Impairment Of The Medial Olivocochlear System Maturation Due To Kcnq4 Deficiency

The medial olivocochlear (MOC) system regulates outer hair cell (OHC) excitability. In response to sound overstimulation, MOC activates Ca2+ influx through nicotinic acetylcholine receptors, which stimulates BK and SK2 channels, helping KCNQ4 to remove K+ and restoring membrane potential. KCNQ4 absence results in chronic depolarization, OHC damage, and hearing loss. We evaluated how the absence of KCNQ4 affects the organization and function of the MOC system. Confocal imaging was used to analyze MOC terminal locations on OHC in Kcnq4+/+ (WT) and Kcnq4-/- (KO) mice at 2, 3, 4, and 10 postnatal weeks (W). At 2W, both genotypes have 49% of synaptic contacts in the basal domain and 51% in the lateral domain. In mature animals (≥3W), WT show all terminals in the basal domain, whereas KO kept 8.7%, 16.5%, and 2.9% in the lateral domain at 3, 4, and 10W, respectively. KO mice also had fewer and smaller synaptic contacts per OHC at 4 and 10W compared to WT. Similar results were found in inner hair cells. Using qPCR we demonstrated that, KO mice had a 6-fold decrease in α10 subunit mRNA, with α9 unchanged, and a ~3-fold decrease in BK and SK2 at 4W. By 10W, all tested genes returned to WT levels. Additionally, BK protein was also mislocalized, and some Ca2+-associated proteins showed altered expression at 4W in KO mice. These findings indicate that chronic depolarization alters MOC system development and efferent components expression, leading to functional impairment and hearing loss.Fil: Rias, Ezequiel Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; ArgentinaFil: Ouwerkerk, Ingrid. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; ArgentinaFil: Spitzmaul, Guillermo Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; ArgentinaFil: Dionisio, Leonardo Raul. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; ArgentinaSociedad Argentina de Investigación en Neurociencias Annual Meeting 2024Buenos AiresArgentinaSociedad Argentina de Investigación en Neurociencia

Chronic depolarization of OHC impairs the maturation process of the MOC system

The efferent pathway mediated by the medial olivocochlear (MOC) system regulates the excitability of outer hair cells (OHC). In re- sponse to sound overstimulation, the MOC system activates nico- tinic acetylcholine receptor α9α10, which in turn, activates BK and SK2 channels, helping KCNQ4 to remove K+, and to restore resting membrane potential (RMP). Several conditions lead to chronic de- polarization by K+ accumulation (i.e. KCNQ4 impairment), damaging OHC and causing hearing loss. We hypothesized that the KCNQ4 absence, by altering RMP impacts the organization and function of the MOC system affecting the setting of the hearing process. Using confocal imaging, we evaluated the location of MOC terminals on OHC in Kcnq4+/+ and Kcnq4-/- animals at different stages: imma- ture (2 postnatal weeks (W)), and fully developed (3, 4, and 10W). At mature ages, MOC terminals are exclusively located in the OHC basal domain in WT animals. At 2W, both genotypes possess 32% of synaptic contacts in the lateral domain. Subsequently, all termi- nals relocated to the basal domain in WT animals. However, in KO ones, 9.5%, 15% and 1.5% of the terminals remained in the lateral domain at 3, 4 and 10W, respectively. Moreover, we detected a de- crease in both, the number of synaptic contacts per OHC and their volume, in 4 and 10W KO animals remaining unaltered in WT ones. On the other hand, we analyzed by qPCR the expression of the post- synaptic efferent components located in the MOC synapse. In 4W Kcnq4-/- animals, the mRNA expression of α10 subunit decreased 3.5-fold with no changes in α9 subunit; and BK and SK2 decreased 8-fold. However, at 10W, α10 expression returned to WT levels while BK increases 6-fold. These findings show that chronic depolariza- tion affect the efferent innervation development and the expression of its components in OHC, impacting the MOC system function. This contributes to hearing impairment by compromising the precise tun- ing role exerted by the MOC system on OHC transductionFil: Rias, Ezequiel Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; ArgentinaFil: Ouwerkerk, Ingrid. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; ArgentinaFil: Spitzmaul, Guillermo Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; ArgentinaFil: Dionisio, Leonardo Raul. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; ArgentinaReunión de Sociedades de Biociencias 2023; LXVIII Annual Meeting of Sociedad Argentina de Investigación Clínica (Saic); Xxv Annual Conferences of Sociedad Argentina de Biología (Sab); Lv Annual Meeting of Asociación Argentina de Farmacología Experimental (Aafe); Viii Regional Scientific Meeting of Asociación Argentina de Ciencia y Tecnología de Animales de Laboratorio (Aacytal)Mar del PlataArgentinaSociedad Argentina de Investigación ClínicaSociedad Argentina de BiologíaAsociación Argentina de Farmacología ExperimentalAsociación Argentina de Ciencia y Tecnología de Animales de Laboratori

