Heterozygous KCNJ10 Variants Affecting Kir4.1 Channel Cause Paroxysmal Kinesigenic Dyskinesia.

BACKGROUND: More than 60% of paroxysmal kinesigenic dyskinesia (PKD) cases are of uncertain variants. OBJECTIVE: The aim was to elucidate novel genetic contribution to PKD. METHODS: A total of 476 probands with uncertain genetic causes were enrolled for whole-exome sequencing. A method of case-control analysis was applied to identify the candidate genes. Whole-cell patch-clamp recording was applied to verify the electrophysiological impact of the identified variants. A mouse model with cerebellar heterozygous knockout of the candidate gene was developed via adeno-associated virus injection, and dystonia-like phenotype inducement and rotarod tests were performed. In vivo multiunit electrical recording was applied to investigate the change in neural excitability in knockout mice. RESULTS: Heterozygous variants of potassium inwardly rectifying channel subfamily J member 10 (KCNJ10) clustered in PKD patients were compared with those in the control groups. Fifteen variants were detected in 16 of 522 probands (frequency = 3.07%). Patients with KCNJ10 variants tended to have a milder manifestation compared to those with PRRT2 (proline-rich transmembrane protein 2) variants. KCNJ10 variants partially altered the transmembrane location of inwardly rectifying potassium channel 4.1 (Kir4.1). The Kcnj10 expression is consistent with the natural course of PKD. Variants resulted in different degrees of reduction in cell Kir4.1 currents, and mice with heterozygous conditional knockout of Kcnj10 in the cerebellum presented dystonic posture, together with poor motor coordination and motor learning ability in rotarod tests. The firing rate of deep cerebellar nuclei was significantly elevated in Kcnj10-cKO mice. CONCLUSION: We identified heterozygous variants of KCNJ10 in PKD. Impaired function of Kir4.1 might lead to abnormal neuronal excitability, which attributed to PKD. © 2024 International Parkinson and Movement Disorder Society.

Delocalized Isoelectronic Heterostructured FeCoOx Sy Catalysts with Tunable Electron Density for Accelerated Sulfur Redox Kinetics in Li-S batteries.

High interconversion energy barriers, depressive reaction kinetics of sulfur species, and sluggish Li+ transport inhibit the wide development of high-energy-density lithium sulfur (Li-S) batteries. Herein, differing from random mixture of selected catalysts, the composite catalyst with outer delocalized isoelectronic heterostructure (DIHC) is proposed and optimized, enhancing the catalytic efficiency for decreasing related energy barriers. As a proof-of-content, the FeCoOx Sy composites with different degrees of sulfurization are fabricated by regulating atoms ratio between O and S. The relationship of catalytic efficiency and principal mechanism in DIHCs are deeply understood from electrochemical experiments to in situ/operando spectral spectroscopies i.e., Raman, XRD and UV/Vis. Consequently, the polysulfide conversion and Li2 S precipitation/dissolution experiments strongly demonstrate the volcano-like catalytic efficiency of various DIHCs. Furthermore, the FeCoOx Sy -decorated cell delivers the high performance (1413 mAh g-1 at 0.1 A g-1 ). Under the low electrolyte/sulfur ratio, the high loading cell stabilizes the areal capacity of 6.67 mAh cm-2 at 0.2 A g-1 . Impressively, even resting for about 17 days for possible polysulfide shuttling, the high-mass-loading FeCoOx Sy -decorated cell stabilizes the same capacity, showing the practical application of the DIHCs in improving catalytic efficiency and reaching high electrochemical performance.

TMEM151A Variants Cause Paroxysmal Kinesigenic Dyskinesia: A Large-Sample Study.

