ABSTRACT
BACKGROUND: Allergy to peanuts and tree nuts is a common cause of food allergy in Spain, with lipid transfer proteins (LTP) being the most frequently recognized panallergen. LTP sensitization often leads to multiple food group sensitivities, resulting in overly restrictive diets that hinder patient's quality of life. This study aimed to assess the tolerance of peanuts and tree nuts (hazelnuts and walnuts) in children sensitized to LTP, potentially mitigating the need for such diets. METHODS: This prospective study enrolled individuals diagnosed with allergy to peanuts, hazelnuts, or walnuts. Data were collected from medical records, including demographics and clinical history. Allergological assessment comprised skin prick tests using commercial extracts and the nuts in question, alongside measurements of total and specific IgE to nuts and their primary molecular components. Participants showing positive LTP sensitization without sensitization to seed storage proteins underwent open oral nut challenges. RESULTS: A total of 75 individuals labeled as allergic to peanuts, 44 to hazelnuts, and 51 to walnuts were included. All of them underwent an open oral provocation test with the incriminated nut, showing a high tolerance rate. Peanut was tolerated by 98.6% of patients, 97.72% tolerated hazelnut, and 84.3% tolerated walnut. CONCLUSION: The findings suggest that the majority of patients allergic to peanuts, hazelnuts, or walnuts, due to LTP sensitization and lacking IgE reactivity to seed storage proteins, can tolerate these nuts. This supports the need for personalized nut tolerance assessments to avoid unnecessary dietary restrictions.
Subject(s)
Arachis , Carrier Proteins , Immune Tolerance , Immunoglobulin E , Nut Hypersensitivity , Skin Tests , Humans , Male , Female , Carrier Proteins/immunology , Child , Spain , Prospective Studies , Child, Preschool , Immunoglobulin E/blood , Immunoglobulin E/immunology , Nut Hypersensitivity/immunology , Nut Hypersensitivity/diagnosis , Arachis/immunology , Peanut Hypersensitivity/immunology , Peanut Hypersensitivity/diagnosis , Allergens/immunology , Juglans/immunology , Nuts/immunology , Adolescent , Corylus/immunology , Nut and Peanut Hypersensitivity/immunology , Antigens, Plant/immunologyABSTRACT
OBJECTIVE: To investigate Brazilian psychiatrists Ì knowledge and perceived confidence, both in diagnosis and in evidence-based treatments for eating disorders (ED). METHODS: In this cross-sectional study, 259 psychiatrists filled out an online form including: sociodemographic data, questions about ED diagnosis and management based on standard guidelines. Descriptive statistics described sample characteristics and levels of ED knowledge and perceived confidence. RESULTS: Sample was composed mainly by women (65,64%), with mean age of 42.86, from the Southeast of Brazil (56,37%), working predominantly in private practice (59,85%), with less than ten years of experience in Psychiatry (51,74%). We found that 33.21% of participants correctly chose diagnostic criteria for anorexia nervosa (AN); 29.73% for bulimia nervosa (BN), and 38.22% for binge eating disorder (BED). Correct answers for therapeutic options were similar in BN and BED (20.8%), being considerably lower for AN (2.7%). Additionally, reported ED training were: 15.1% during medical school; 59.8% during medical residency/postgraduate studies; 58.7% as complementary training. Only 8.89% felt satisfied with their ED training; 50.97% felt confident diagnosing ED and 37.07% in managing ED patients. CONCLUSION: These results demonstrated an important gap in ED knowledge of Brazilian psychiatrists, and its consequences on their confidence and competence in managing ED patients.
