BACKGROUND

Observational studies have increasingly reported transthyretin amyloid cardiomyopathy (ATTR-CM) as an under-recognized cause of heart failure. We report the first ATTR-CM diagnosed via multi-modality imaging in the Philippines signifying an important milestone in recognition and management of this formerly believed rare disease, locally. Utilization of non-invasive imaging such as echocardiography, cardiac MRI and technetium-99m pyrophosphate scintigraphy (PYP) demonstrates the potential for accurate diagnosis as well as timely and appropriate treatment strategies.

An 81/M Filipino with a history of carpal tunnel surgery, post-percutaneous coronary intervention (PCI), had three months’ history of refractory heart failure symptoms despite optimized medical treatment. His 2D-echo showed an ejection fraction (EF): 45%-50%, increased left ventricular (LV) posterior wall thickness with mild basal inferior wall hypokinesia and ECG: atrial fibrillation with low voltage. Speckle tracking imaging showed average global longitudinal strain: - 6.5% with cherry-on-top pattern on polar strain map. Cardiac MRI demonstrated diffuse late gadolinium enhancement from endocardial to transmural layers of biventricular and biatrial walls, highly suggestive of cardiac amyloidosis (CA). Light-chain amyloidosis was excluded by negative serum/urine protein electrophoresis/immunofixation. Tc-99m PYP scan revealed greater myocardial-than-bone uptake with a Perugini score 3 and calculated heart-to-contralateral ratio of 1.7. Congestion was controlled with intravenous loop diuretics and he was discharged stable with metoprolol succinate, dapagliflozin and apixaban. At the time of paper submission, he is currently being evaluated for tafamidis treatment.

The case highlighted the advantage of multi-modality imaging for noninvasive yet accurate identification of the disease. A tailored approach is required in slowing the disease progression and improving outcomes.

Objective This study aims to achieve high-yield functional expression of the human voltage-gated potassium channel K_V3.1 using an Escherichia coli cell-free protein synthesis system, thereby providing a novel synthetic approach for drug screening, structural analysis and functional characterization of K_V3.1. Methods K_V3.1 was expressed in an Escherichia coli cell-free protein synthesis system for 10 hours in the presence of peptide surfactant A₆K. The secondary structure of K_V3.1 was analyzed by circular dichroism spectroscopy. The potassium channel activity of the recombinant protein liposome K_V3.1-A₆K was investigated using fluorescent dyes Oxonol VI as indicators, which are capable of reflecting alterations in membrane potential. Results Soluble K_V3.1 protein was successfully synthesized, achieving a purified yield of up to 1.2 mg/mL via an Escherichia coli cell-free protein synthesis system. Circular dichroism spectroscopy revealed that K_V3.1 exhibited characteristic α-helical secondary structures. Membrane potential fluorescence assays demonstrated that the K_V3.1-A₆K proteoliposomes, which were reconstructed with surfactant peptide A₆K, exhibited remarkable potassium ion permeability. Conclusion This study successfully achieved high-yield expression of human K_V3.1 with activity using an Escherichia coli-based cell-free protein synthesis system. This innovative method not only significantly enhances the expression yield of K_V3.1, but also maintains its functional activity, thereby establishing a novel and efficient synthetic platform for drug screening and advancing our understanding of structure-function relationships in K_V3.1 research.
Humans ; Escherichia coli/metabolism* ; Shaw Potassium Channels/biosynthesis* ; Cell-Free System ; Circular Dichroism ; Protein Biosynthesis ; Recombinant Proteins/metabolism* ; Membrane Potentials ; Shab Potassium Channels

