ABSTRACT
BACKGROUND: Acute otitis media (AOM) causes inflammation and hearing loss. Ventilation tubes are key in treatment. 3D printing improves prostheses in otorhinolaryngology, offering precision and greater adaptability. MATERIALS AND METHODS: An experimental study was conducted with Wistar rats from July to December 2020. 3D tympanostomy tube models were designed, with technical specifications and tests performed on inexpensive 3D printers. The tympanostomy tube was inserted endoscopically. RESULTS: Procedures were performed on five rats with implants in both ears. Pre-intervention pathologies, such as atical retraction and glue ear, were found. The PLA-printed tympanostomy tube showed improvement after adjustments. Histopathological results revealed significant middle and inner ear damage. CONCLUSION: In our study, the design and 3D printing of implants fulfilled the desired functions when modified, with a height of 5 mm. Complications included PLA degradation and ear damage. There were no adverse events during observation, highlighting the need for further research on 3D-printed implants.
ABSTRACT
OBJECTIVE: To evaluate whether hydroxychloroquine (HCQ) or chloroquine (CQ) are effective for the treatment of oral lichen planus (OLP). MATERIALS AND METHODS: A literature search was conducted in four databases. Clinical studies investigating the effect of HCQ/CQ in patients with OLP were included. RESULTS: Eleven studies were included. Four were RCTs and seven quasi-experimental studies. The studies included 390 patients diagnosed with OLP, of which 326 and 7 received HCQ and CQ, respectively. 46 patients received topical dexamethasone, 5 placebo and 6 griseofulvin as controls. Five studies assessed pain, and all of them obtained pain reduction with the use of HCQ. Six studies reported objective clinical improvement of OLP with the use of HCQ. Five studies that used a subjective scale obtained that 24%-100% of the patients achieved a complete/almost complete improvement of OLP lesions and its symptomatology. The most frequent side effects were vision problems, gastric discomfort, rash, nauseas, headaches, skin pigmentation, and elevated kidney function. 17 patients had to withdraw from the studies. CONCLUSIONS: Current evidence is scarce to confirm HCQ as a therapeutic option for OLP. More RCTs are needed to compare its efficacy with topical corticosteroids and to evaluate whether HCQ reduces relapses of OLP.
ABSTRACT
Allergic conjunctivitis (AC) is the most common form of allergic eye disease and an increasingly prevalent condition. Topical eye drop treatments are the usual approach for managing AC, although their impact on the ocular surface is not frequently investigated. The aim of this study was to perform a comparative physicochemical characterization, and in vitro biological evaluations in primary conjunctival and corneal epithelial cells of the new multidose preservative-free bilastine 0.6% and main commercially available eye drops. MTT assay was used to measure cell viability; oxidative stress was analyzed with a ROS-sensitive probe; and apoptosis was evaluated monitoring caspase 3/7 activation. Differences in pH value, osmolarity, viscosity and phosphate levels were identified. Among all formulations, bilastine exhibited pH, osmolarity and viscosity values closer to tear film (7.4, 300 mOsm/l and ~ 1.5-10 mPa·s, respectively), and was the only phosphates-free solution. Single-dose ketotifen did not induce ROS production, and single-dose azelastine and bilastine only induced a mild increase. Bilastine and single-dose ketotifen and azelastine showed high survival rates attributable to the absence of preservative in its formulation, not inducing caspase-3/7-mediated apoptosis after 24 h. Our findings support the use of the new bilastine 0.6% for treating patients with AC to preserve and maintain the integrity of the ocular surface.