ABSTRACT
BACKGROUND: Andersen-Tawil syndrome type 1 is a rare heritable disease caused by mutations in the gene coding the strong inwardly rectifying K+ channel Kir2.1. The extracellular Cys (cysteine)122-to-Cys154 disulfide bond in the channel structure is crucial for proper folding but has not been associated with correct channel function at the membrane. We evaluated whether a human mutation at the Cys122-to-Cys154 disulfide bridge leads to Kir2.1 channel dysfunction and arrhythmias by reorganizing the overall Kir2.1 channel structure and destabilizing its open state. METHODS: We identified a Kir2.1 loss-of-function mutation (c.366 A>T; p.Cys122Tyr) in an ATS1 family. To investigate its pathophysiological implications, we generated an AAV9-mediated cardiac-specific mouse model expressing the Kir2.1C122Y variant. We employed a multidisciplinary approach, integrating patch clamping and intracardiac stimulation, molecular biology techniques, molecular dynamics, and bioluminescence resonance energy transfer experiments. RESULTS: Kir2.1C122Y mice recapitulated the ECG features of ATS1 independently of sex, including corrected QT prolongation, conduction defects, and increased arrhythmia susceptibility. Isolated Kir2.1C122Y cardiomyocytes showed significantly reduced inwardly rectifier K+ (IK1) and inward Na+ (INa) current densities independently of normal trafficking. Molecular dynamics predicted that the C122Y mutation provoked a conformational change over the 2000-ns simulation, characterized by a greater loss of hydrogen bonds between Kir2.1 and phosphatidylinositol 4,5-bisphosphate than wild type (WT). Therefore, the phosphatidylinositol 4,5-bisphosphate-binding pocket was destabilized, resulting in a lower conductance state compared with WT. Accordingly, on inside-out patch clamping, the C122Y mutation significantly blunted Kir2.1 sensitivity to increasing phosphatidylinositol 4,5-bisphosphate concentrations. In addition, the Kir2.1C122Y mutation resulted in channelosome degradation, demonstrating temporal instability of both Kir2.1 and NaV1.5 proteins. CONCLUSIONS: The extracellular Cys122-to-Cys154 disulfide bond in the tridimensional Kir2.1 channel structure is essential for the channel function. We demonstrate that breaking disulfide bonds in the extracellular domain disrupts phosphatidylinositol 4,5-bisphosphate-dependent regulation, leading to channel dysfunction and defects in Kir2.1 energetic stability. The mutation also alters functional expression of the NaV1.5 channel and ultimately leads to conduction disturbances and life-threatening arrhythmia characteristic of Andersen-Tawil syndrome type 1.
Subject(s)
Andersen Syndrome , Humans , Mice , Animals , Andersen Syndrome/genetics , Andersen Syndrome/metabolism , Mutation , Myocytes, Cardiac/metabolism , Cardiac Conduction System Disease , Disulfides , Phosphatidylinositols/metabolismABSTRACT
AIMS: Short QT syndrome type 3 (SQTS3) is a rare arrhythmogenic disease caused by gain-of-function mutations in KCNJ2, the gene coding the inward rectifier potassium channel Kir2.1. We used a multidisciplinary approach and investigated arrhythmogenic mechanisms in an in-vivo model of de-novo mutation Kir2.1E299V identified in a patient presenting an extremely abbreviated QT interval and paroxysmal atrial fibrillation. METHODS AND RESULTS: We used intravenous adeno-associated virus-mediated gene transfer to generate mouse models, and confirmed cardiac-specific expression of Kir2.1WT or Kir2.1E299V. On ECG, the Kir2.1E299V mouse recapitulated the QT interval shortening and the atrial-specific arrhythmia of the patient. The PR interval was also significantly shorter in Kir2.1E299V mice. Patch-clamping showed extremely abbreviated action potentials in both atrial and ventricular Kir2.1E299V cardiomyocytes due to a lack of inward-going rectification and increased IK1 at voltages positive to -80â mV. Relative to Kir2.1WT, atrial Kir2.1E299V cardiomyocytes had a significantly reduced slope conductance at voltages negative to -80â mV. After confirming a higher proportion of heterotetrameric Kir2.x channels containing Kir2.2 subunits in the atria, in-silico 3D simulations predicted an atrial-specific impairment of polyamine block and reduced pore diameter in the Kir2.1E299V-Kir2.2WT channel. In ventricular cardiomyocytes, the mutation increased excitability by shifting INa activation and inactivation in the hyperpolarizing direction, which protected the ventricle against arrhythmia. Moreover, Purkinje myocytes from Kir2.1E299V mice manifested substantially higher INa density than Kir2.1WT, explaining the abbreviation in the PR interval. CONCLUSION: The first in-vivo mouse model of cardiac-specific SQTS3 recapitulates the electrophysiological phenotype of a patient with the Kir2.1E299V mutation. Kir2.1E299V eliminates rectification in both cardiac chambers but protects against ventricular arrhythmias by increasing excitability in both Purkinje-fiber network and ventricles. Consequently, the predominant arrhythmias are supraventricular likely due to the lack of inward rectification and atrial-specific reduced pore diameter of the Kir2.1E299V-Kir2.2WT heterotetramer.