Recent studies have revealed a significant relationship between erectile dysfunction (ED) and lower urinary tract symptoms (LUTS), both of which commonly affect middle-aged and older men. These conditions share underlying causes, particularly endothelial dysfunction, atherosclerosis, and chronic pelvic ischemia (CPI). This study investigated the therapeutic potential of LDD175, a large-conductance Ca 2+ -activated K + channel (BKCa channel) opener, in simultaneously treating both conditions using a CPI animal model of male Sprague Dawley rats. Our study investigated the induction of CPI through surgical endothelial damage combined with a high-cholesterol diet. We assessed erectile and voiding functions by measuring intracavernosal pressure (ICP) and intraurethral pressure (IUP), respectively, after nerve stimulation. We performed histological examinations of vascular changes and western blot analyses of cavernous and prostate tissues to understand the underlying mechanisms. This study evaluated the effectiveness of LDD175 compared to standard treatments, such as sildenafil for ED and tamsulosin for LUTS. Therefore, the CPI model successfully demonstrated ED and LUTS symptoms with decreased ICP and increased IUP. Analysis revealed elevated levels of hypoxia-inducible factor-1α, transforming growth factor-β1 and β2 in cavernous tissue, and increased α1A-adrenoceptor expression in prostate tissue. LDD175 administration showed promising results, with dose-dependent improvements in ICP and IUP, and therapeutic effects comparable to those of established treatments. Our findings suggest a novel therapeutic approach that can simultaneously address ED and LUTS, opening new possibilities for clinical application in the treatment of these interconnected conditions.
Male ; Animals ; Erectile Dysfunction/etiology* ; Rats, Sprague-Dawley ; Lower Urinary Tract Symptoms/etiology* ; Ischemia/drug therapy* ; Rats ; Tamsulosin ; Hypoxia-Inducible Factor 1, alpha Subunit/drug effects* ; Sildenafil Citrate/therapeutic use* ; Penis/blood supply* ; Disease Models, Animal ; Transforming Growth Factor beta1/metabolism* ; Pelvis/blood supply* ; Prostate/metabolism* ; Sulfonamides/therapeutic use* ; Large-Conductance Calcium-Activated Potassium Channels/agonists*

Although salt-related behaviors may influence urinary salt excretion in early childhood, this relationship remains unclear. This study aimed to examine salt-related behaviors using data from a salt check sheet and urinary salt excretion parameters using spot urine samples from 4-year-old children. This cross-sectional study included all 4-year-old children who underwent health checkups in Ohnan Town, Shimane Prefecture. The study sample consisted of 109 children (49 boys). Measures from spot urine samples included estimated salt excretion (g/day) and the sodium-potassium (Na/K) ratio. Salt-related behaviors were assessed using a salt check sheet that was completed by the parents or guardians. The associations between salt-related behaviors and urinary salt excretion parameters were analyzed using a generalized linear model. The median (M) and interquartile range (IQR) for urinary measures in 4-year-old children were as follows: estimated salt excretion (M = 4.4, IQR: 3.3-6.2) and Na/K ratio (M = 2.3, IQR: 1.4-3.3). The low frequency of consumption of high-salt foods ("such as pickles, pickled plums, etc." and "noodles such as udon and ramen") was associated with low salt excretion and low Na/K ratio. However, in the case of "consumption of udon, ramen, or other soups", the Na/K ratio was higher for "About half a bowl" and "Some" than for "An entire bowl." Additionally, for "eating out or having convenience-store-bought bento (lunch plate) for lunch", the Na/K ratio was higher for "No" than for "Almost every day." In conclusion, the frequency of high-sodium food intake was associated with both urinary sodium excretion and the Na/K ratio in 4-year-old children. Longitudinal investigations using the 24-hour urine collection method are needed to confirm these salt-related behaviors.
Humans ; Child, Preschool ; Male ; Cross-Sectional Studies ; Female ; Sodium Chloride, Dietary/urine* ; Parents ; Sodium/urine* ; Japan ; Potassium/urine*

The KCNQ potassium channels play a crucial role in modulating neural excitability, and their dysfunction is closely associated with epileptic disorders. While variants in KCNQ2 have been extensively studied, KCNQ3-related disorders have rarely been reported. With advances in next-generation sequencing technologies, an increasing number of cases of KCNQ3-related disorders have been identified. However, the correlation between genotype and phenotype remains poorly understood. In this study, we established a variant library consisting of 24 missense mutations in KCNQ3 and introduced these mutations into three different template types: KCNQ3, KCNQ3-A315T (Q3*), and KCNQ3-KCNQ2 tandem (Q3-Q2). We then analyzed the effects of these mutations on the KCNQ3 channel function using patch-clamp recording. The most informative parameter across all three backgrounds was the current density of the mutant channels. The current density patterns in the Q3* and Q3-Q2 backgrounds were similar, with most mutations resulting in an almost complete loss of function (LOF), they were concentrated in the pore-forming domain of KCNQ3. In contrast, mutations in the voltage-sensing domain or C-terminus did not show significant differences from the wild-type channel. Interestingly, these LOF mutations were typically associated with self-limited familial neonatal epilepsy, while neurodevelopmental disorders (NDD) were more closely associated with mutations that did not significantly differ from the wild-type. V_1/2, another important parameter of the electrophysiological properties, could not be accurately determined in the majority of KCNQ3 mutations due to its nearly complete LOF in the Q3* and Q3-Q2 backgrounds. Intriguingly, the V_1/2 of functional mutations were primarily leftward shifted, indicating a gain-of-function (GOF) effect, which was typically associated with NDD. In addition to previously reported mutations, we identified G553R as a novel GOF mutation. In the co-transfection background, parameters such as V_1/2 could be determined, but the dysfunctional effects of these mutations were mitigated by the co-expression of wild-type KCNQ3 and KCNQ2 subunits, resulting in no significant differences between most mutations and the wild-type channel. Furthermore, we applied KCNQ modulators to reverse the electrophysiological abnormalities caused by KCNQ3 variants. The LOF mutations were reversed by the application of Pynegabine (HN37), a KCNQ opener, while the GOF mutation responded well to Amitriptyline (AMI), a KCNQ inhibitor. These findings provide essential insights into the pathogenic mechanisms underlying KCNQ3-related disorders and may inform clinical decision-making.
KCNQ3 Potassium Channel/genetics* ; Humans ; Mutation, Missense/genetics* ; KCNQ2 Potassium Channel/genetics* ; Patch-Clamp Techniques ; HEK293 Cells ; Animals ; Phenylenediamines/pharmacology* ; Carbamates

