RESUMEN
The mammalian cochlear epithelium undergoes substantial remodeling and maturation before the onset of hearing. However, very little is known about the transcriptional network governing cochlear late-stage maturation and particularly the differentiation of its lateral nonsensory region. Here, we establish ZBTB20 as an essential transcription factor required for cochlear terminal differentiation and maturation and hearing. ZBTB20 is abundantly expressed in the developing and mature cochlear nonsensory epithelial cells, with transient expression in immature hair cells and spiral ganglion neurons. Otocyst-specific deletion of Zbtb20 causes profound deafness with reduced endolymph potential in mice. The subtypes of cochlear epithelial cells are normally generated, but their postnatal development is arrested in the absence of ZBTB20, as manifested by an immature appearance of the organ of Corti, malformation of tectorial membrane (TM), a flattened spiral prominence (SP), and a lack of identifiable Boettcher cells. Furthermore, these defects are related with a failure in the terminal differentiation of the nonsensory epithelium covering the outer border Claudius cells, outer sulcus root cells, and SP epithelial cells. Transcriptome analysis shows that ZBTB20 regulates genes encoding for TM proteins in the greater epithelial ridge, and those preferentially expressed in root cells and SP epithelium. Our results point to ZBTB20 as an essential regulator for postnatal cochlear maturation and particularly for the terminal differentiation of cochlear lateral nonsensory domain.
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Cóclea , Células Ciliadas Auditivas , Animales , Ratones , Cóclea/metabolismo , Células Ciliadas Auditivas/fisiología , Audición/fisiología , Mamíferos , Ganglio Espiral de la Cóclea , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
Hearing loss affects â¼10% of adults worldwide. Most sensorineural hearing loss is caused by the progressive loss of mechanosensitive hair cells (HCs) in the cochlea. The molecular mechanisms underlying HC maintenance and loss remain poorly understood. LBH, a transcription co-factor implicated in development, is abundantly expressed in outer hair cells (OHCs). We used Lbh-null mice to identify its role in HCs. Surprisingly, Lbh deletion did not affect differentiation and the early development of HCs, as nascent HCs in Lbh knockout mice had normal looking stereocilia. The stereocilia bundle was mechanosensitive and OHCs exhibited the characteristic electromotility. However, Lbh-null mice displayed progressive hearing loss, with stereocilia bundle degeneration and OHC loss as early as postnatal day 12. RNA-seq analysis showed significant gene enrichment of biological processes related to transcriptional regulation, cell cycle, DNA damage/repair and autophagy in Lbh-null OHCs. In addition, Wnt and Notch pathway-related genes were found to be dysregulated in Lbh-deficient OHCs. Our study implicates, for the first time, loss of LBH function in progressive hearing loss, and demonstrates a critical requirement of LBH in promoting HC survival in adult mice.
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Pérdida Auditiva , Factores de Transcripción , Animales , Cóclea , Células Ciliadas Auditivas Externas , Ratones , EstereociliosRESUMEN
Signaling networks are at the heart of almost all biological processes. Most of these networks contain large number of components, and often either the connections between these components are not known or the rate equations that govern the dynamics of soluble signaling components are not quantified. This uncertainty in network topology and parameters can make it challenging to formulate detailed mathematical models. Boolean networks, in which all components are either on or off, have emerged as viable alternatives to detailed mathematical models that contain rate constants and other parameters. Therefore, open-source platforms of Boolean models for community use are desirable. Here, we present Boolink, a freely available graphical user interface that allows users to easily construct and analyze existing Boolean networks. Boolink can be applied to any Boolean network. We demonstrate its application using a previously published network for abscisic acid (ABA)-driven stomatal closure in Arabidopsis spp. (Arabidopsis thaliana). We also show how Boolink can be used to generate testable predictions by extending the network to include CO2 regulation of stomatal movements. Predictions of the model were experimentally tested, and the model was iteratively modified based on experiments showing that ABA effectively closes Arabidopsis stomata at near-zero CO2 concentrations (1.5-ppm CO2). Thus, Boolink enables public generation and the use of existing Boolean models, including the prior developed ABA signaling model with added CO2 signaling components.