Subject(s)
Apoptosis , Benzimidazoles , Caspase 3 , Cell Survival , Ophthalmic Solutions , Preservatives, Pharmaceutical , Ophthalmic Solutions/pharmacology , Humans , Preservatives, Pharmaceutical/pharmacology , Cell Survival/drug effects , Benzimidazoles/pharmacology , Benzimidazoles/chemistry , Caspase 3/metabolism , Apoptosis/drug effects , Piperidines/pharmacology , Oxidative Stress/drug effects , Epithelial Cells/drug effects , Epithelial Cells/metabolism , Conjunctiva/drug effects , Conjunctiva/metabolism , Conjunctiva/pathology , Caspase 7/metabolism , Reactive Oxygen Species/metabolism , Conjunctivitis, Allergic/drug therapy , Conjunctivitis, Allergic/pathology , Conjunctivitis, Allergic/metabolism , Phthalazines/pharmacology , Osmolar Concentration , Epithelium, Corneal/drug effects , Epithelium, Corneal/metabolism , Cells, Cultured , ViscosityABSTRACT
BACKGROUND: The CROM instrument is widely used clinically and in research to measure neck range of motion. However, its measurement proprieties during the assessment of protraction and retraction movements were not examined so far. OBJECTIVE: To analyse the intra- and inter-rater reliability, the concurrent validity of the CROM for measuring head posture, retraction and protraction in healthy subjects. METHODS: Thirty-three asymptomatic subjects were recruited and assigned in a random order to one of two raters. After a 10-min break, they were examined by a second rater (Assessment 1). After a 30-min break, both raters repeated the examination (Assessment 2). The examination consisted of measuring the head posture, maximum head protraction and maximum retraction. Each movement was repeated 3 times and measured simultaneously with the CROM and with a 3D capture system laboratory. RESULTS: The intra-rater reliability of the CROM was excellent for both raters for head posture and all head movements (ICC>0.9, 95% CI: 0.82-0.99, p < 0.01). The inter-rater reliability was excellent for head posture (ICC>0.95, 95% CI: 0.92-0.98, p < 0.01) and good-to-excellent for all movements at both time-points (ICC = 0.73-0.98, 95%CI: 0.45-0.99, p < 0.01). The validity analysis showed moderate-to-strong correlation between instruments for the head posture and head movements [(r) = -0.47 to -0.78), 95% CI: 0.99 to -0.24, p < 0.01]. CONCLUSION: The CROM instrument has good-to-excellent reliability and adequate validity for measuring cervical position and displacement in the sagittal plane.
Subject(s)
Posture , Range of Motion, Articular , Humans , Male , Female , Adult , Posture/physiology , Reproducibility of Results , Range of Motion, Articular/physiology , Head/physiology , Head Movements/physiology , Neck/physiology , Observer Variation , Healthy Volunteers , Young AdultSubject(s)
Airway Extubation , Ventilator Weaning , Humans , Ventilator Weaning/methods , Ventilator Weaning/standards , Airway Extubation/methods , Airway Extubation/adverse effects , Airway Extubation/standards , Airway Extubation/statistics & numerical data , Intensive Care Units/organization & administrationSubject(s)
Ventilator Weaning , Humans , Ventilator Weaning/methods , Respiration, Artificial , Time FactorsABSTRACT
Acute respiratory failure due to COVID-19 pneumonia often requires a comprehensive approach that includes non-pharmacological strategies such as non-invasive support (including positive pressure modes, high flow therapy or awake proning) in addition to oxygen therapy, with the primary goal of avoiding endotracheal intubation. Clinical issues such as determining the optimal time to initiate non-invasive support, choosing the most appropriate modality (based not only on the acute clinical picture but also on comorbidities), establishing criteria for recognition of treatment failure and strategies to follow in this setting (including palliative care), or implementing de-escalation procedures when improvement occurs are of paramount importance in the ongoing management of severe COVID-19 cases. Organizational issues, such as the most appropriate setting for management and monitoring of the severe COVID-19 patient or protective measures to prevent virus spread to healthcare workers in the presence of aerosol-generating procedures, should also be considered. While many early clinical guidelines during the pandemic were based on previous experience with acute respiratory distress syndrome, the landscape has evolved since then. Today, we have a wealth of high-quality studies that support evidence-based recommendations to address these complex issues. This document, the result of a collaborative effort between four leading scientific societies (SEDAR, SEMES, SEMICYUC, SEPAR), draws on the experience of 25 experts in the field to synthesize knowledge to address pertinent clinical questions and refine the approach to patient care in the face of the challenges posed by severe COVID-19 infection.
