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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
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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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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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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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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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
The widely used chemotherapy cisplatin causes permanent hearing loss in 40%-60% of patients with cancer. One drug, sodium thiosulfate, is approved by the FDA for use in pediatric patients with localized solid tumors for preventing cisplatin-induced hearing loss, but more drugs are desperately needed. Here, we tested dabrafenib, an FDA-approved BRAF kinase inhibitor and anticancer drug, in a clinically relevant multidose cisplatin mouse model. The protective effects of dabrafenib, given orally twice daily with cisplatin, were determined by functional hearing tests and cochlear outer hair cell counts. Toxicity of the drug cotreatment was evaluated, and levels of phosphorylated ERK were measured. A dabrafenib dose of 3 mg/kg BW, twice daily, in mice, was determined to be the minimum effective dose, and it is equivalent to one-tenth of the daily FDA-approved dose for human cancer treatment. The levels of hearing protection acquired, 20-25 dB at the 3 frequencies tested, in both female and male mice, persisted for 4 months after completion of treatments. Moreover, dabrafenib exhibited a good in vivo therapeutic index (> 25), protected hearing in 2 mouse strains, and diminished cisplatin-induced weight loss. This study demonstrates that dabrafenib is a promising candidate drug for protection from cisplatin-induced hearing loss.
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Antineoplásicos , Sordera , Pérdida Auditiva , Neoplasias , Humanos , Masculino , Femenino , Niño , Ratones , Animales , Cisplatino/toxicidad , Pérdida Auditiva/inducido químicamente , Pérdida Auditiva/prevención & control , Pérdida Auditiva/tratamiento farmacológico , Antineoplásicos/toxicidad , Imidazoles/farmacología , Imidazoles/uso terapéutico , Neoplasias/tratamiento farmacológicoRESUMEN
BACKGROUND: The Ascertain Dementia 8-item Questionnaire (AD8) is a screening tool for cognitive impairment that can be administered to older persons and/or their informants. OBJECTIVES: To evaluate the diagnostic accuracy and compare the predictive parameters of the informant and participant-completed Ascertain Dementia 8-item Questionnaire (iAD8 and pAD8, respectively) in older adults with cognitive impairment. METHODS/DESIGN: We searched ten electronic databases (including MEDLINE (Ovid), Embase) from tool inception to March 2022. We included studies with patients ≥60 years old that were screened for cognitive impairment using AD8 in any healthcare setting. Predictive parameters were assessed against reference standards to estimate accuracy and diagnostic ability using bivariate random-effects meta-analyses. We used QUADAS-2 criteria to assess risk of bias. RESULTS: A cut-off of ≥2/8 was used to classify mild cognitive impairment (MCI), dementia, and cognitive impairment (MCI or dementia). Seven studies using the iAD8 (n = 794) showed a sensitivity of 80% and specificity of 79% to detect MCI. Nine studies using the iAD8 (n = 2393) established 91% sensitivity and 64% specificity to detect dementia. To detect MCI using the pAD8, four studies (n = 836) showed 57% sensitivity and 71% specificity. To detect dementia using the pAD8, four studies (n = 3015) demonstrated 82% sensitivity and 75% specificity. Recurring high or unclear risk of bias was noted in the domains of "Index test" and "reference standard". CONCLUSIONS: The diagnostic accuracy of iAD8 is superior to that of pAD8 when screening for cognitive impairment. The AD8 may be an acceptable alternative to screen for cognitive impairment in older adults when there are limitations to formal testing.
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Disfunción Cognitiva , Demencia , Anciano , Anciano de 80 o más Años , Humanos , Persona de Mediana Edad , Disfunción Cognitiva/diagnóstico , Correlación de Datos , Bases de Datos Factuales , Demencia/diagnóstico , Instituciones de SaludRESUMEN
STUDY OBJECTIVE: To assess the incidence of postoperative delirium and its outcomes in older non-cardiac surgical patients. DESIGN: A systematic review and meta-analysis with multiple databases searched from inception to February 22, 2022. SETTING: Postoperative assessments. PATIENTS: Non-cardiac and non-neurological surgical patients aged ≥60 years with and without postoperative delirium. Included studies must report ≥1 postoperative outcome. Studies with a small sample size (N < 100 subjects) were excluded. MEASUREMENTS: Outcomes comprised the pooled incidence of postoperative delirium and its postoperative outcomes, including mortality, complications, unplanned intensive care unit admissions, length of stay, and non-home discharge. For dichotomous and continuous outcomes, OR and difference in means were computed, respectively, with a 95% CI. MAIN RESULTS: Fifty-four studies (20,988 patients, 31 elective studies, 23 emergency studies) were included. The pooled incidence of postoperative delirium was 19% (95% CI: 16%, 23%) after elective surgery and 32% (95% CI: 25%, 39%) after emergency surgery. In elective surgery, postoperative delirium was associated with increased mortality at 1-month (OR: 6.60; 95% CI: 1.58, 27.66), 6-month (OR: 5.69; 95% CI: 2.33, 13.88), and 1-year (OR: 2.87; 95% CI: 1.63, 5.06). The odds of postoperative complications, unplanned intensive care unit admissions, prolonged length of hospital stay, and non-home discharge were also higher in delirium cases. In emergency surgery, patients with postoperative delirium had greater odds of mortality at 1-month (OR: 3.56; 95% CI: 1.77, 7.15), 6-month (OR: 2.60; 95% CI: 1.88, 3.61), and 1-year (OR: 2.30; 95% CI: 1.77, 3.00). CONCLUSIONS: Postoperative delirium was associated with higher odds of mortality, postoperative complications, unplanned intensive care unit admissions, length of hospital stay, and non-home discharge. Prevention and perioperative management of delirium may optimize surgical outcomes.