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Algoritmos , Fenómenos Bioquímicos , Dióxido de Carbono/metabolismo , Estomas de Plantas/fisiología , Transducción de Señal/fisiología , Interpretación Estadística de Datos , Modelos TeóricosRESUMEN
BACKGROUND: The SCN11A gene, encoded Nav1.9 TTX resistant sodium channels, is a main effector in peripheral inflammation related pain in nociceptive neurons. The role of SCN11A gene in the auditory system has not been well characterized. We therefore examined the expression of SCN11A in the murine cochlea, the morphological and physiological features of Nav1.9 knockout (KO) ICR mice. RESULTS: Nav1.9 expression was found in the primary afferent endings beneath the inner hair cells (IHCs). The relative quantitative expression of Nav1.9 mRNA in modiolus of wild-type (WT) mice remains unchanged from P0 to P60. The number of presynaptic CtBP2 puncta in Nav1.9 KO mice was significantly lower than WT. In addition, the number of SGNs in Nav1.9 KO mice was also less than WT in the basal turn, but not in the apical and middle turns. There was no lesion in the somas and stereocilia of hair cells in Nav1.9 KO mice. Furthermore, Nav1.9 KO mice showed higher and progressive elevated ABR threshold at 16 kHz, and a significant increase in CAP thresholds. CONCLUSIONS: These data suggest a role of Nav1.9 in regulating the function of ribbon synapses and the auditory nerves. The impairment induced by Nav1.9 gene deletion mimics the characters of cochlear synaptopathy.
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Nervio Coclear/patología , Pérdida Auditiva Sensorineural/genética , Canal de Sodio Activado por Voltaje NAV1.9/genética , Sinapsis/patología , Animales , Nervio Coclear/metabolismo , Eliminación de Gen , Células Ciliadas Auditivas Internas/metabolismo , Células Ciliadas Auditivas Internas/patología , Pérdida Auditiva Sensorineural/metabolismo , Pérdida Auditiva Sensorineural/patología , Ratones , Ratones Endogámicos ICR , Ratones Noqueados , Sinapsis/metabolismoRESUMEN
The LIM homeodomain transcription factor Lmx1a shows a dynamic expression in the developing mouse ear that stabilizes in the non-sensory epithelium. Previous work showed that Lmx1a functional null mutants have an additional sensory hair cell patch in the posterior wall of a cochlear duct and have a mix of vestibular and cochlear hair cells in the basal cochlear sensory epithelium. In E13.5 mutants, Sox2-expressing posterior canal crista is continuous with an ectopic "crista sensory epithelium" located in the outer spiral sulcus of the basal cochlear duct. The medial margin of cochlear crista is in contact with the adjacent Sox2-expressing basal cochlear sensory epithelium. By E17.5, this contact has been interrupted by the formation of an intervening non-sensory epithelium, and Atoh1 is expressed in the hair cells of both the cochlear crista and the basal cochlear sensory epithelium. Where cochlear crista was formerly associated with the basal cochlear sensory epithelium, the basal cochlear sensory epithelium lacks an outer hair cell band, and gaps are present in its associated Bmp4 expression. Further apically, where cochlear crista was never present, the cochlear sensory epithelium forms a poorly ordered but complete organ of Corti. We propose that the core prosensory posterior crista is enlarged in the mutant when the absence of Lmx1a expression allows JAG1-NOTCH signaling to propagate into the adjacent epithelium and down the posterior wall of the cochlear duct. We suggest that the cochlear crista propagates in the mutant outer spiral sulcus because it expresses Lmo4 in the absence of Lmx1a.