Subject(s)
COVID-19 , Noninvasive Ventilation , Humans , COVID-19/complications , COVID-19/therapy , Respiratory Insufficiency/therapy , Respiratory Insufficiency/etiology , Oxygen Inhalation Therapy , Consensus , SARS-CoV-2 , Pandemics , Interdisciplinary Communication , Positive-Pressure RespirationABSTRACT
The function of the smooth muscle cells lining the walls of mammalian systemic arteries and arterioles is to regulate the diameter of the vessels to control blood flow and blood pressure. Here, we describe an in silico model, which we call the 'Hernandez-Hernandez model', of electrical and Ca2+ signaling in arterial myocytes based on new experimental data indicating sex-specific differences in male and female arterial myocytes from murine resistance arteries. The model suggests the fundamental ionic mechanisms underlying membrane potential and intracellular Ca2+ signaling during the development of myogenic tone in arterial blood vessels. Although experimental data suggest that KV1.5 channel currents have similar amplitudes, kinetics, and voltage dependencies in male and female myocytes, simulations suggest that the KV1.5 current is the dominant current regulating membrane potential in male myocytes. In female cells, which have larger KV2.1 channel expression and longer time constants for activation than male myocytes, predictions from simulated female myocytes suggest that KV2.1 plays a primary role in the control of membrane potential. Over the physiological range of membrane potentials, the gating of a small number of voltage-gated K+ channels and L-type Ca2+ channels are predicted to drive sex-specific differences in intracellular Ca2+ and excitability. We also show that in an idealized computational model of a vessel, female arterial smooth muscle exhibits heightened sensitivity to commonly used Ca2+ channel blockers compared to male. In summary, we present a new model framework to investigate the potential sex-specific impact of antihypertensive drugs.
High blood pressure is a major risk factor for heart disease, which is one of the leading causes of death worldwide. While drugs are available to control blood pressure, male and female patients can respond differently to treatment. However, the biological mechanisms behind this sex difference are not fully understood. Blood pressure is controlled by cells lining the artery walls called smooth muscle cells which alter the width of blood vessels. On the surface of smooth muscle cells are potassium and calcium channels which control the cell's electrical activity. When calcium ions enter the cell via calcium channels, this generates an electrical signal that causes the smooth muscle to contract and narrow the blood vessel. Potassium ions then flood out of the cell via potassium channels to dampen the rise in electrical activity, causing the muscle to relax and widen the artery. There are various sub-types of potassium and calcium channels in smooth muscle cells. Here, Hernandez-Hernandez et al. set out to find how these channels differ between male and female mice, and whether these sex differences could alter the response to blood pressure medication. The team developed a computational model of a smooth muscle cell, incorporating data from laboratory experiments measuring differences in cells isolated from the arteries of male and female mice. The model predicted that the sub-types of potassium and calcium channels in smooth muscle cells varied between males and females, and how the channels impacted electrical activity also differed. For instance, the potassium channel Kv2.1 was found to have a greater role in controlling electrical activity in female mice, and this sex difference impacted blood vessel contraction. The model also predicted that female mice were more sensitive than males to calcium channel blockers, a drug commonly prescribed to treat high blood pressure. The findings by Hernandez-Hernandez et al. provide new insights into the biological mechanisms underlying sex differences in response to blood pressure medication. They also demonstrate how computational models can be used to predict the effects of drugs on different individuals. In the future, these predictions may help researchers to identify better, more personalized treatments for blood pressure.
Subject(s)
Calcium Channel Blockers , Potassium Channels, Voltage-Gated , Mice , Male , Female , Animals , Calcium Channel Blockers/pharmacology , Calcium Channel Blockers/metabolism , Muscle, Smooth, Vascular/metabolism , Arteries/metabolism , Blood Pressure , Potassium Channels, Voltage-Gated/metabolism , Calcium/metabolism , Mammals/metabolismABSTRACT
BACKGROUND: Hypersensitivity reactions to toothpastes are rare. The objective of this study was to present the authors' clinical cases in the past 10 years and perform a scoping review of gingival hypersensitivity responses to toothpastes. TYPES OF STUDIES REVIEWED: The authors reviewed records of documented gingival hypersensitivity reactions to dentifrices at the Postgraduate Clinic of Oral Medicine, Complutense University, Madrid, Spain, from January 2013 through December 2022. Furthermore, the authors conducted a search in PubMed with no date limit for articles reporting these hypersensitivity responses up through October 18, 2023. RESULTS: Eleven cases were collected from the clinic. Eight gingival hypersensitivity reactions occurred in women, and 6 were associated with cinnamon. The most frequent lesions diagnosed were red gingiva. The discontinuation of the toothpaste led to the disappearance of the lesions. The search yielded 643 references. Thirteen articles were included in the scoping review, all of them case series and case reports, reporting 32 cases. Lesions affected middle-aged women most frequently, the most common hypersensitivity reaction was gingival redness, and the cases implicated toothpastes containing cinnamon and herbal composition. PRACTICAL IMPLICATIONS: This study provides clues for diagnosing and treating hypersensitivity reactions to toothpastes, which may improve the identification, management, and reporting of these cases.