Subject(s)
Atrial Fibrillation , Disease Models, Animal , Myocytes, Cardiac , Potassium Channels, Inwardly Rectifying , Animals , Humans , Mice , Action Potentials , Arrhythmias, Cardiac/genetics , Arrhythmias, Cardiac/physiopathology , Arrhythmias, Cardiac/metabolism , Atrial Fibrillation/genetics , Atrial Fibrillation/physiopathology , Atrial Fibrillation/metabolism , Genetic Predisposition to Disease , Heart Rate/genetics , Heart Ventricles/metabolism , Heart Ventricles/physiopathology , Mice, Inbred C57BL , Mice, Transgenic , Mutation , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/pathology , Phenotype , Potassium Channels, Inwardly Rectifying/genetics , Potassium Channels, Inwardly Rectifying/metabolismABSTRACT
Nanotechnological platforms offer advantages over conventional therapeutic and diagnostic modalities. However, the efficient biointerfacing of nanomaterials for biomedical applications remains challenging. In recent years, nanoparticles (NPs) with different coatings have been developed to reduce nonspecific interactions, prolong circulation time, and improve therapeutic outcomes. This study aims to compare various NP coatings to enhance surface engineering for more effective nanomedicines. We prepared and characterized polystyrene NPs with different coatings of poly(ethylene glycol), bovine serum albumin, chitosan, and cell membranes from a human breast cancer cell line. The coating was found to affect the colloidal stability, adhesion, and elastic modulus of NPs. Protein corona formation and cellular uptake of NPs were also investigated, and a 3D tumor model was employed to provide a more realistic representation of the tumor microenvironment. The prepared NPs were found to reduce protein adsorption, and cell-membrane-coated NPs showed significantly higher cellular uptake. The secretion of proinflammatory cytokines in human monocytes after incubation with the prepared NPs was evaluated. Overall, the study demonstrates the importance of coatings in affecting the behavior and interaction of nanosystems with biological entities. The findings provide insight into bionano interactions and are important for the effective implementation of stealth surface engineering designs.
Subject(s)
Nanoparticles , Neoplasms , Humans , Cell Membrane/metabolism , Polyethylene Glycols/metabolism , Serum Albumin, Bovine/metabolism , Nanoparticles/metabolism , Nanomedicine , Neoplasms/metabolismABSTRACT
Several studies showed an association between metabolic syndrome (MetS) and Parkinson's disease (PD). The linking mechanisms remain unclear. MetS promotes low-grade peripheral oxidative stress and inflammation and dysregulation of the adipose renin-angiotensin system (RAS). Interestingly, brain RAS dysregulation is involved in the progression of dopaminergic degeneration and PD. Circulating extracellular vesicles (EVs) from MetS fat tissue can cross the brain-blood barrier and may act as linking signals. We isolated and characterized EVs from MetS and control rats and analyzed their mRNA and protein cargo using RT-PCR and the ExoView R200 platform, respectively. Furthermore, cultures of the N27 dopaminergic cell line and the C6 astrocytic cell line were treated with EVs from MetS rats. EVs were highly increased in MetS rat serum, which was inhibited by treatment of the rats with the angiotensin type-1-receptor blocker candesartan. Furthermore, EVs from MetS rats showed increased pro-oxidative/pro-inflammatory and decreased anti-oxidative/anti-inflammatory RAS components, which were inhibited in candesartan-treated MetS rats. In cultures, EVs from MetS rats increased N27 cell death and modulated C6 cell function, upregulating markers of neuroinflammation and oxidative stress, which were inhibited by the pre-treatment of cultures with candesartan. The results from rat models suggest EVs and their RAS cargo as a mechanism linking Mets and PD.
ABSTRACT
BACKGROUND: Pru p 7 has been reported as a major allergen in peach allergy, associated with severe clinical symptoms and related to IgE sensitisation to cypress pollen. The main objective of this study was to prospectively evaluate the frequency of sensitisation to Pru p 7 and its clinical relevance amongst pediatric patients with peach allergy in Madrid (Spain). METHODS: Patients with a history of IgE-mediated symptoms (oral allergy syndrome, urticaria/angioedema, rhinoconjunctivitis/asthma, gastrointestinal symptoms, or anaphylaxis) occurring within 2 h after peach intake or contact were prospectively recruited from February 2020 to September 2021. Skin tests, sIgE by ImmunoCAP® (Pru p 1, Pru p 3, Pru p 4, Pru p 7, and Cupressus arizonica) and oral food challenge (OFC) were performed. The study was approved by the local Ethics Committee (PI-4513). RESULTS: Ninety-two patients were included (53.3% male); median age, 10 (IQR 6.0-14.75) years. Seventy-four (80.4%) patients had a reaction after ingestion of fresh peach (25.0% from peel, 23.9% from pulp, and 44.6% from both). Fifteen (16.3%) patients were sensitised to Pru p 7. Upper airway symptoms, anaphylaxis, and grade 2 reactions were statistically more frequent in patients sensitised to Pru p 7. Seven (7.9%) patients presented with exercise as a cofactor, four of whom were sensitised to Pru p 7 (p = .001). Patients sensitised to Pru p 7 were significantly more likely to have a positive OFC result than patients who were not (p = .008). Four patients who reacted to peach at OFC were sensitised to Pru p 7. Specific IgE against Cupressus arizonica pollen was positive in 25 (62.5%) patients. CONCLUSIONS: Pru p 7 sensitisation was observed in 16.3% of our population and was related to severe reactions, upper airway symptoms, anaphylaxis, and the presence of an eliciting cofactor.