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Proteínas Adaptadoras Transductoras de Señales/metabolismo , Células Ciliadas Auditivas Externas/metabolismo , Proteínas con Dominio LIM/metabolismo , Proteínas con Homeodominio LIM/metabolismo , Factores de Transcripción/metabolismo , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Proteína Morfogenética Ósea 4/metabolismo , Células Ciliadas Auditivas Externas/citología , Proteínas con Homeodominio LIM/genética , Ratones , Ratones Mutantes , Mutación , Factores de Transcripción SOXB1/metabolismo , Factores de Transcripción/genéticaRESUMEN
Research on data-driven fault diagnosis methods has received much attention in recent years. The deep belief network (DBN) is a commonly used deep learning method for fault diagnosis. In the past, when people used DBN to diagnose gear pitting faults, it was found that the diagnosis result was not good with continuous time domain vibration signals as direct inputs into DBN. Therefore, most researchers extracted features from time domain vibration signals as inputs into DBN. However, it is desirable to use raw vibration signals as direct inputs to achieve good fault diagnosis results. Therefore, this paper proposes a novel method by stacking spare autoencoder (SAE) and Gauss-Binary restricted Boltzmann machine (GBRBM) for early gear pitting faults diagnosis with raw vibration signals as direct inputs. The SAE layer is used to compress the raw vibration data and the GBRBM layer is used to effectively process continuous time domain vibration signals. Vibration signals of seven early gear pitting faults collected from a gear test rig are used to validate the proposed method. The validation results show that the proposed method maintains a good diagnosis performance under different working conditions and gives higher diagnosis accuracy compared to other traditional methods.
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Trastornos del Sueño-Vigilia , Sueño , Anciano , Humanos , Procedimientos Quirúrgicos OperativosRESUMEN
The purpose of this study was to examine the morphological and functional development of the lateral wall of the scala media of the cochlea in miniature pigs; light and transmission electron microscopy and electrophysiology were used for this purpose. We showed that the lateral wall of the scala media of the cochlea appears at embryonic Day 21 (E21) when the cochlear duct begins to form. From E28 to E49, the lateral wall can be distinguished according to its position along the cochlea. At E56, cells in the lateral wall begin to differentiate into three different types. At E70, three cell types, marginal, intermediate and basal, can be clearly distinguished. At E91, the stria vascularis is adult-like and the organ of Corti is also morphologically mature. The average endocochlear potential measured from the second turn of the cochlea (at E98, postnatal Day 1 (P1), P13 and P30) was 71.4±2.5 (n=7), 78.8±1.5 (n=10), 77.3±2.3 (n=10) and 78.0±2.1 mV (n=10), respectively. Our results suggest that in miniature pigs the stria vascularis develops during the embryonic period, concurrent with maturation of the organ of Corti. The magnitude of the endocochlear potential reached its mature level when the stria vascularis was morphologically adult-like at E98. These findings provide a morphological and functional basis for future animal studies using the miniature pig model concerning the pathogenesis of various inner-ear diseases.
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Cóclea/embriología , Organogénesis/fisiología , Estría Vascular/citología , Animales , Cóclea/citología , Porcinos , Porcinos EnanosRESUMEN
Prestin is the motor protein of cochlear outer hair cells. Its unique capability to perform direct, rapid, and reciprocal electromechanical conversion depends on membrane potential and interaction with intracellular anions. How prestin senses the voltage change and interacts with anions are still unknown. Our three-dimensional model of prestin using molecular dynamics simulations predicts that prestin contains eight transmembrane-spanning segments and two helical re-entry loops and that tyrosyl residues are the structural specialization of the molecule for the unique function of prestin. Using site-directed mutagenesis and electrophysiological techniques, we confirmed that residues Tyr(367), Tyr(486), Tyr(501), and Tyr(508) contribute to anion binding, interacting with intracellular anions through novel anion-π interactions. Such weak interactions, sensitive to voltage and mechanical stimulation, confer prestin with a unique capability to perform electromechanical and mechanoelectric conversions with exquisite sensitivity. This novel mechanism is completely different from all known mechanisms seen in ion channels, transporters, and motor proteins.