Subject(s)
Gingiva , Toothpastes , Middle Aged , Humans , Female , Toothpastes/adverse effectsABSTRACT
INTRODUCTION: Burnout syndrome is a global burden characterized by exhaustion, work detachment, and a sense of ineffectiveness. It affects millions of individuals worldwide, with a particularly high prevalence among medical students. Factors such as demanding education, exposure to suffering, and the COVID-19 pandemic have contributed to elevated stress levels. Addressing this issue is crucial due to its impact on well-being and health-care quality. MATERIALS AND METHODS: This cross-sectional survey study assessed fear of COVID-19 and burnout levels among medical student interns in hospitals in Guadalajara, Jalisco. The study used validated scales and collected data from September 2021 to September 2022. A snowball sampling method was employed and a minimum sample size of 198 participants was calculated. RESULTS: This study included 311 medical students (62.1% female and 37.9% male with a mean age of 23.51 ± 2.21 years). The majority were in their second semester of internship (60.5%) and from public hospitals (89.1%). Most students believed that the COVID-19 pandemic affected the quality of their internship (82.6%). Female students had higher personal burnout scores, while male students had higher work-related burnout scores. The mean score for fear of COVID-19 was 13.71 ± 6.28, with higher scores among women (p = 0.004) and those from public hospitals (p = 0.009). A positive weak correlation was found between COVID-19 scores and burnout subscales. CONCLUSION: Our study emphasizes the significant impact of various factors on burnout levels among medical students and health-care professionals during the COVID-19 pandemic. Prolonged exposure to COVID-19 patients, reduced staffing, and increased workload contributed to burnout, affecting well-being and quality of care. Targeted interventions and resilience-building strategies are needed to mitigate burnout and promote well-being in health-care settings.
Subject(s)
Burnout, Professional , COVID-19 , Humans , Male , Female , Young Adult , Adult , COVID-19/epidemiology , Mental Health , Cross-Sectional Studies , Pandemics , Hospitals, Private , Burnout, Professional/epidemiology , Burnout, Professional/psychology , Surveys and QuestionnairesABSTRACT
The function of the smooth muscle cells lining the walls of mammalian systemic arteries and arterioles is to regulate the diameter of the vessels to control blood flow and blood pressure. Here, we describe an in-silico model, which we call the "Hernandez-Hernandez model", of electrical and Ca2+ signaling in arterial myocytes based on new experimental data indicating sex-specific differences in male and female arterial myocytes from murine resistance arteries. The model suggests the fundamental ionic mechanisms underlying membrane potential and intracellular Ca2+ signaling during the development of myogenic tone in arterial blood vessels. Although experimental data suggest that KV1.5 channel currents have similar amplitudes, kinetics, and voltage dependencies in male and female myocytes, simulations suggest that the KV1.5 current is the dominant current regulating membrane potential in male myocytes. In female cells, which have larger KV2.1 channel expression and longer time constants for activation than male myocytes, predictions from simulated female myocytes suggest that KV2.1 plays a primary role in the control of membrane potential. Over the physiological range of membrane potentials, the gating of a small number of voltage-gated K+ channels and L-type Ca2+ channels are predicted to drive sex-specific differences in intracellular Ca2+ and excitability. We also show that in an idealized computational model of a vessel, female arterial smooth muscle exhibits heightened sensitivity to commonly used Ca2+ channel blockers compared to male. In summary, we present a new model framework to investigate the potential sex-specific impact of anti-hypertensive drugs.