Subject(s)
Anaphylaxis , Food Hypersensitivity , Prunus persica , Humans , Male , Child , Female , Allergens , Prunus persica/adverse effects , Anaphylaxis/diagnosis , Anaphylaxis/epidemiology , Anaphylaxis/etiology , Antigens, Plant , Plant Proteins , Immunoglobulin EABSTRACT
Herein, we report the direct synthesis of a wide variety of functionalized aromatic bromides, chlorides, iodides, and fluorides from nitroarenes in a sequential one-pot operation. This protocol is based on an air- and moisture-tolerant dioxomolybdenum-catalyzed reduction of nitroaromatics, employing pinacol as a reducing agent, which enables subsequent diazotization and halogenation steps. This methodology represents a step-economical, practical, and alternative procedure for synthesizing haloaromatics directly from nitroaromatics.
ABSTRACT
Cardiotoxicity due to anthracyclines (CDA) affects cancer patients, but we cannot predict who may suffer from this complication. CDA is a complex trait with a polygenic component that is mainly unidentified. We propose that levels of intermediate molecular phenotypes (IMPs) in the myocardium associated with histopathological damage could explain CDA susceptibility, so variants of genes encoding these IMPs could identify patients susceptible to this complication. Thus, a genetically heterogeneous cohort of mice (n = 165) generated by backcrossing were treated with doxorubicin and docetaxel. We quantified heart fibrosis using an Ariol slide scanner and intramyocardial levels of IMPs using multiplex bead arrays and QPCR. We identified quantitative trait loci linked to IMPs (ipQTLs) and cdaQTLs via linkage analysis. In three cancer patient cohorts, CDA was quantified using echocardiography or Cardiac Magnetic Resonance. CDA behaves as a complex trait in the mouse cohort. IMP levels in the myocardium were associated with CDA. ipQTLs integrated into genetic models with cdaQTLs account for more CDA phenotypic variation than that explained by cda-QTLs alone. Allelic forms of genes encoding IMPs associated with CDA in mice, including AKT1, MAPK14, MAPK8, STAT3, CAS3, and TP53, are genetic determinants of CDA in patients. Two genetic risk scores for pediatric patients (n = 71) and women with breast cancer (n = 420) were generated using machine-learning Least Absolute Shrinkage and Selection Operator (LASSO) regression. Thus, IMPs associated with heart damage identify genetic markers of CDA risk, thereby allowing more personalized patient management.