BACKGROUND: Paroxysmal kinesigenic dyskinesia (PKD) is the most common type of paroxysmal dyskinesias. Only one-third of PKD patients are attributed to proline-rich transmembrane protein 2 (PRRT2) mutations. OBJECTIVE: We aimed to explore the potential causative gene for PKD. METHODS: A cohort of 196 PRRT2-negative PKD probands were enrolled for whole-exome sequencing (WES). Gene Ranking, Identification and Prediction Tool, a method of case-control analysis, was applied to identify the candidate genes. Another 325 PRRT2-negative PKD probands were subsequently screened with Sanger sequencing. RESULTS: Transmembrane Protein 151 (TMEM151A) variants were mainly clustered in PKD patients compared with the control groups. 24 heterozygous variants were detected in 25 of 521 probands (frequency = 4.80%), including 18 missense and 6 nonsense mutations. In 29 patients with TMEM151A variants, the ratio of male to female was 2.63:1 and the mean age of onset was 12.93 ± 3.15 years. Compared with PRRT2 mutation carriers, TMEM151A-related PKD were more common in sporadic PKD patients with pure phenotype. There was no significant difference in types of attack and treatment outcome between TMEM151A-positive and PRRT2-positive groups. CONCLUSIONS: We consolidated mutations in TMEM151A causing PKD with the aid of case-control analysis of a large-scale WES data, which broadens the genotypic spectrum of PKD. TMEM151A-related PKD were more common in sporadic cases and tended to present as pure phenotype with a late onset. Extensive functional studies are needed to enhance our understanding of the pathogenesis of TMEM151A-related PKD. © 2021 International Parkinson and Movement Disorder Society.

Neurology practice and stroke services across East China: a multi-site, county-level hospital-based survey.

BACKGROUND: Neurological disorders are an economic and public health burden which requires efficient and adequate medical resources. Currently, little is known about the status of the quality of neurological care services available in China. As neurological primary care is mostly provided at the county hospital level, investigation of this geographical level is required. The aim of this study is to evaluate currently available neurology care services in Yangtze River Delta Urban Agglomerations in east China. METHODS: A multi-site, county-level hospital-based observational survey was conducted in east China from January 2017 to December 2017. A questionnaire was made to assess hospital and the departmental patient care capabilities, human resources and technical capacity in neurology departments. RESULTS: Of 228 hospitals across the Yangtze River Delta Urban Agglomerations, 217 documents were returned. Of these, 22 were excluded due to invalid hospital information or duplicate submission. Overall, most hospitals have neurology departments (162, 83.1%) while less than half of the hospitals have a stroke center (80, 41.0%) and neurology emergency department (46, 23.6%). Among 162 hospitals with neurology department, 5 were excluded due to inadequate sharing, leaving 157 hospitals for analysis. About 84.1% of these neurology departments can administer intravenous thrombolysis while about one third of them has the ability to perform arterial thrombectomy (36.9%). In addition, 46.2% of hospitals can carry out computed tomography angiography (CTA) in emergency room. Tertiary care hospitals are much more equipped with modern medical resources compared to the secondary hospitals. In four administrative regions, the neurology services are better in more economically advanced regions. CONCLUSIONS: Neurological care services need to be enhanced at the county-level hospitals to improve health care delivery.

Autocrine protective mechanisms of human granulocyte colony-stimulating factor (G-CSF) on retinal ganglion cells after optic nerve crush.

This study investigated the role of autocrine mechanisms in the anti-apoptotic effects of human granulocyte colony-stimulating factor (G-CSF) on retinal ganglion cells (RGCs) after optic nerve (ON) crush. We observed that both G-CSF and G-CSF receptor (G-CSFR) are expressed in normal rat retina. Further dual immunofluorescence staining showed G-CSFR immunoreactive cells were colocalized with RGCs, Müller cells, horizontal and amacrine cells. These results confirm that G-CSF is an endogenous ligand in the retina. The semi-quantitative RT-PCR finding demonstrated the transcription levels of G-CSF and G-CSFR were up-regulated after ON crush injury. G-CSF treatment further increased and prolonged the expression level of G-CSFR in the retina. G-CSF has been shown to enhance transdifferentiation of the mobilized hematopoietic stem cells into tissue to repair central nervous system injury. We test the hypothesis that the hematopoietic stem cells recruited by G-CSF treatment can transdifferentiate into RGCs after ON crush by performing sublethal irradiation of the rats 5 days before ON crush. The flow cytometric analysis showed the number of CD34 positive cells in the peripheral blood is significantly lower in the irradiated, crushed and G-CSF-treated group than the sham control group or crush and G-CSF treated group. Nevertheless, the G-CSF treatment enhances the RGC survival after sublethal irradiation and ON crush injury. These data indicate that G-CSF seems unlikely to induce hematopoietic stem cell transdifferentiation into RGCs after ON crush injury. In conclusion, G-CSF may serve an endogenous protective signaling in the retina through direct activation of intrinsic G-CSF receptors and downstream signaling pathways to rescue RGCs after ON crush injury, exogenous G-CSF administration can enhance the anti-apoptotic effects on RGCs.

An Electroencephalography Profile of Paroxysmal Kinesigenic Dyskinesia.