The prelimbic cortex (PL) plays a critical role in processing both the sensory and affective components of pain. However, the underlying molecular mechanisms remain poorly understood. In this study, we observed a reduction in hyperpolarization-activated cation current (I_h) in layer V pyramidal neurons of the contralateral PL in a mouse model of spared nerve injury (SNI). The expression of hyperpolarization-activated cyclic nucleotide-gated 2 (HCN2) channels was also decreased in the contralateral PL. Conversely, microinjection of fisetin, a partial agonist of HCN2, produced both analgesic and anxiolytic effects. Additionally, we found that cyclin-dependent kinase 5 (CDK5) was activated in the contralateral PL, where it formed a complex with HCN2 and phosphorylated its C-terminus. Knockdown of CDK5 restored HCN2 expression and alleviated both pain hypersensitivity and anxiety-like behaviors. Collectively, these results indicate that CDK5-mediated dysfunction of HCN2 in the PL underlies nerve injury-induced mechanical hypersensitivity and anxiety.
Animals ; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels/metabolism* ; Hyperalgesia/metabolism* ; Cyclin-Dependent Kinase 5/metabolism* ; Neuralgia/metabolism* ; Male ; Anxiety/metabolism* ; Mice ; Potassium Channels/metabolism* ; Mice, Inbred C57BL ; Disease Models, Animal ; Pyramidal Cells/metabolism*

OBJECTIVE: To investigate the relationship between the trajectories of serum potassium changes after intensive care unit (ICU) admission and 30-day death risk in patients with sepsis. METHODS: A retrospective cohort study was conducted, including adult patients with sepsis admitted to the comprehensive ICU, medical intensive care unit (MICU) and emergency intensive care unit (EICU) of Guizhou Medical University Affiliated Hospital from January 2020 to January 2024. The patients who had a minimum of 5 days' hospitalisation in the ICU and who had at least 7 consecutive days of the serum potassium measurements were classified into five trajectories groups according to group-based trajectory modelling (GBTM) using SAS software. This was based on tendency changes in serum potassium levels in patients after admission to the ICU, which was categorized as follows: slowly increased from a low level group, slowly increased from a medium level of normal range group, slowly decreased from a medium level of normal range group, slowly decreased from a high level group, and slowly increased from a high level of normal range group. The patient's gender, age, medical history, and white blood cell count (WBC), platelet count (PLT), procalcitonin (PCT), activated partial thromboplastin time (APTT), prothrombin time (PT), blood sodium, and serum creatinine (SCr) at the time of admission to the ICU were collected. At the same time, the patient's worst sequential organ failure assessment (SOFA) score within 24 hours of admission to the ICU, length of ICU stay, and 30-day outcome were record. The differences in clinical data among different groups of patients were compared. The 30-day cumulative survival rates of the various serum potassium trajectories were plotted using Kaplan-Meier survival curves, the groups were then compared using the Log-Rank test. A multivariate Cox proportional risk regression analysis was developed to evaluate the independent effect of serum potassium trajectory on 30-day death risk. RESULTS: Finally, 342 ICU sepsis patients were enrolled, of which 42 patients in the slowly increased from a low level group (12.28%), 127 patients in the slowly increased from a medium level of normal range group (37.14%), 118 patients in the slowly decreased from a medium level of normal range group (34.50%), 28 patients in the slowly decreased from a high level group (8.19%), and 27 patients in the slowly increased from a high level of normal range group (7.89%). Except for age and APTT differences, there were no statistically significant differences in other clinical characteristics among the patients in the different serum potassium trajectories groups. Kaplan-Meier survival curves showed that there was statistically significant difference in the 30-day cumulative survival rate among the patients in the different serum potassium trajectories groups (Log-Rank test: χ² = 14.696, P = 0.005), with the lowest in the slowly increased from a high level of normal range group (39.3%). Multivariate Cox proportional risk regression analysis showed that the patients with the serum potassium trajectory of slowly increased from a high level of normal range had the highest 30-day death risk [hazard ratio (HR) = 2.341, 95% confidence interval (95%CI) was 1.049-5.226, P = 0.038]. This association persisted after adjustment for variables such as gender, age, medical history, SOFA score, WBC, PLT, PCT, APTT, PT, blood sodium, and SCr (HR = 3.058, 95%CI was 1.249-7.488, P = 0.014). CONCLUSION Compared with the patients whose serum potassium fluctuated within the normal range, the sepsis patients in the ICU with a serum potassium trajectory that slowly increased from a high level of normal range had a significantly higher 30-day death risk.
Humans ; Retrospective Studies ; Intensive Care Units ; Sepsis/blood* ; Potassium/blood* ; Male ; Female ; Middle Aged ; Aged ; Risk Factors ; Hospital Mortality ; Prognosis