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Sistema de Transporte de Aminoácidos X-AG/metabolismo , Proteínas de Transporte de Anión/química , Células Ciliadas Auditivas Externas/metabolismo , Animales , Aniones , Dicroismo Circular , Cristalografía por Rayos X , Electroquímica , Electrofisiología , Gerbillinae , Células HEK293 , Audición , Humanos , Microscopía Confocal , Simulación de Dinámica Molecular , Mutagénesis Sitio-Dirigida , Péptidos/química , Unión Proteica , Conformación Proteica , Pliegue de Proteína , Pyrococcus horikoshii/metabolismo , Ratas , Transportadores de Sulfato , Tirosina/químicaRESUMEN
Inner hair cells (IHCs) and outer hair cells (OHCs) are the two types of sensory receptor cells that are critical for hearing in the mammalian cochlea. IHCs and OHCs have different morphology and function. The genetic mechanisms that define their morphological and functional specializations are essentially unknown. The transcriptome reflects the genes that are being actively expressed in a cell and holds the key to understanding the molecular mechanisms of the biological properties of the cell. Using DNA microarray, we examined the transcriptome of 2000 individually collected IHCs and OHCs from adult mouse cochleae. We show that 16,647 and 17,711 transcripts are expressed in IHCs and OHCs, respectively. Of those genes, â¼73% are known genes, 22% are uncharacterized sequences, and 5.0% are noncoding RNAs in both populations. A total of 16,117 transcripts are expressed in both populations. Uniquely and differentially expressed genes account for <15% of all genes in either cell type. The top 10 differentially expressed genes include Slc17a8, Dnajc5b, Slc1a3, Atp2a3, Osbpl6, Slc7a14, Bcl2, Bin1, Prkd1, and Map4k4 in IHCs and Slc26a5, C1ql1, Strc, Dnm3, Plbd1, Lbh, Olfm1, Plce1, Tectb, and Ankrd22 in OHCs. We analyzed commonly and differentially expressed genes with the focus on genes related to hair cell specializations in the apical, basolateral, and synaptic membranes. Eighty-three percent of the known deafness-related genes are expressed in hair cells. We also analyzed genes involved in cell-cycle regulation. Our dataset holds an extraordinary trove of information about the molecular mechanisms underlying hair cell morphology, function, pathology, and cell-cycle control.
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Cóclea/citología , Células Ciliadas Auditivas Internas/metabolismo , Células Ciliadas Auditivas Externas/metabolismo , Transcriptoma , Animales , Cóclea/metabolismo , Células Ciliadas Auditivas Internas/citología , Células Ciliadas Auditivas Externas/citología , RatonesRESUMEN
Cochlear outer hair cells (OHCs) alter their length in response to transmembrane voltage changes. This so-called electromotility is the result of conformational changes of membrane-bound prestin. Prestin-based OHC motility is thought to be responsible for cochlear amplification, which contributes to the exquisite frequency selectivity and sensitivity of mammalian hearing. Prestin belongs to an anion transporter family, the solute carrier protein 26A (SLC26A). Prestin is unique in this family in that it functions as a voltage-dependent motor protein manifested by two hallmarks, nonlinear capacitance and motility. Evidence suggests that prestin orthologs from zebrafish and chicken are anion exchangers or transporters with no motor function. We identified a segment of 11 amino acid residues in eutherian prestin that is extremely conserved among eutherian species but highly variable among non-mammalian orthologs and SLC26A paralogs. To determine whether this sequence represents a motif that facilitates motor function in eutherian prestin, we utilized a chimeric approach by swapping corresponding residues from the zebrafish and chicken with those of gerbil. Motility and nonlinear capacitance were measured from chimeric prestin-transfected human embryonic kidney 293 cells using a voltage-clamp technique and photodiode-based displacement measurement system. We observed a gain of motor function with both of the hallmarks in the chimeric prestin without loss of transport function. Our results show, for the first time, that the substitution of a span of 11 amino acid residues confers the electrogenic anion transporters of zebrafish and chicken prestins with motor-like function. Thus, this motif represents the structural adaptation that assists gain of motor function in eutherian prestin.