Paroxysmal kinesigenic dyskinesia (PKD) is associated with a disturbance of neural circuit and network activities, while its neurophysiological characteristics have not been fully elucidated. This study utilized the high-density electroencephalogram (hd-EEG) signals to detect abnormal brain activity of PKD and provide a neural biomarker for its clinical diagnosis and PKD progression monitoring. The resting hd-EEGs are recorded from two independent datasets and then source-localized for measuring the oscillatory activities and function connectivity (FC) patterns of cortical and subcortical regions. The abnormal elevation of theta oscillation in wildly brain regions represents the most remarkable physiological feature for PKD and these changes returned to healthy control level in remission patients. Another remarkable feature of PKD is the decreased high-gamma FCs in non-remission patients. Subtype analyses report that increased theta oscillations may be related to the emotional factors of PKD, while the decreased high-gamma FCs are related to the motor symptoms. Finally, the authors established connectome-based predictive modelling and successfully identified the remission state in PKD patients in dataset 1 and dataset 2. The findings establish a clinically relevant electroencephalography profile of PKD and indicate that hd-EEG can provide robust neural biomarkers to evaluate the prognosis of PKD.

NaF-rich interphase and high initial coulombic efficiency of red phosphorus anode for sodium-ion batteries by chemical presodiation.

Red phosphorus/carbon (P/C) materials have been extensively studied as promising anodes for sodium-ion batteries (SIBs) owing to their high capacities and moderate working potentials. However, the low initial Coulombic efficiency (ICE) and unstable solid-electrolyte interphase (SEI) of P/C composites limit their widespread applications. In this study, we develop an effective presodiation method to compensate for the irreversible sodium loss of the S-doped P/C (P/C@S) anode and yield a thin, uniform, and NaF-rich SEI layer on the presodiated P/C@S (pNa-P/C@S) anode during cycling. Consequently, the pNa-P/C@S anode exhibits a remarkable ICE of 98.7% as well as superior cycling performance and rate capability in the half cell. When pNa-P/C@S anode is coupled with conventional Na3V2(PO4)2F3, Na3V2(PO4)3, and NaCu0.12Ni0.23Fe0.33Mn0.33 cathodes, all the full cells demonstrate desirable ICEs (>98%), high energy densities, and excellent cycling performance. The proposed method has been extended to another anode (SnO2) to demonstrate its applicability in fabricating anodes with a high ICE and stable NaF-rich SEI layer.

Impact of the COVID-19 pandemic on acute stroke care: An analysis of the 24-month data from a comprehensive stroke center in Shanghai, China.

INTRODUCTION: Whether the coronavirus disease-2019 (COVID-19) pandemic is associated with a long-term negative impact on acute stroke care remains uncertain. This study aims to compare the timing of key aspects of stroke codes between patients before and after the COVID-19 pandemic. METHODS: This retrospective cohort study was conducted at an academic hospital in Shanghai, China and included all adult patients with acute ischemic stroke hospitalized via the emergency department (ED) stroke pathway during the 24 months since the COVID-19 outbreak (COVID-19: January 1, 2020-December 31, 2021). The comparison cohort included patients with ED stroke pathway visits and hospitalizations during the same period (pre-COVID-19: January 1, 2018-December 31, 2019). We compared critical time points of prehospital and intrahospital acute stroke care between patients during the COVID-19 era and patients during the pre-COVID-19 era using t test, χ2 , and Mann-Whitney U test where appropriate. RESULTS: A total of 1194 acute ischemic stroke cases were enrolled, including 606 patients in COVID-19 and 588 patients in pre-COVID-19. During the COVID-19 pandemic, the median onset-to-hospital time was about 108 min longer compared with the same period of pre-COVID-19 (300 vs 192 min, p = 0.01). Accordingly, the median onset-to-needle time was 169 min in COVID-19 and 113 min in pre-COVID-19 (p = 0.0001), and the proportion of patients with onset-to-hospital time within 4.5 h was lower (292/606 [48.2%] vs 328/558 [58.8%], p = 0.0003) during the pandemic period. Furthermore, the median door-to-inpatient admission and door-to-inpatient rehabilitation times increased from 28 to 37 h and from 3 to 4 days (p = 0.014 and 0.0001). CONCLUSIONS: During the 24 months of COVID-19, a prolongation of stroke onset to hospital arrival and to intravenous rt-PA administration times were noted. Meanwhile, acute stroke patients needed to stay in the ED for a longer time before hospitalization. Educational system support and process optimization should be pursued in order to acquire timely delivery of stroke care during the pandemic.