Effect of the Application of Trial Inclusion Criteria on the Efficacy of Adalimumab Therapy in a Rheumatoid Arthritis Cohort

Objective. To evaluate the influence of inclusion criteria used in rheumatoid arthritis (RA) trials with adalimumab on clinical outcome and response. Methods. The different inclusion criteria of published trials of adalimumab in RA were separately applied to a large prospective cohort of patients with RA treated with adalimumab (AdRA cohort), thereby mimicking patient selection for a clinical trial. Clinical response and outcome in the resulting 11 projection groups were compared using the 28-joint Disease Activity Score (DAS28) and time-averaged DAS28 as outcome measures of efficacy. Results. Thirteen trials (n = 54-799) with 11 different sets of entry criteria were identified, resulting in 11 projection groups (n = 22-168). The DA528 at baseline was similar in the original trial and each projection group based on this trial (5.1-6.4, total AdRA cohort 5.1). After 28 weeks, the efficacy varied substantially among the 11 projected groups (change from baseline DAS28: -1.65 to -2.65, time-averaged DAS28 3.67-4.53). Expressed as outcome (DA528 at 28 weeks), the efficacy was much more similar for almost all projection groups (3.5-4.0) and thus appeared to be mostly independent of disease activity at baseline. Conclusion. We observed that different inclusion criteria for clinical trials can have a marked effect on the expected response, i.e., improvement from baseline. A novel finding is that final disease activity appeared much less dependent on initial disease activity. Our study suggests that for daily practice, one can assume that adalimumab treatment will on average result in a DAS28 between 3.5 and 4.0 after 28 weeks of treatment, regardless of baseline disease activity. (First Release June 15 2011; J Rheumatol 2011;38:1884-90; doi:10.3899/jrheum.101283

Dynamic Ejection Fraction Trajectory in Patients With Dilated Cardiomyopathy With a Truncating Titin Variant

status: publishe

High prevalence of cardiovascular disease in South Asians: Central role for brown adipose tissue?

Diabetes mellitus: pathophysiological changes and therap

Socioeconomic Status and Outcomes in Heart Failure With Reduced Ejection Fraction From Asia

Background: Little is known regarding the impact of socioeconomic factors on the use of evidence-based therapies and outcomes in patients with heart failure with reduced ejection fraction across Asia. Methods: We investigated the association of both patient-level (household income, education levels) and country-level (regional income level by World Bank classification, income disparity by Gini index) socioeconomic indicators on use of guideline-directed therapy and clinical outcomes (composite of 1-year mortality or HF hospitalization, quality of life) in the prospective multinational ASIAN-HF study (Asian Sudden Cardiac Death in Heart Failure). Results: Among 4540 patients (mean age: 60±13 years, 23% women) with heart failure with reduced ejection fraction, 39% lived in low-income regions; 34% in regions with high-income disparity (Gini ≥42.8%); 64.4% had low monthly household income (&lt;US$1000); and 29.5% had no/only primary education. The largest disparity in treatment across regional income levels pertained to β-blocker and device therapies, with patients from low-income regions being less likely to receive these treatments compared with those from high-income regions and even greater disparity among patients with lower education status and lower household income within each regional income strata. Higher country- and patient-level socioeconomic indicators related to higher quality of life scores and lower risk of the primary composite outcome. Notably, we found a significant interaction between regional income level and both household income and education status ( P interaction &lt;0.001 for both), where the association of low household income and low education status with poor outcomes was more pronounced in high-income compared with lower income regions. Conclusions: These findings highlight the importance of socioeconomic determinants among patients with heart failure in Asia and suggest that attention should be paid to address disparities in access to care among the poor and less educated, including those from wealthy regions. Registration: URL: https://clinicaltrials.gov ; Unique Identifier: NCT01633398. </jats:sec