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Adaptación Fisiológica/fisiología , Proteínas de Transporte de Anión/química , Proteínas de Transporte de Anión/metabolismo , Proteínas Aviares/química , Proteínas Aviares/metabolismo , Pollos , Evolución Molecular , Proteínas de Pez Cebra/química , Proteínas de Pez Cebra/metabolismo , Pez Cebra , Secuencias de Aminoácidos , Secuencia de Aminoácidos , Aminoácidos , Animales , Proteínas de Transporte de Anión/genética , Proteínas Aviares/genética , Secuencia de Consenso , Capacidad Eléctrica , Formiatos/metabolismo , Gerbillinae , Células HEK293 , Humanos , Transporte Iónico , Datos de Secuencia Molecular , Proteínas Recombinantes de Fusión/química , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Relación Estructura-Actividad , Proteínas de Pez Cebra/genéticaRESUMEN
In recent years, acoustic emission (AE) sensors and AE-based techniques have been developed and tested for gearbox fault diagnosis. In general, AE-based techniques require much higher sampling rates than vibration analysis-based techniques for gearbox fault diagnosis. Therefore, it is questionable whether an AE-based technique would give a better or at least the same performance as the vibration analysis-based techniques using the same sampling rate. To answer the question, this paper presents a comparative study for gearbox tooth damage level diagnostics using AE and vibration measurements, the first known attempt to compare the gearbox fault diagnostic performance of AE- and vibration analysis-based approaches using the same sampling rate. Partial tooth cut faults are seeded in a gearbox test rig and experimentally tested in a laboratory. Results have shown that the AE-based approach has the potential to differentiate gear tooth damage levels in comparison with the vibration-based approach. While vibration signals are easily affected by mechanical resonance, the AE signals show more stable performance.
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Acústica , Enfermedades Dentales/diagnóstico , Vibración , Humanos , Enfermedades Dentales/patologíaRESUMEN
STUDY OBJECTIVE: To determine the diagnostic accuracy of the Montreal Cognitive Assessment (MoCA) in detecting cognitive impairment (CI) and assess the association of MoCA scores with adverse postoperative outcomes in surgical populations. DESIGN: Systematic review and meta-analysis. SETTING: Perioperative setting. PATIENTS: Adults undergoing elective or emergent surgery screened for CI preoperatively using the MoCA. MEASUREMENTS: The outcomes included the diagnostic accuracy of the MoCA in screening for CI and the pooled prevalence of CI in various surgical populations. CI and its association with adverse events including delirium, hospital length-of-stay (LOS), postoperative complications, discharge destination, and mortality was determined. MAIN RESULTS: Twenty-six studies (5059 patients, 18 non-cardiac studies, 8 cardiac studies) were included. With a MoCA cut-off score of <26, the prevalence of preoperative CI was 48% (95% CI: 41%-54%). The MoCA had 0.87 (95% CI: 0.79-0.93) sensitivity, 0.72 (95% CI: 0.62-0.80) specificity, PPV of 0.74 (95% CI: 0.65-0.81), and NPV of 0.86 (95% CI: 0.77-0.92) when validated against Petersen criteria, the Diagnostic and Statistical Manual of Mental Disorders, or the National Institute on Aging and the Alzheimer's Association criteria to identify CI. Using the MoCA as a screening tool, the LOS was 3.75 (95% CI: -0.03-7.53, P = 0.05, not significant) days longer in the CI group after non-cardiac surgeries and 3.33 (95% CI: 1.24-5.41, P < 0.002) days longer after cardiac surgeries than the non-cognitively impaired group. CONCLUSIONS: MoCA had been validated in the surgical population. MoCA with a cut-off score of <26 was shown to have 87% sensitivity and 72% specificity in identifying CI. A positive screen in MoCA was associated with a 3-day longer hospital LOS in cardiac surgery in the CI group than in the non-CI group.