Tuning of spinel magnesium ferrite nanoparticles with enhanced magnetic properties.

Monodispersed magnesium ferrite nanoparticles with enhanced magnetic properties were successfully fabricated by a simple solvothermal method without employing any templates, complex apparatus or techniques. The structure, morphology, composition, and magnetic properties of the products were tuned and characterized by X-ray powder diffraction, transmission electron microscopy, scanning electron microscopy and vibrating sample magnetometry. The results show that the reaction time and temperature have an important influence on the morphology, composition, structure and particle size of the synthesized MgFe2O4 nanoparticles. Not only the size, size distribution, crystallization, but also the atomic ratio of Mg : Fe has a decisive effect on their magnetic properties. The MgFe2O4 magnetic nanoparticles synthesized at 180 °C for 12 hours have excellent dispersion, narrow size distribution, good crystallinity and a Mg : Fe atomic ratio of approximately 1 : 4.53 and an average particle size of 114.3 nm, thus the highest saturation magnetization of 67.35 emu g-1. It provides a reliable synthesis method for the better application of spinel structure magnesium ferrite nanoparticles in the future.

How to optimize switch virtual keyboards to trade off speed and accuracy.

In some circumstances, people interact with a virtual keyboard by triggering a binary switch to guide a moving cursor to target characters or items. Such switch keyboards are commonly used by patients with severely restricted motor capabilities. Typing with such systems enables patients to interact with colleagues, but it is slow and error prone. We develop a methodology that can automate an important part of the design process for optimally structured switch keyboards. We show how to optimize the design of simple switch keyboard systems in a way that minimizes the average entry time while satisfying an acceptable error rate. The first step is to model the user's ability to use a switch keyboard correctly for different cursor durations. Once the model is defined, our optimization approach assigns characters to locations on the keyboard, identifies an optimal cursor duration, and considers a variety of cursor paths. For our particular case, we show how to build a user model from empirical data and demonstrate that the resulting optimized keyboards are quite different from existing keyboard designs.

Magnetofection based on superparamagnetic iron oxide nanoparticle-mediated low lncRNA HOTAIR expression decreases the proliferation and invasion of glioma stem cells.

Glioma stem cells (GSCs) are a special subpopulation of glioma cells that are key to the sensitivity of tumors to treatments and to the possibility of tumor recurrence. Identifying new strategies that inhibit the growth of GSCs are therefore important for developing novel therapies for glioblastoma multiforme (GBM). In this study, CD133+ human glioma stem cells were isolated and cultured. Magnetic nanoparticles were used to mediate the expression of siRNAs targeting the HOTAIR (si-HOTAIR) sequence in human gliomas. Effect of downregulation of HOTAIR expression on proliferation, invasion and in vivo tumorigenicity of human GSCs and underlying molecular mechanisms were further evaluated. The results of the MTT assay and flow cytometric analysis showed that downregulation of HOTAIR expression inhibited cell proliferation and induced cell cycle arrest. Transwell assays demonstrated that downregulation of HOTAIR expression resulted in a decrease in the invasive capability of GSCs. Moreover, magnetic nanoparticle-mediated low expression of HOTAIR effectively reduced the tumorigenic capacity of glioma stem cells in vivo. In addition, the results of qRT-PCR and western blot analysis demonstrated that downregulation of HOTAIR expression significantly increased the expression of PDCD4 in GSCs, in addition to reducing the expression of CCND1 and CDK4. An in-depth mechanistic analysis showed that downregulation of HOTAIR expression reduced the recruitment of downstream molecules, EZH2 and LSD1, thereby activating the expression of PDCD4 at the transcriptional level. In conclusion, downregulation of HOTAIR expression effectively promoted the expression of PDCD4, thereby inhibiting the proliferation, invasion and in vivo tumorigenicity of human GSCs.

Fluoroscopic investigation of Riata® transvenous defibrillator leads.