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Delirio , Delirio del Despertar , Humanos , Anciano , Delirio/epidemiología , Delirio/etiología , Delirio/prevención & control , Hospitalización , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Tiempo de InternaciónRESUMEN
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
Chronic, pathological pain is a highly debilitating condition that can arise and be maintained through central sensitization. Central sensitization shares mechanistic and phenotypic parallels with memory formation. In a sensory model of memory reconsolidation, plastic changes underlying pain hypersensitivity can be dynamically regulated and reversed following the reactivation of sensitized sensory pathways. However, the mechanisms by which synaptic reactivation induces destabilization of the spinal "pain engram" are unclear. We identified nonionotropic N-methyl-d-aspartate receptor (NI-NMDAR) signaling as necessary and sufficient for the reactive destabilization of dorsal horn long-term potentiation and the reversal of mechanical sensitization associated with central sensitization. NI-NMDAR signaling engaged directly or through the reactivation of sensitized sensory networks was associated with the degradation of excitatory postsynaptic proteins. Our findings identify NI-NMDAR signaling as a putative synaptic mechanism by which engrams are destabilized in reconsolidation and as a potential means of treating underlying causes of chronic pain.
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Nociceptores , Receptores de N-Metil-D-Aspartato , Humanos , Receptores de N-Metil-D-Aspartato/metabolismo , Nociceptores/metabolismo , Dolor , Asta Dorsal de la Médula Espinal/metabolismo , Transducción de SeñalRESUMEN
STUDY OBJECTIVE: Instrumental activities of daily living (IADLs) are essential to patient function and quality of life after surgery. In older surgical patients, the incidence of preoperative IADL dependence has not been well characterized in the literature. This systematic review and meta-analysis aimed to determine the pooled incidence of preoperative IADL dependence and the associated adverse outcomes in the older surgical population. DESIGN: Systematic review and meta-analysis. SETTING: MEDLINE, MEDLINE Epub Ahead of Print and In-Process, In-Data-Review & Other Non-Indexed Citations, Embase/Embase Classic, Cochrane CENTRAL, and Cochrane Database of Systematic Reviews, ClinicalTrials.Gov, the WHO ICTRP (International Clinical Trials Registry Platform) were searched for relevant articles from 1969 to April 2022. PATIENTS: Patients aged ≥60 years old undergoing surgery with preoperative IADL assessed by the Lawton IADL Scale. INTERVENTIONS: Preoperative assessment. MEASUREMENT: The primary outcome was the pooled incidence of preoperative IADL dependency. Additional outcomes included post-operative mortality, postoperative delirium [POD], functional status improvement, and discharge disposition. MAIN RESULTS: Twenty-one studies (n = 5690) were included. In non-cardiac surgeries, the pooled incidence of preoperative IADL dependence was 37% (95% CI: 26.0%, 48.0%) among 2909 patients. Within cardiac surgeries, the pooled incidence of preoperative IADL dependence was 53% (95% CI: 24.0%, 82.0%) among 1074 patients. Preoperative IADL dependence was associated with an increased risk of postoperative delirium than those without IADL dependence (44.9% vs 24.4, OR 2.26; 95% CI: 1.42, 3.59; I2: 0%; P = 0.0005). CONCLUSIONS: There is a high incidence of IADL dependence in older surgical patients undergoing non-cardiac and cardiac surgery. Preoperative IADL dependence was associated with a two-fold risk of postoperative delirium. Further work is needed to determine the feasibility of using the IADL scale preoperatively as a predictive tool for postoperative adverse outcomes.
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Procedimientos Quirúrgicos Cardíacos , Delirio del Despertar , Humanos , Anciano , Persona de Mediana Edad , Actividades Cotidianas , Calidad de Vida , IncidenciaRESUMEN
Cochlear and vestibular hair cells are highly specialized sensory receptors for hearing and balance. Here, we report a serendipitous identification of a hair-cell-specific organelle in neonatal mouse inner ear, which we name "apicosome." The apicosome is â¼500 nm in diameter and shows itinerant nature and transient appearance during development in cochlear hair cells. In contrast to cochlear hair cells, the apicosome persists in vestibular hair cells even in adult. The timing of apicosome translocation and disappearance in cochlear hair cells during development is correlated with kinocilium development and maintenance. The apicosome is not seen in supporting cells despite the fact that nascent supporting cells have microvilli and a primary cilium. Interestingly, transdifferentiated hair cells from supporting cells also contain apicosome, suggesting that it is unique to hair cells. Thus, our study identifies a previously undescribed organelle in hair cells and lays the foundation for further characterization of this specialized structure.