Pathological vascular remodeling is a hallmark of various vascular diseases. Previous research has established the significance of andrographolide in maintaining gastric vascular homeostasis and its pivotal role in modulating endothelial barrier dysfunction, which leads to pathological vascular remodeling. Potassium dehydroandrographolide succinate (PDA), a derivative of andrographolide, has been clinically utilized in the treatment of inflammatory diseases precipitated by viral infections. This study investigates the potential of PDA in regulating pathological vascular remodeling. The effect of PDA on vascular remodeling was assessed through the complete ligation of the carotid artery in C57BL/6 mice. Experimental approaches, including rat aortic primary smooth muscle cell culture, flow cytometry, bromodeoxyuridine (BrdU) incorporation assay, Boyden chamber cell migration assay, spheroid sprouting assay, and Matrigel-based tube formation assay, were employed to evaluate the influence of PDA on the proliferation and motility of smooth muscle cells (SMCs). Molecular docking simulations and co-immunoprecipitation assays were conducted to examine protein interactions. The results revealed that PDA exacerbates vascular injury-induced pathological remodeling, as evidenced by enhanced neointima formation. PDA treatment significantly increased the proliferation and migration of SMCs. Further mechanistic studies disclosed that PDA upregulated myeloid differentiation factor 88 (MyD88) expression in SMCs and interacted with T-cadherin (CDH13). This interaction augmented proliferation, migration, and extracellular matrix deposition, culminating in pathological vascular remodeling. Our findings underscore the critical role of PDA in the regulation of pathological vascular remodeling, mediated through the MyD88/CDH13 signaling pathway.
Mice ; Rats ; Animals ; Myeloid Differentiation Factor 88/metabolism* ; Vascular Remodeling ; Cell Proliferation ; Vascular System Injuries/pathology* ; Carotid Artery Injuries/pathology* ; Molecular Docking Simulation ; Muscle, Smooth, Vascular ; Cell Movement ; Mice, Inbred C57BL ; Signal Transduction ; Succinates/pharmacology* ; Potassium/pharmacology* ; Cells, Cultured ; Diterpenes ; Cadherins

CAPOS syndrome is an autosomal dominant neurological disorder caused by mutations in the ATP1A3 gene. Initial symptoms, often fever-induced, include recurrent acute ataxic encephalopathy in childhood, featuring cerebellar ataxia, optic atrophy, areflflexia, sensorineural hearing loss, and in some cases, pes cavus. This report details a case of CAPOS syndrome resulting from a maternal ATP1A3 gene mutation. Both the child and her mother exhibited symptoms post-febrile induction,including severe sensorineural hearing loss in both ears, ataxia, areflexia, and decreased vision. Additionally, the patient's mother presented with pes cavus. Genetic testing revealed a c. 2452G>A（Glu818Lys） heterozygous mutation in theATP1A3 gene in the patient . This article aims to enhance clinicians' understanding of CAPOS syndrome, emphasizing the case's clinical characteristics, diagnostic process, treatment, and its correlation with genotypeic findings.
Humans ; Child ; Female ; Cerebellar Ataxia/diagnosis* ; Talipes Cavus ; Hearing Loss, Sensorineural/diagnosis* ; Optic Atrophy/diagnosis* ; Mutation ; Phenotype ; Sodium-Potassium-Exchanging ATPase/genetics* ; Foot Deformities, Congenital ; Reflex, Abnormal

Sodium ; Wastewater ; Potassium ; Diet ; Blood Pressure ; China ; Sodium, Dietary ; Sodium Chloride, Dietary