BACKGROUND: Implantable cardioverter-defibrillator leads from Riata® family (St. Jude Medical Inc., Sylmar, CA, USA) have been recently recalled by Food and Drug Administration for concerns of a unique type of "inside-out" insulation failure leading to conductor externalization. The objective of this study was to evaluate the prevalence and predictors of conductor externalization in patients implanted with Riata 8 French (Fr) and 7 Fr leads. METHODS: Patients implanted with Riata® and Riata ST® who were actively followed up in our institution were scheduled for high resolution 3 view fluoroscopy and device interrogation including high voltage (HV) lead impedance testing. Fluoroscopic images were graded as presence of externalization or no externalization. RESULTS: Of the 90 patients who underwent screening fluoroscopy, majority had dual coil leads (62.5%) and median duration from the implant time to screening was 79.5 months. Twenty four (26.7%) patients exhibited evidence of lead externalization with 10 (41.6%) of these showing electrical abnormalities at the time of screening. No externalization was seen in the 7 Fr leads. Pacing thresholds were significantly elevated in the externalized cohort compared to non-externalized group (1.42 ± 1.23 vs. 0.93 ± 0.53; p = 0.01). Time since lead implant and lead diameter emerged as significant predictors of lead externalization on univariate analysis with only lead diameter being significant on multivariate analysis (odds ratio 30.68; 4.95-∞, p = 0.001). CONCLUSIONS: Prevalence of insulation failure exhibiting as conductor externalization is high (26.7%) among the large diameter 8 Fr Riata® leads with a significant proportion of patients manifesting electrical failure. High resolution 3 view fluoroscopy is a reasonable approach to screen for this unique type of insulation failure.

Effect of race on the frequency of postoperative atrial fibrillation following coronary artery bypass grafting.

Atrial fibrillation (AF) commonly complicates the postoperative course after coronary artery bypass grafting (CABG). Among the general population, African Americans have been shown to have a lower prevalence of AF than European Americans. Although many factors have been identified to predict risk for postoperative AF, race has not been examined. All patients aged ≥18 years who underwent CABG at Henry Ford Hospital during a 5-year period from January 1, 2004, to December 31, 2008, were included. Patients were excluded for any previous diagnosis of AF or if they had concomitant valve surgery at the time of CABG. The incidence of AF was determined by International Classification of Diseases, Ninth Revision, coding from postoperative hospitalization records. Overall, 1,001 patients were eligible for analysis. Of these, 731 (73%) were European American and 270 (27%) were African American. The African American group had a higher prevalence of hypertension (75.6% vs 58.8%, p <0.001) and heart failure (22.6% vs 15.7%, p = 0.01) and a trend toward a higher prevalence of diabetes mellitus (38.1% vs 33.4%, p = 0.159). Postoperative AF was diagnosed in 214 European Americans (29.3%) and 50 African Americans (18.5%) (p = 0.001). In multivariate analysis adjusting for age strata, gender, hypertension, diabetes, and heart failure, African Americans had less postoperative AF than European Americans, with an adjusted odds ratio of 0.539 (95% confidence interval 0.374 to 0.777, p = 0.001). In conclusion, African Americans have a significantly reduced incidence of AF compared to European Americans after CABG.

Infrared spectral features of exfoliated cervical cells, cervical adenocarcinoma tissue, and an adenocarcinoma cell line (SiSo).

OBJECTIVE: The objective of the present study is to evaluate and compare the infrared spectral features of normal and malignant exfoliated cervical cells, cells from malignant tissue, and the SiSo cell line. METHODS: Infrared spectra of cervical adenocarcinoma (CA) tissue, normal and malignant exfoliated cervical cells, and a uterine cervical adenocarcinoma cell line (SiSo) were obtained. Spectral qualities in terms of band intensity ratio and band position, which reflect configurational changes in the functional groups of the above samples, were measured. RESULTS: Spectral bands of CA tissue, exfoliated cells from CA, and the cell line were similar but markedly different from that of exfoliated normal cervical cells. Significant changes in bands at 1025 cm(-1) (glycogen), 1080 cm(-1) (glycogen and nucleic acids), 1155 cm(-1) (C-OH groups of serine, threonine, and tyrosine of cell proteins, and C-O groups of carbohydrates), 1240 cm(-1) (PO(2) groups of nucleic acids), 1400 cm(-1) (methyl group of lipids and proteins), and 1450 cm(-1) (methylene group of lipids and proteins) were noted in the CA tissue, exfoliated CA cells, and adenocarcinoma cell line compared with exfoliated normal cells. Marked shifts in band positions from 1080 to 1086 cm(-1), 1153 to 1160 cm(-1), and 935 to 970 cm(-1) in CA tissue, exfoliated CA cells, and the adenocarcinoma cell line were noted. CONCLUSION: Spectral bands of the adenocarcinoma cell line matched very well with those of cervical CA tissue and exfoliated CA cells in terms of position. In contrast, spectral bands of the SiSo cell line differed greatly from those of normal exfoliated cells.