with the ground. LOS are estimated from ellipses fit to center-of-mass position data obtained during the leaning protocol. The LOS of nine healthy subjects were found to be 20-59% closer to the center of stance than the more frequently used anatomical boundaries and were reduced by closing the eyes. We conclude that functional stability boundaries should be used when the outcome measure is related to fall risk.
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Equilíbrio Postural/fisiologia , Acidentes por Quedas , Adulto , Estatura , Peso Corporal , Feminino , Pé/anatomia & histologia , Humanos , Masculino , Postura , Medição de RiscoRESUMO
UNLABELLED: Virtual reality (VR) simulation has been used to improve training for manual laparoscopy and to give surgeons superior performance in the operating room. However, VR has not been used to train surgeons in robotic laparoscopy. SUBJECTS: Five students of the University of Nebraska Medical Center (UNMC) and the University of Nebraska at Omaha gave consent according to UNMC ethical guidelines. EXPERIMENTAL PROTOCOL: Subjects performed with the Da Vinci robotic surgical system 5 trials for each of two tasks (Bimanual Carrying, BC; Needle Passing, NP). Each task was performed first in the actual robotic operating environment and then in VR. The data analysis included time to task completion, instrument tips distance traveled and the corresponding speed, and range of motion of the elbow flexion and extension of each subject. RESULTS: The BC and NP tasks were not significantly different between the two environments with respect to robot tip speed and the elbow range of motion for both arms. Time to task completion and distance traveled were significantly different between the two environments for both tasks. Survey results showed that subjects partially agreed that it was easy to adapt to VR and felt comfortable manipulating the robot controls in VR. They also suggested that they would like to have VR as part of their regular training. Our preliminary efforts showed promise that our VR environment is valid and it can be used for training of robotic laparoscopy. However, the differences identified need to be further explored and point to the need to further improve our VR simulation.