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BACKGROUND: The Mini-Cog is a rapid screening tool that can be administered to older adults to detect cognitive impairment (CI); however, the accuracy of the Mini-Cog to detect CI for older patients in various healthcare settings is unclear. OBJECTIVES: To evaluate the diagnostic accuracy of the Mini-Cog to screen for cognitive impairment in older patients across different healthcare settings. METHODS/DESIGN: We searched nine electronic databases (including MEDLINE, Embase) from inception to January 2023. We included studies with patients ≥60 years old undergoing screening for cognitive impairment using the Mini-Cog across all healthcare settings. A cut-off of ≤ 2/5 was used to classify dementia, mild cognitive impairment (MCI), and cognitive impairment (defined as either MCI or dementia) across various settings. The diagnostic accuracy of the Mini-Cog was assessed against gold standard references such as the Diagnostic and Statistical Manual of Mental Disorders (DSM). A bivariate random-effects model was used to estimate accuracy and diagnostic ability. The risk of bias was assessed using QUADAS-2 criteria. RESULTS: The systematic search resulted in 4,265 articles and 14 studies were included for analysis. To detect dementia (six studies, n = 4772), the Mini-Cog showed 76% sensitivity and 83% specificity. To detect MCI (two studies, n = 270), it showed 84% sensitivity and 79% specificity. To detect CI (eight studies, n = 2152), it had 67% sensitivity and 83% specificity. In the primary care setting, to detect either MCI, dementia, or CI (eight studies, n = 5620), the Mini-Cog demonstrated 73% sensitivity and 84% specificity. Within the secondary care setting (seven studies, n = 1499), the Mini-Cog to detect MCI, dementia or CI demonstrated 73% sensitivity and 76% specificity. A high or unclear risk of bias persisted in the patient selection and timing domain. CONCLUSIONS: The Mini-Cog is a quick and freely available screening tool and has high sensitivity and specificity to screen for CI in older adults across various healthcare settings. It is a practical screening tool for use in time-sensitive and resource-limited healthcare settings.
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Disfunción Cognitiva , Demencia , Humanos , Disfunción Cognitiva/diagnóstico , Demencia/diagnóstico , Anciano , Sensibilidad y Especificidad , Tamizaje Masivo/métodos , Persona de Mediana Edad , Anciano de 80 o más AñosRESUMEN
Hair cells (HCs) are the sensory receptors of the auditory and vestibular systems in the inner ears of vertebrates that selectively transduce mechanical stimuli into electrical activity. Although all HCs have the hallmark stereocilia bundle for mechanotransduction, HCs in non-mammals and mammals differ in their molecular specialization in the apical, basolateral and synaptic membranes. HCs of non-mammals, such as zebrafish (zHCs), are electrically tuned to specific frequencies and possess an active process in the stereocilia bundle to amplify sound signals. Mammalian cochlear HCs, in contrast, are not electrically tuned and achieve amplification by somatic motility of outer HCs (OHCs). To understand the genetic mechanisms underlying differences among adult zebrafish and mammalian cochlear HCs, we compared their RNA-seq-characterized transcriptomes, focusing on protein-coding orthologous genes related to HC specialization. There was considerable shared expression of gene orthologs among the HCs, including those genes associated with mechanotransduction, ion transport/channels, and synaptic signaling. For example, both zebrafish and mouse HCs express Tmc1, Lhfpl5, Tmie, Cib2, Cacna1d, Cacnb2, Otof, Pclo and Slc17a8. However, there were some notable differences in expression among zHCs, OHCs, and inner HCs (IHCs), which likely underlie the distinctive physiological properties of each cell type. Tmc2 and Cib3 were not detected in adult mouse HCs but tmc2a and b and cib3 were highly expressed in zHCs. Mouse HCs express Kcna10, Kcnj13, Kcnj16, and Kcnq4, which were not detected in zHCs. Chrna9 and Chrna10 were expressed in mouse HCs. In contrast, chrna10 was not detected in zHCs. OHCs highly express Slc26a5 which encodes the motor protein prestin that contributes to OHC electromotility. However, zHCs have only weak expression of slc26a5, and subsequently showed no voltage dependent electromotility when measured. Notably, the zHCs expressed more paralogous genes including those associated with HC-specific functions and transcriptional activity, though it is unknown whether they have functions similar to their mammalian counterparts. There was overlap in the expressed genes associated with a known hearing phenotype. Our analyses unveil substantial differences in gene expression patterns that may explain phenotypic specialization of zebrafish and mouse HCs. This dataset also includes several protein-coding genes to further the functional characterization of HCs and study of HC evolution from non-mammals to mammals.
