Subthalamic nucleus deep brain stimulation alleviates oxidative stress via mitophagy in Parkinson's disease.

Subthalamic nucleus deep brain stimulation (STN-DBS) has the potential to delay Parkinson's disease (PD) progression. Whether oxidative stress participates in the neuroprotective effects of DBS and related signaling pathways remains unknown. To address this, we applied STN-DBS to mice and monkey models of PD and collected brain tissue to evaluate mitophagy, oxidative stress, and related pathway. To confirm findings in animal experiments, a cohort of PD patients was recruited and oxidative stress was evaluated in cerebrospinal fluid. When PD mice received STN stimulation, the mTOR pathway was suppressed, accompanied by elevated LC3 II expression, increased mitophagosomes, and a decrease in p62 expression. The increase in mitophagy and balance of mitochondrial fission/fusion dynamics in the substantia nigra caused a marked enhancement of the antioxidant enzymes superoxide dismutase and glutathione levels. Subsequently, fewer mitochondrial apoptogenic factors were released to the cytoplasm, which resulted in a suppression of caspase activation and reservation of dopaminergic neurons. While interfaced with an mTOR activator, oxidative stress was no longer regulated by STN-DBS, with no neuroprotective effect. Similar results to those found in the rodent experiments were obtained in monkeys treated with chronic STN stimulation. Moreover, antioxidant enzymes in PD patients were increased after the operation, however, there was no relation between changes in antioxidant enzymes and motor impairment. Collectively, our study found that STN-DBS was able to increase mitophagy via an mTOR-dependent pathway, and oxidative stress was suppressed due to removal of damaged mitochondria, which was attributed to the dopaminergic neuroprotection of STN-DBS in PD.

Identification and characterization of a novel CASR mutation causing familial hypocalciuric hypercalcemia.

Context: Although a monoallelic mutation in the calcium-sensing receptor (CASR) gene causes familial hypocalciuric hypercalcemia (FHH), the functional characterization of the identified CASR mutation linked to the clinical response to calcimimetics therapy is still limited. Objective: A 45-year-old male presenting with moderate hypercalcemia, hypocalciuria, and inappropriately high parathyroid hormone (PTH) had a good response to cinacalcet (total serum calcium (Ca2+) from 12.5 to 10.1 mg/dl). We identified the genetic mutation and characterized the functional and pathophysiological mechanisms, and then linked the mutation to calcimimetics treatment in vitro. Design: Sanger sequencing of the CASR, GNA11, and AP2S1 genes was performed in his family. The simulation model was used to predict the function of the identified mutant. In vitro studies, including immunoblotting, immunofluorescence, a cycloheximide chase study, Calbryte™ 520 Ca2+ detection, and half-maximal effective concentration (EC50), were examined. Results: This proband was found to carry a de novo heterozygous missense I554N in the cysteine-rich domain of CASR, which was pathogenic based on the different software prediction models and ACGME criteria. The simulation model showed that CASR I554N mutation decreased its binding energy with Ca2+. Human CASR I554N mutation attenuated the stability of CASR protein, reduced the expression of p-ERK 1/2, and blunted the intracellular Ca2+ response to gradient extracellular Ca2+ (eCa2+) concentration. The EC50 study also demonstrated the correctable effect of calcimimetics on the function of the CASR I554N mutation. Conclusion: This novel CASR I554N mutation causing FHH attenuates CASR stability, its binding affinity with Ca2+, and the response to eCa2+ corrected by therapeutic calcimimetics.

Effectively α-Terpineol Suppresses Glioblastoma Aggressive Behavior and Downregulates KDELC2 Expression.