ABSTRACT
PURPOSE: Evaluate the safety profile of expanded allogeneic adipose-derived mesenchymal stem cell (eASC) for the treatment of severe community-acquired bacterial pneumonia (CABP). MATERIALS AND METHODS: Randomized, multicenter, double-blind, placebo-controlled, phase 1b/2a trial. Patients with severe CABP were enrolled to receive intravenous infusions of Cx611 or placebo. The primary objective was safety including hypersensitivity reactions, thromboembolic events, and immunological responses to Cx611. The secondary endpoints included the clinical cure rate, ventilation-free days, and overall survival (Day 90). RESULTS: Eighty-three patients were randomized and received infusions (Cx611: n = 42]; placebo: n = 41]. The mean age was similar (Cx611: 61.1 [11.2] years; placebo: 63.4 [10.4] years). The number of AEs and treatment-emergent AEs were similar (243; 184 and 2; 1) in Cx611 and placebo respectively. Hypersensitivity reactions or thromboembolic events were similar (Cx611: n = 9; placebo: n = 12). Each study arm had similar anti-HLA antibody/DSA levels at Day 90. The clinical cure rate (Cx611: 86.7%; placebo: 93.8%), mean number of ventilator-free days (Cx611: 12.2 [10.29] days; placebo: 15.4 [10.75] days), and overall survival (Cx611: 71.5%; placebo: 77.0%) did not differ between study arms. CONCLUSION: Cx611 was well tolerated in severe CABP. These data provide insights for future stem cell clinical study designs, endpoints and sample size calculation. TRIAL REGISTRATION: NCT03158727 (retrospectively registered: May 09, 2017). Full study protocol: https://clinicaltrials.gov/ProvidedDocs/27/NCT03158727/Prot_000.pdf.
Subject(s)
COVID-19 , Community-Acquired Infections , Pneumonia, Bacterial , Thromboembolism , Humans , Community-Acquired Infections/drug therapy , Double-Blind Method , SARS-CoV-2 , Treatment Outcome , Middle Aged , AgedABSTRACT
In arterial myocytes, the canonical function of voltage-gated CaV1.2 and KV2.1 channels is to induce myocyte contraction and relaxation through their responses to membrane depolarization, respectively. Paradoxically, KV2.1 also plays a sex-specific role by promoting the clustering and activity of CaV1.2 channels. However, the impact of KV2.1 protein organization on CaV1.2 function remains poorly understood. We discovered that KV2.1 forms micro-clusters, which can transform into large macro-clusters when a critical clustering site (S590) in the channel is phosphorylated in arterial myocytes. Notably, female myocytes exhibit greater phosphorylation of S590, and macro-cluster formation compared to males. Contrary to current models, the activity of KV2.1 channels seems unrelated to density or macro-clustering in arterial myocytes. Disrupting the KV2.1 clustering site (KV2.1S590A) eliminated KV2.1 macro-clustering and sex-specific differences in CaV1.2 cluster size and activity. We propose that the degree of KV2.1 clustering tunes CaV1.2 channel function in a sex-specific manner in arterial myocytes.
Subject(s)
Muscle Cells , Shab Potassium Channels , Male , Female , Humans , Shab Potassium Channels/genetics , Shab Potassium Channels/metabolism , Phosphorylation , Myocytes, Smooth Muscle/metabolismABSTRACT
OBJECTIVES: To evaluate whether the severity of xerostomia in older polymedicated patients impacts oral health-related quality of life (OHRQoL). BACKGROUND: Medication-associated xerostomia is common in older people. Xerostomia may impair OHRQoL. MATERIALS AND METHODS: This cross-sectional study included older hypertensive patients from two health centres. We assessed the severity of xerostomia and OHRQoL using the Xerostomia Inventory (XI) tool, and the Oral Health Impact Profile-14 (OHIP-14) instrument, respectively. We measured unstimulated (UWS) and stimulated (SWS) salivary flows. Univariate and multiple linear regression analyses evaluated the associations of XI and OHIP-14 and different explanatory variables. RESULTS: Of the 218 patients enrolled, 51.8% had xerostomia, and 38.1% and 27.5% suffered from UWS and SWS hyposalivation, respectively. Patients with xerostomia, UWS, and SWS hyposalivation scored significantly higher on the XI. However, only those with xerostomia or UWS hyposalivation had significantly higher OHIP-14 scores. A moderate correlation was observed between XI and OHIP-14 scores. The multiple regression model showed that factors with the greatest impact on XI were the patient's complaint of xerostomia, UWS flow rate, age and sex. However, only the XI score was significantly associated with the OHIP-14 score. CONCLUSION: Xerostomia has a negative impact on OHRQoL in older polymedicated patients, but this impact is less than in other types of xerostomia. Longitudinal studies are needed to determine whether changes in the detected explanatory variables influence XI and OHIP scores in these patients.