Subject(s)
Cardiotoxicity , Neoplasms , Female , Animals , Mice , Cardiotoxicity/etiology , Anthracyclines/adverse effects , Genetic Markers , Antibiotics, Antineoplastic/therapeutic use , Neoplasms/drug therapy , PhenotypeABSTRACT
Background: Andersen-Tawil Syndrome Type 1 (ATS1) is a rare heritable disease caused by mutations in the strong inwardly rectifying K+ channel Kir2.1. The extracellular Cys122-to-Cys154 disulfide bond in the Kir2.1 channel structure is crucial for proper folding, but has not been associated with correct channel function at the membrane. We tested whether a human mutation at the Cys122-to-Cys154 disulfide bridge leads to Kir2.1 channel dysfunction and arrhythmias by reorganizing the overall Kir2.1 channel structure and destabilizing the open state of the channel. Methods and Results: We identified a Kir2.1 loss-of-function mutation in Cys122 (c.366 A>T; p.Cys122Tyr) in a family with ATS1. To study the consequences of this mutation on Kir2.1 function we generated a cardiac specific mouse model expressing the Kir2.1C122Y mutation. Kir2.1C122Y animals recapitulated the abnormal ECG features of ATS1, like QT prolongation, conduction defects, and increased arrhythmia susceptibility. Kir2.1C122Y mouse cardiomyocytes showed significantly reduced inward rectifier K+ (IK1) and inward Na+ (INa) current densities independently of normal trafficking ability and localization at the sarcolemma and the sarcoplasmic reticulum. Kir2.1C122Y formed heterotetramers with wildtype (WT) subunits. However, molecular dynamic modeling predicted that the Cys122-to-Cys154 disulfide-bond break induced by the C122Y mutation provoked a conformational change over the 2000 ns simulation, characterized by larger loss of the hydrogen bonds between Kir2.1 and phosphatidylinositol-4,5-bisphosphate (PIP2) than WT. Therefore, consistent with the inability of Kir2.1C122Y channels to bind directly to PIP2 in bioluminescence resonance energy transfer experiments, the PIP2 binding pocket was destabilized, resulting in a lower conductance state compared with WT. Accordingly, on inside-out patch-clamping the C122Y mutation significantly blunted Kir2.1 sensitivity to increasing PIP2 concentrations. Conclusion: The extracellular Cys122-to-Cys154 disulfide bond in the tridimensional Kir2.1 channel structure is essential to channel function. We demonstrated that ATS1 mutations that break disulfide bonds in the extracellular domain disrupt PIP2-dependent regulation, leading to channel dysfunction and life-threatening arrhythmias.
ABSTRACT
A new two-step procedure for the synthesis of 1,4-dicarbonyls has been developed involving an efficient and clean Mo-catalyzed oxidative cleavage of cyclobutane-1,2-diols with DMSO, which is used as solvent and oxidant. The required starting glycols were prepared by nucleophilic additions of organolithiums and Grignard reagents to easily available 2-hydroxycyclobutanones.
ABSTRACT
BACKGROUND: SARS-CoV-2 virus originated in Wuhan (China) in December (2019) and quickly spread worldwide. Antigen tests are rapid diagnostic tests (RDT) that produce results in 15-30 min and are an important tool for the scale-up of COVID-19 testing. COVID-19 diagnostic tests are authorized for self-testing at home in some countries, including Brazil. Widespread COVID-19 diagnostic testing is required to guide public health policies and control the speed of transmission and economic recovery. METHODS: Patients with suspected COVID-19 were recruited at the Hospital da Baleia (Belo Horizonte, Brazil). The SARS-CoV-2 antigen-detecting rapid diagnostic tests were evaluated from June 2020 to June 2021 using saliva, nasal, and nasopharyngeal swab samples from 609 patients. Patient samples were simultaneously tested using a molecular assay (RT-qPCR). Sensitivity, specificity, accuracy, and positive and negative predictive values were determined using the statistical program, MedCalc, and GraphPad Prism 8.0. RESULTS: The antigen-detecting rapid diagnostic tests displayed 98% specificity, 60% sensitivity, 96% positive predictive value, and moderate concordance with RT-qPCR. Substantial agreement was found between the two methods for patients tested < 7 days of symptom onset. CONCLUSIONS: Our findings support the use of Ag-RDT as a valuable and safe diagnostic method. Ag-RDT was also demonstrated to be an important triage tool for suspected COVID-19 patients in emergencies. Overall, Ag-RDT is an effective strategy for reducing the spread of SARS-CoV-2 and contributing to COVID-19 control.
Subject(s)
COVID-19 , Humans , COVID-19 Testing , SARS-CoV-2 , Self-Testing , Biological AssayABSTRACT
Cardiotoxicity due to anthracyclines (CDA) affects cancer patients, but we cannot predict who may suffer from this complication. CDA is a complex disease whose polygenic component is mainly unidentified. We propose that levels of intermediate molecular phenotypes in the myocardium associated with histopathological damage could explain CDA susceptibility; so that variants of genes encoding these intermediate molecular phenotypes could identify patients susceptible to this complication. A genetically heterogeneous cohort of mice generated by backcrossing (N = 165) was treated with doxorubicin and docetaxel. Cardiac histopathological damage was measured by fibrosis and cardiomyocyte size by an Ariol slide scanner. We determine intramyocardial levels of intermediate molecular phenotypes of CDA associated with histopathological damage and quantitative trait loci (ipQTLs) linked to them. These ipQTLs seem to contribute to the missing heritability of CDA because they improve the heritability explained by QTL directly linked to CDA (cda-QTLs) through genetic models. Genes encoding these molecular subphenotypes were evaluated as genetic markers of CDA in three cancer patient cohorts (N = 517) whose cardiac damage was quantified by echocardiography or Cardiac Magnetic Resonance. Many SNPs associated with CDA were found using genetic models. LASSO multivariate regression identified two risk score models, one for pediatric cancer patients and the other for women with breast cancer. Molecular intermediate phenotypes associated with heart damage can identify genetic markers of CDA risk, thereby allowing a more personalized patient management. A similar strategy could be applied to identify genetic markers of other complex trait diseases.