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STUDY OBJECTIVES: To determine the prevalence of suspected cognitive impairment using the Centers for Disease Control and Prevention (CDC) cognitive question, Ascertain Dementia Eight-item Questionnaire (AD8), Modified Telephone Interview for Cognitive Status (TICS-M), and Telephone Montreal Cognitive Assessment (T-MoCA), the agreement between each tool beyond chance, and the risk factors associated with a positive screen. DESIGN: Multicenter prospective study. SETTING: Remote preoperative assessments. PATIENTS: 307 non-cardiac surgical patients aged ≥65 years. MEASUREMENTS: Prevalence, Cohen's kappa (κ). MAIN RESULTS: The T-MoCA detected the highest prevalence of suspected cognitive impairment (28%), followed by the AD8 (17%), CDC cognitive question (9%), and TICS-M (6%). The four screening tools showed poor agreement beyond chance with one another, with the CDC cognitive question and AD8 approaching the threshold for weak agreement (κ = 0.39). Depression was associated with screening positive on the CDC cognitive question (OR: 2.81; 95% CI: 1.04, 7.68). Obstructive sleep apnea (OSA) (OR: 3.10; 95% CI: 1.26, 7.71) and functional disability (OR: 3.74; 95% CI: 1.34, 11.11) were associated with a positive AD8 screen. Older age (OR: 1.56; 95% CI: 1.01, 2.41), male sex (OR: 3.08; 95% CI: 1.09, 9.40), and higher pain level (OR: 1.21; 95% CI: 1.01, 1.47) were associated with a positive TICS-M screen. Similarly, older age (OR: 1.33; 95% CI: 1.03, 1.73), male sex (OR: 2.02; 95% CI: 1.09, 3.83), and higher pain level (OR: 1.15; 95% CI: 1.02, 1.30) were associated with a positive T-MoCA screen. CONCLUSIONS: The CDC cognitive question, AD8, TICS-M, and T-MoCA were easily implemented during preoperative assessment among older surgical patients. OSA, functional disability, and depression were associated with complaints on the CDC cognitive question and AD8. Older age, male sex, and higher pain level were associated with screening positive on the TICS-M and T-MoCA. Early remote cognitive screening may enhance risk stratification of vulnerable patients.
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Body temperature should be tightly regulated for optimal sleep. However, various extrinsic and intrinsic factors can alter body temperature during sleep. In a free-living study, we examined how sleep and cardiovascular health metrics were affected by sleeping for one week with (Pod ON) vs. without (Pod OFF), an active temperature-controlled mattress cover (the Eight Sleep Pod). A total of 54 subjects wore a home sleep test device (HST) for eight nights: four nights each with Pod ON and OFF (>300 total HST nights). Nightly sleeping heart rate (HR) and heart rate variability (HRV) were collected. Compared to Pod OFF, men and women sleeping at cooler temperatures in the first half of the night significantly improved deep (+14 min; +22% mean change; p = 0.003) and REM (+9 min; +25% mean change; p = 0.033) sleep, respectively. Men sleeping at warm temperatures in the second half of the night significantly improved light sleep (+23 min; +19% mean change; p = 0.023). Overall, sleeping HR (-2% mean change) and HRV (+7% mean change) significantly improved with Pod ON (p < 0.01). To our knowledge, this is the first study to show a continuously temperature-regulated bed surface can (1) significantly modify time spent in specific sleep stages in certain parts of the night, and (2) enhance cardiovascular recovery during sleep.