ABSTRACT
This study is an interdisciplinary research into Uruguayan ayahuasca users belonging to one neo-shamanic and one Santo Daime group. The study involved the chemical analysis of ayahuasca samples, an ethnographic description of the two traditions and rituals, and the application of psychometric scales to measure personality differences, and the acute psychological effects during an ayahuasca ritual. Personality measurements showed lower scores for Santo Daime in Neuroticism-Anxiety, Dependence, Low Self-Esteem, Anger and Restlessness. These differences may be related to the presence of participants under treatment in the neo-shamanic group and/or to the protective effects of a church religion such as Santo Daime. Regarding acute effects, the neo-shamanic group showed higher scores in Somesthesia and Perception, which can be related to the high-arousal ritual setting. Chemical analysis for the ayahuasca samples showed a typical composition of alkaloids. No adulterants were found. The sample from the neo-shamanic group displayed a higher ß-carbolines:DMT ratio compared to the Santo Daime sample, which could be related to the higher effects observed for Somesthesia for the neo-shamanic group. Significant positive correlations between some personality traits and acute effects were found only in the neo-shamanic group, which may be related to the more individualistic approach of this tradition.
Subject(s)
Alkaloids , Banisteriopsis , Humans , Banisteriopsis/chemistry , Religion , Uruguay , PersonalityABSTRACT
To compare the diagnostic effectiveness of chest computed tomography (CT) utilizing a single- versus a dual-reviewer approach in patients with pneumonia secondary to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), we conducted a retrospective observational study of data from a cross-section of 4809 patients with probable SARS-CoV-2 from March to November 2020. All patients had a CT radiological report and reverse-transcription polymerase chain reaction (PCR) results. A dual-reviewer approach was applied to two groups while conducting a comparative examination of the data. Reviewer 1 reported 108 patients negative and 374 patients positive for coronavirus disease 2019 (COVID-19) in group A, and 266 negative and 142 positive in group B. Reviewer 2 reported 150 patients negative and 332 patients positive for COVID-19 in group A, and 277 negative and 131 positive in group B. The consensus result reported 87 patients negative and 395 positive for COVID-19 in group A and 274 negative and 134 positive in group B. These findings suggest that a dual-reviewer approach improves chest CT diagnosis compared to a conventional single-reviewer approach.
Subject(s)
COVID-19 , Pneumonia , Humans , SARS-CoV-2 , COVID-19/complications , COVID-19/diagnostic imaging , Tomography, X-Ray Computed , COVID-19 TestingABSTRACT
In arterial myocytes, the canonical function of voltage-gated Ca V 1.2 and K V 2.1 channels is to induce myocyte contraction and relaxation through their responses to membrane depolarization, respectively. Paradoxically, K V 2.1 also plays a sex-specific role by promoting the clustering and activity of Ca V 1.2 channels. However, the impact of K V 2.1 protein organization on Ca V 1.2 function remains poorly understood. We discovered that K V 2.1 forms micro-clusters, which can transform into large macro-clusters when a critical clustering site (S590) in the channel is phosphorylated in arterial myocytes. Notably, female myocytes exhibit greater phosphorylation of S590, and macro-cluster formation compared to males. Contrary to current models, the activity of K V 2.1 channels seems unrelated to density or macro-clustering in arterial myocytes. Disrupting the K V 2.1 clustering site (K V 2.1 S590A ) eliminated K V 2.1 macro-clustering and sex-specific differences in Ca V 1.2 cluster size and activity. We propose that the degree of K V 2.1 clustering tunes Ca V 1.2 channel function in a sex-specific manner in arterial myocytes.
ABSTRACT
In arterial myocytes, the canonical function of voltage-gated CaV1.2 and KV2.1 channels is to induce myocyte contraction and relaxation through their responses to membrane depolarization, respectively. Paradoxically, KV2.1 also plays a sex-specific role by promoting the clustering and activity of CaV1.2 channels. However, the impact of KV2.1 protein organization on CaV1.2 function remains poorly understood. We discovered that KV2.1 forms micro-clusters, which can transform into large macro-clusters when a critical clustering site (S590) in the channel is phosphorylated in arterial myocytes. Notably, female myocytes exhibit greater phosphorylation of S590, and macro-cluster formation compared to males. Contrary to current models, the activity of KV2.1 channels seems unrelated to density or macro-clustering in arterial myocytes. Disrupting the KV2.1 clustering site (KV2.1S590A) eliminated KV2.1 macro-clustering and sex-specific differences in CaV1.2 cluster size and activity. We propose that the degree of KV2.1 clustering tunes CaV1.2 channel function in a sex-specific manner in arterial myocytes.