ABSTRACT
The metabolic syndrome has been associated to chronic peripheral inflammation and related with neuroinflammation and neurodegeneration, including Parkinson's disease. However, the responsible mechanisms are unclear. Previous studies have involved the brain renin-angiotensin system in progression of Parkinson's disease and the angiotensin receptor type 1 (AT1) has been recently revealed as a major marker of dopaminergic vulnerability in humans. Dysregulation of tissue renin-angiotensin system is a key common mechanism for all major components of metabolic syndrome. Circulating AT1 agonistic autoantibodies have been observed in several inflammation-related peripheral processes, and activation of AT1 receptors of endothelial cells, dopaminergic neurons and glial cells have been observed to disrupt endothelial blood -brain barrier and induce neurodegeneration, respectively. Using a rat model, we observed that metabolic syndrome induces overactivity of nigral pro-inflammatory renin-angiotensin system axis, leading to increase in oxidative stress and neuroinflammation and enhancing dopaminergic neurodegeneration, which was inhibited by treatment with AT1 receptor blockers (ARBs). In rats, metabolic syndrome induced the increase in circulating levels of LIGHT and other major pro-inflammatory cytokines, and 27-hydroxycholesterol. Furthermore, the rats showed a significant increase in serum levels of proinflammatory AT1 and angiotensin converting enzyme 2 (ACE2) autoantibodies, which correlated with levels of several metabolic syndrome parameters. We also found AT1 and ACE2 autoantibodies in the CSF of these rats. Effects of circulating autoantibodies were confirmed by chronic infusion of AT1 autoantibodies, which induced blood-brain barrier disruption, an increase in the pro-inflammatory renin-angiotensin system activity in the substantia nigra and a significant enhancement in dopaminergic neuron death in two different rat models of Parkinson's disease. Observations in the rat models, were analyzed in a cohort of parkinsonian and non-parkinsonian patients with or without metabolic syndrome. Non-parkinsonian patients with metabolic syndrome showed significantly higher levels of AT1 autoantibodies than non-parkinsonian patients without metabolic syndrome. However, there was no significant difference between parkinsonian patients with metabolic syndrome or without metabolic syndrome, which showed higher levels of AT1 autoantibodies than non-parkinsonian controls. This is consistent with our recent studies, showing significant increase of AT1 and ACE2 autoantibodies in parkinsonian patients, which was related to dopaminergic degeneration and neuroinflammation. Altogether may lead to a vicious circle enhancing the progression of the disease that may be inhibited by strategies against production of these autoantibodies or AT1 receptor blockers (ARBs).
Subject(s)
Metabolic Syndrome , Parkinson Disease , Animals , Humans , Rats , Angiotensin II/metabolism , Angiotensin II/pharmacology , Angiotensin Receptor Antagonists/metabolism , Angiotensin Receptor Antagonists/pharmacology , Angiotensin-Converting Enzyme 2/metabolism , Angiotensin-Converting Enzyme Inhibitors/metabolism , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Autoantibodies/metabolism , Dopamine/metabolism , Dopaminergic Neurons/metabolism , Endothelial Cells/metabolism , Inflammation/metabolism , Metabolic Syndrome/metabolism , Neuroinflammatory Diseases , Parkinson Disease/metabolism , Receptor, Angiotensin, Type 1/metabolismABSTRACT
Andersen-Tawil syndrome (ATS) is a rare inheritable disease associated with loss-of-function mutations in KCNJ2, the gene coding the strong inward rectifier potassium channel Kir2.1, which forms an essential membrane protein controlling cardiac excitability. ATS is usually marked by a triad of periodic paralysis, life-threatening cardiac arrhythmias and dysmorphic features, but its expression is variable and not all patients with a phenotype linked to ATS have a known genetic alteration. The mechanisms underlying this arrhythmogenic syndrome are poorly understood. Knowing such mechanisms would be essential to distinguish ATS from other channelopathies with overlapping phenotypes and to develop individualized therapies. For example, the recently suggested role of Kir2.1 as a countercurrent to sarcoplasmic calcium reuptake might explain the arrhythmogenic mechanisms of ATS and its overlap with catecholaminergic polymorphic ventricular tachycardia. Here we summarize current knowledge on the mechanisms of arrhythmias leading to sudden cardiac death in ATS. We first provide an overview of the syndrome and its pathophysiology, from the patient's bedside to the protein and discuss the role of essential regulators and interactors that could play a role in cases of ATS. The review highlights novel ideas related to some post-translational channel interactions with partner proteins that might help define the molecular bases of the arrhythmia phenotype. We then propose a new all-embracing classification of the currently known ATS loss-of-function mutations according to their position in the Kir2.1 channel structure and their functional implications. We also discuss specific ATS pathogenic variants, their clinical manifestations, and treatment stratification. The goal is to provide a deeper mechanistic understanding of the syndrome toward the development of novel targets and personalized treatment strategies.