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Determining the prevalence and risk factors related to sleep disturbance in surgical patients would be beneficial for risk stratification and perioperative care planning. The objectives of this systematic review and meta-analysis are to determine the prevalence and risk factors of sleep disturbances and their associated postoperative complications in surgical patients. The inclusion criteria were: (1) patients ≥18 years old undergoing a surgical procedure, (2) in-patient population, and (3) report of sleep disturbances using a validated sleep assessment tool. The systematic search resulted in 21,951 articles. Twelve patient cohorts involving 1497 patients were included. The pooled prevalence of sleep disturbances at preoperative assessment was 60% (95% Confidence Interval (CI): 50%, 69%) and the risk factors for postoperative sleep disturbances were a high preoperative Pittsburgh sleep quality index (PSQI) score indicating preexisting disturbed sleep and anxiety. Notably, patients with postoperative delirium had a higher prevalence of pre- and postoperative sleep disturbances and high preoperative wake after sleep onset percentage (WASO%). The high prevalence of preoperative sleep disturbances in surgical patients has a negative impact on postoperative outcomes and well-being. Further work in this area is warranted.
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Trastornos del Sueño-Vigilia , Sueño , Humanos , Adolescente , Prevalencia , Factores de Riesgo , Ansiedad , Trastornos del Sueño-Vigilia/epidemiología , Trastornos del Sueño-Vigilia/etiologíaAsunto(s)
Trastornos del Sueño-Vigilia , Sueño , Anciano , Humanos , Procedimientos Quirúrgicos OperativosRESUMEN
Vertigo is a debilitating disease affecting 15-20% of adults worldwide. Vestibular peripheral vertigo is the most common cause of vertigo, often due to Meniere's disease and benign paroxysmal positional vertigo. Although some vertigo symptoms can be controlled by conservative treatment and/or vestibular rehabilitation therapy, these treatments do not work for some patients. Semicircular canal occlusion surgery has proven to be very effective for these patients with intractable vertigo. However, its application is limited due to concern that the procedure will disrupt normal hearing. In this study, we investigated if occlusion of two semicircular canals would jeopardize auditory function by comparing auditory function and hair cell morphology between the surgical and contralateral ears before and after the surgery in a mouse model. By measuring the auditory brainstem response and distortion product otoacoustic emission 4 weeks post-surgery, we show that auditory function does not significantly change between the surgical and contralateral ears. In addition, confocal imaging has shown no hair cell loss in the cochlear and vestibular sensory epithelia, and scanning electron microscopy also indicates normal stereocilia morphology in the surgical ear. More importantly, the endocochlear potential measured from the surgical ear is not significantly different than that seen in the contralateral ear. Our study suggests that occlusion of two semicircular canals does not disrupt normal hearing in the mouse model, providing a basis to extend the procedure to patients, even those with normal hearing, benefitting more patients with intractable vertigo attacks.
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Juvenile and mature mouse cochleae contain various low-abundant, vulnerable sensory epithelial cells embedded in the calcified temporal bone, making it challenging to profile the dynamic transcriptome changes of these cells during maturation at the single-cell level. Here we performed the 10x Genomics single-cell RNA sequencing (scRNA-seq) of mouse cochleae at postnatal days 14 (P14) and 28. We attained the transcriptomes of multiple cell types, including hair cells, supporting cells, spiral ganglia, stria fibrocytes, and immune cells. Our hair cell scRNA-seq datasets are consistent with published transcripts from bulk RNA-seq. We also mapped known deafness genes to corresponding cochlear cell types. Importantly, pseudotime trajectory analysis revealed that inner hair cell maturation peaks at P14 while outer hair cells continue development until P28. We further identified and confirmed a long non-coding RNA gene Miat to be expressed during maturation in cochlear hair cells and spiral ganglia neurons, and Pcp4 to be expressed during maturation in cochlear hair cells. Our transcriptomes of juvenile and mature mouse cochlear cells provide the sequel to those previously published at late embryonic and early postnatal ages and will be valuable resources to investigate cochlear maturation at the single-cell resolution.
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Antibiotic resistance is a global health issue and a potential risk for society. Antibiotics administered through conventional formulations are devoid of targeting effect and often spread to various undesired body sites, leading to sub-lethal concentrations at the site of action and thus resulting in emergence of resistance, as well as side effects. Moreover, we have a very slim antibiotic pipeline. Drug-delivery systems have been designed to control the rate, time, and site of drug release, and innovative approaches for antibiotic delivery provide a glint of hope for addressing these issues. This review elaborates different delivery strategies and approaches employed to overcome the limitations of conventional antibiotic therapy. These include antibiotic conjugates, prodrugs, and nanocarriers for local and targeted antibiotic release. In addition, a wide range of stimuli-responsive nanocarriers and biological carriers for targeted antibiotic delivery are discussed. The potential advantages and limitations of targeted antibiotic delivery strategies are described along with possible solutions to avoid these limitations. A number of antibiotics successfully delivered through these approaches with attained outcomes and potentials are reviewed.