ABSTRACT
Congenital dyserythropoietic anemia type II (CDA II) is an inherited autosomal recessive blood disorder which belongs to the wide group of ineffective erythropoiesis conditions. It is characterized by mild to severe normocytic anemia, jaundice, and splenomegaly owing to the hemolytic component. This often leads to liver iron overload and gallstones. CDA II is caused by biallelic mutations in the SEC23B gene. In this study, we report 9 new CDA II cases and identify 16 pathogenic variants, 6 of which are novel. The newly reported variants in SEC23B include three missenses (p.Thr445Arg, p.Tyr579Cys, and p.Arg701His), one frameshift (p.Asp693GlyfsTer2), and two splicing variants (c.1512-2A>G, and the complex intronic variant c.1512-3delinsTT linked to c.1512-16_1512-7delACTCTGGAAT in the same allele). Computational analyses of the missense variants indicated a loss of key residue interactions within the beta sheet and the helical and gelsolin domains, respectively. Analysis of SEC23B protein levels done in patient-derived lymphoblastoid cell lines (LCLs) showed a significant decrease in SEC23B protein expression, in the absence of SEC23A compensation. Reduced SEC23B mRNA expression was only detected in two probands carrying nonsense and frameshift variants; the remaining patients showed either higher gene expression levels or no expression changes at all. The skipping of exons 13 and 14 in the newly reported complex variant c.1512-3delinsTT/c.1512-16_1512-7delACTCTGGAAT results in a shorter protein isoform, as assessed by RT-PCR followed by Sanger sequencing. In this work, we summarize a comprehensive spectrum of SEC23B variants, describe nine new CDA II cases accounting for six previously unreported variants, and discuss innovative therapeutic approaches for CDA II.
Subject(s)
Anemia, Dyserythropoietic, Congenital , Humans , Anemia, Dyserythropoietic, Congenital/genetics , Anemia, Dyserythropoietic, Congenital/metabolism , Mutation , Mutation, Missense , Exons , Alleles , Vesicular Transport Proteins/genetics , Vesicular Transport Proteins/metabolismABSTRACT
Introducción: La modalidad no presencial del proceso de enseñanza-aprendizaje se incrementó como respuesta a las condiciones creadas por la COVID-19, sin la necesaria preparación y experiencia de los docentes para implementarla. Objetivo: Proponer algunas consideraciones didácticas que tributan al adecuado manejo del docente de los componentes del proceso de enseñanza-aprendizaje en la implementación de la modalidad no presencial. Posicionamiento de los autores: La exitosa implementación de cualquier variante de modalidad no presencial dependerá de la preparación del docente, particularmente en Didáctica, al asumir las tecnologías de la información y las comunicaciones como medios de enseñanza en la misión de hacer que sus estudiantes aprendan. Conclusiones: La no presencialidad en el proceso de enseñanza-aprendizaje se considera una alternativa viable en circunstancias de pandemia u otras equivalentes, y debe ser una modalidad complementaria en la etapa posCOVID-19. Así que los profesores tendrán que replantear el proceso en todos sus componentes, en un contexto digital que ya no tiene vuelta atrás(AU)
Introduction: Within the teaching-learning process, the non-face-to-face modality was increased as a response to the conditions created by COVID-19, but without the necessary preparation and experience for professors to implement it. Objective: To propose some didactic considerations that contribute to the professor's adequate management of the components of the teaching-learning process in the implementation of the non-face-to-face modality. Authors' position: The successful implementation of any variant of the non-face-to-face modality will depend on the professor's preparation, particularly in didactics, when assuming information and communication technologies as teaching means in the mission of making their students learn. Conclusions: Within the teaching-learning process, the non-face-to-face condition is considered a viable alternative in pandemic, or other equivalent, circumstances; it should be a complementary modality in the post-COVID-19 stage. Thus, professors will have to rethink the process focusing on all its components, within a digital context that has no turning back(AU)