Subject(s)
Andersen Syndrome , Tachycardia, Ventricular , Humans , Andersen Syndrome/diagnosis , Andersen Syndrome/genetics , Andersen Syndrome/therapy , Tachycardia, Ventricular/diagnosis , Tachycardia, Ventricular/genetics , Mutation , Phenotype , Death, Sudden, Cardiac/etiologyABSTRACT
AIMS: Health literacy (HL), the ability to obtain and understand health information, is critical to self-care in chronic disorders. A low HL is common among these patients and has been associated with a worse prognosis. Nevertheless, the relationship between HL and the prognosis of heart failure (HF) with reduced (HFrEF) vs. preserved (HFpEF) ejection fraction remains unsettled. To analyse the relationship between HL and the prognosis of patients with incident HFrEF and HFpEF. METHODS AND RESULTS: Prospective study over 10 years (2010-19) on 6444 patients diagnosed with incident HF. The main outcomes were mortality, hospitalizations, and visits to emergency services. The independent relationship between HL and the prognosis, stratifying patients for cardiovascular comorbidity after propensity score-matching was analysed.After matching 5355 HF patients, 1785 with low HL (874 with HFrEF and 911 with HFpEF) vs. 3570 with adequate HL (1748 with HFrEF and 1822 with HFpEF), during a median follow-up of 5.41 years, 3874 patients died (72.3%) and 3699 patients were hospitalized (69.1%). After adjustment for potential confounders, an adequate HL was associated with a lower all-cause and cardiovascular mortality, less hospitalizations, and less 30-day readmissions [relative risk (RR) for HF <0.72 (0.66-0.86), RR for HFrEF <0.69 (0.63-0.95), and RR for HFpEF <0.62 (0.55-0.88), P < 0.001 in all cases], both for patients with HFrEF and HFpEF. Analyses of recurrent hospitalizations gave larger HL effects than time-to-first-event analyses. CONCLUSIONS: In this propensity-matched study, a low HL is associated with a worse prognosis of patients with incident HFrEF and HFpEF.
Subject(s)
Health Literacy , Heart Failure , Humans , Prospective Studies , Stroke Volume , PrognosisABSTRACT
ABSTRACT Background: SARS-CoV-2 virus originated in Wuhan (China) in December (2019) and quickly spread worldwide. Antigen tests are rapid diagnostic tests (RDT) that produce results in 15-30 min and are an important tool for the scale-up of COVID-19 testing. COVID-19 diagnostic tests are authorized for self-testing at home in some countries, including Brazil. Widespread COVID-19 diagnostic testing is required to guide public health policies and control the speed of transmission and economic recovery. Methods: Patients with suspected COVID-19 were recruited at the Hospital da Baleia (Belo Horizonte, Brazil). The SARS-CoV-2 antigen-detecting rapid diagnostic tests were evaluated from June 2020 to June 2021 using saliva, nasal, and nasopharyngeal swab samples from 609 patients. Patient samples were simultaneously tested using a molecular assay (RT-qPCR). Sensitivity, specificity, accuracy, and positive and negative predictive values were determined using the statistical program, MedCalc, and GraphPad Prism 8.0. Results: The antigen-detecting rapid diagnostic tests displayed 98% specificity, 60% sensitivity, 96% positive predictive value, and moderate concordance with RT-qPCR. Substantial agreement was found between the two methods for patients tested < 7 days of symptom onset. Conclusions: Our findings support the use of Ag-RDT as a valuable and safe diagnostic method. Ag-RDT was also demonstrated to be an important triage tool for suspected COVID-19 patients in emergencies. Overall, Ag-RDT is an effective strategy for reducing the spread of SARS-CoV-2 and contributing to COVID-19 control.