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Hearing loss is a major health concern in our society, affecting more than 400 million people worldwide. Among the causes, aminoglycoside therapy can result in permanent hearing loss in 40% to 60% of patients receiving treatment, and despite these high numbers, no drug for preventing or treating this type of hearing loss has yet been approved by the US Food and Drug Administration. We have previously conducted high-throughput screenings of bioactive compounds, using zebrafish as our discovery platform, and identified piplartine as a potential therapeutic molecule. In the present study, we expanded this work and characterized piplartine's physicochemical and therapeutic properties. We showed that piplartine had a wide therapeutic window and neither induced nephrotoxicity in vivo in zebrafish nor interfered with aminoglycoside antibacterial activity. In addition, a fluorescence-based assay demonstrated that piplartine did not inhibit cytochrome C activity in microsomes. Coadministration of piplartine protected from kanamycin-induced hair cell loss in zebrafish and protected hearing function, outer hair cells, and presynaptic ribbons in a mouse model of kanamycin ototoxicity. Last, we investigated piplartine's mechanism of action by phospho-omics, immunoblotting, immunohistochemistry, and molecular dynamics experiments. We found an up-regulation of AKT1 signaling in the cochleas of mice cotreated with piplartine. Piplartine treatment normalized kanamycin-induced up-regulation of TRPV1 expression and modulated the gating properties of this receptor. Because aminoglycoside entrance to the inner ear is, in part, mediated by TRPV1, these results suggested that by regulating TRPV1 expression, piplartine blocked aminoglycoside's entrance, thereby preventing the long-term deleterious effects of aminoglycoside accumulation in the inner ear compartment.
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Aminoglicósidos , Pérdida Auditiva , Canales Catiónicos TRPV , Pez Cebra , Animales , Canales Catiónicos TRPV/metabolismo , Aminoglicósidos/farmacología , Pérdida Auditiva/inducido químicamente , Pérdida Auditiva/metabolismo , Pérdida Auditiva/prevención & control , Pérdida Auditiva/patología , Ratones , Ototoxicidad/metabolismo , Kanamicina , Dioxolanos/farmacología , PiperidonasRESUMEN
Ischaemic preconditioning is one of the most potent experimental modalities known to decrease infarct size after ischaemia and reperfusion. Much interest has been stimulated by the phenomenon of remote ischaemic conditioning (RIC), in which the preconditioning stimulus is applied to a limb remote from the heart to stimulate cardioprotection via an unidentified humoral factor, believed to be a protein between 3.5 and 15 kDa. Stromal cell-derived factor-1 (SDF-1α or CXCL12) is a chemokine of 10 kDa that is induced by hypoxia and recruits stem cells, but also exerts direct, acute, cardioprotection via its receptor, CXCR4. The serum dipeptidase DPPIV cleaves and inactivates SDF-1α. We measured SDF-1α in rat plasma and found it was significantly increased by RIC. DPPIV activity was unchanged after RIC, suggesting that increased synthesis or release or SDF-1α caused the increase in plasma levels. AMD3100, a highly specific inhibitor of CXCR4, was used to investigate the hypothesis that SDF-1α is involved in RIC. RIC in rats, which decreased infarct size from 53 ± 3 % to 27 ± 3 % (n = 6, P < 0.05), was blocked in rats treated with AMD3100 (40 ± 4 %). RIC also improved functional recovery of cardiac papillary muscle, and this, too, was blocked by AMD3100. Direct application of SDF-1α was confirmed to be protective in this model and was blocked by AMD3100. RIC stimulates SDF-1α release, and this 10-kDa peptide appears to be required for the mechanism of RIC.