ABSTRACT
Abstract This article briefly presents the theoretical-methodological perspective of the Network of Meanings and its methodological implications. The aim is to question the use of autobiographical narratives as a possible methodological tool to approach the study of development, with the specificity of understanding processes of constitutive transformations in human ontogenesis, from an interactional perspective, as is the case of the Network of Meanings. We revisit a study based on autobiographical narratives with five adult drag queens, aged between 20 and 39 years old, exploring personal and artistic experiences. Their narratives were analyzed microgenetically and some central concepts of the Network of Meanings were raised - dialogic interactive fields, socio-historical matrix, and temporalities. The autobiographical narrative of the participants constitutes a fruitful field of qualitative analysis, allowing us to approach the processes of change and transformation throughout life. As a result, a dialogue between Developmental Psychology and Social and Cultural Psychology is promoted.
Resumo O estudo apresenta brevemente a perspectiva teórico-metodológica da Rede de Significações (RedSig) e suas implicações metodológicas. O presente estudo teve como objetivo problematizar a narrativa autobiográfica como ferramenta metodológica possível para abordar o estudo do desenvolvimento com a especificidade de compreender processos de transformações constitutivos da ontogênese humana, em uma perspectiva interacional como é o caso da RedSig. Retoma-se um estudo realizado a partir de narrativas autobiográficas com cinco drag queens adultas, com idade entre 20 e 39 anos, explorando experiências pessoais e artísticas. Suas narrativas foram analisadas microgeneticamente e são alçados alguns conceitos centrais da Rede de Significações − campos interativos dialógicos, matriz sócio-histórica e temporalidades. A narrativa autobiográfica das participantes se constitui como um campo profícuo de análise qualitativa, permitindo abordar os processos de mudança e transformação ao longo da vida. Em decorrência, promove-se um diálogo entre a Psicologia do Desenvolvimento e a Psicologia Social e Cultural.
Resumen El artículo presenta brevemente la perspectiva teórico-metodológica de la Red de Sentidos y sus implicaciones metodológicas. El objetivo es problematizar el uso de la narrativa autobiográfica como posible herramienta metodológica para abordar el estudio del desarrollo, con la especificidad de comprender procesos de transformaciones constitutivas de la ontogénesis humana. Retomamos un estudio realizado con cinco drag queens adultas, con edades entre 20 y 39 años, a partir de narrativas autobiográficas, explorando experiencias personales y artísticas. Sus narrativas fueron analizadas microgenéticamente y se plantean algunos conceptos centrales de la Red de Sentidos: campos interactivos dialógicos, matriz sociohistórica y temporalidades. La narrativa autobiográfica de los participantes constituye un campo fecundo de análisis cualitativo, que permite abordar los procesos de cambio y transformación a lo largo de la vida. Como resultado, se promueve un diálogo entre la Psicología del Desarrollo y la Psicología Social y Cultural.
Subject(s)
Autobiography , Qualitative Research , Methodology as a Subject , Gender Identity , Human DevelopmentABSTRACT
In the US, over 95 million people have been infected with COVID and over 1 million have died. 10% of Californians are infected with COVID with higher rates reported among Latinx, Pacific Islanders, and low-income people. Higher death rates have been reported among African Americans. People living with Alzheimer's Disease (AD) are also more likely to be infected with COVID. African Americans with AD have three times the COVID rate of Whites. Homecare workers who care for moderate to severe AD in home and community settings are frontline essential workers who manage complex AD-related problems like incontinence. Little is known about communication and problem-solving processes between homecare workers and families of people with AD to manage continence at home. This report describes the challenges facing homecare workers illustrated by an African American family caring for a relative with advanced AD during pandemic.
ABSTRACT
Spleen is a key organ for immunologic surveillance, acting as a firewall for antigens and parasites that spread through the blood. However, how spleen leukocytes evolve across the developmental phase, and how they spatially organize and interact in vivo is still poorly understood. Using a novel combination of selected antibodies and fluorophores to image in vivo the spleen immune environment, we described for the first time the dynamics of immune development across postnatal period. We found that spleens from adults and infants had similar numbers and arrangement of lymphoid cells. In contrast, splenic immune environment in newborns is sharply different from adults in almost all parameters analysed. Using this in vivo approach, B cells were the most frequent subtype throughout the development. Also, we revealed how infections - using a model of malaria - can change the spleen immune profile in adults and infants, which could become the key to understanding different severity grades of infection. Our new imaging solutions can be extremely useful for different groups in all areas of biological investigation, paving a way for new intravital approaches and advances.