BACKGROUND: Glioblastoma (GBM) is notorious for the aggressive behaviors and easily results in chemo-resistance. Studies have shown that the use of herbal medicines as treatments for GBM as limited by the blood-brain barrier (BBB) and glioma stem cells. PURPOSE: The aim of this study was to investigate the relationship between GBM suppression and α-terpineol, the monoterpenoid alcohol derived from Eucalyptus glubulus and Pinus merkusii. STUDY DESIGN: Using serial in-vitro and in-vivo studies to confirm the mechanism of α-terpineol on down-regulating GBM development. METHODS: The 3-[4,5-dimethylthiazol-2-yl)]-2,5-diphenyltetrazolium bromide (MTT) assay was performed to evaluate IC50 of α-terpineol to inhibit GBM cell survival. In order to evaluate the impact of GBM aggressive behaviors by α-terpineol, the analysis of cell migration, invasion and colony formation were implemented. In addition, the ability of tumor spheres and WB of CD44 and OCT3/4 were evaluated under the impression of α-terpineol decreased GBM stemness. The regulation of neoangiogenesis by α-terpineol via the WB of angiogenic factors and human umbilical vein endothelial cells (HUVEC) tube assay. To survey the decided factors of α-terpineol downregulating GBM chemoresistance depended on the impact of O6-methylguanine-DNA methyltransferase (MGMT) expression and autophagy-related factors activation. Additionally, WB and quantitative real-time polymerase chain reaction (qRT/PCR) of KDEL (Lys-Asp-Glu-Leu) containing 2 (KDELC2), endoplasmic reticulum (ER) stress, phosphoinositide 3-kinase (PI3k), mammalian target of rapamycin (mTOR) and mitogen-activated protein kinase (MAPK) cascade signaling factors were examined to explore the mechanism of α-terpineol inhibiting GBM viability. Finally, the orthotopic GBM mouse model was applied to prove the efficacy and toxicity of α-terpineol on regulating GBM survival. RESULTS: α-terpineol significantly suppressed GBM growth, migration, invasion, angiogenesis and temozolomide (TMZ) resistance. Furthermore, α-terpineol specifically targeted KDELC2 to downregulate Notch and PI3k/mTOR/MAPK signaling pathway. Finally, we also demonstrated that α-terpineol could penetrate the BBB to inhibit GBM proliferation, which resulted in reduced cytotoxicity to vital organs. CONCLUSION: Compared to published literatures, we firstly proved α-terpineol possessed the capability to inhibit GBM through various mechanisms and potentially decreased the occurrence of chemoresistance, making it a promising alternative therapeutic option for GBM in the future.

A co-regulatory network of SPIB, AQP8, and GUCA2B related to immune infiltration for early-stage colorectal cancer in silico and in vitro.

In early-stage colorectal cancer (CRC), AQP8, GUCA2B, and SPIB were important suppressor genes and frequently co-expressed. However, the underlying co-regulation effect remains unknown and need to be elucidated. We aimed to investigate the co-regulatory network of AQP8, GUCA2B, and SPIB in CRC using in vitro and in silico methods. Q-PCR, western blot, and immunohistochemistry were used to assess the co-regulatory network of the target genes in the HCT-116 cell line and fresh tumor tissues. Bioinformatical methods were used to validate the findings using the Cancer Genome Atlas COlon ADenocarcinoma and REctum ADenocarcinoma datasets, as well as large scale integrated data sets from Gene Expression Omnibus. In clinical CRC tissues, SPIB, AQP8, and GUCA2B were barely expressed compared to normal mucosa. When compared to 22 well-known genetic biomarkers, they are independent predictors of CRC identification with near 100% accuracy. In the co-regulatory network, they were co-upregulated at the mRNA and protein expression levels. AQP8, GUCA2B and SPIB were linked to immune cell infiltration and GUCA2B and SPIB were negatively associated with tumor purity. The co-regulatory network in miRNA-mRNA analysis was mediated by cancer-related microRNAs miR-182-5p and miR-27a-3. The functional analysis of the co-regulatory network's protein-protein interaction networks reveals three clusters and three major functions: complex interactions of transcription factors in mediating cytokine biology in T cells (SPIB cluster), guanylin, and Intestinal infectious diseases (GUCA2B cluster), and water channel activity balance (AQP8 cluster). The co-regulatory network of SPIB, AQP8, and GUCA2B was confirmed. MiR-27a-3p and miR-182-5p were two possible mediators. The mechanisms of SPIB, AQP8, GUCA2B, miR-182-5p, and miR-27a-3p in CRC merit further investigation.

The Related Factors and Effect of Electrode Displacement on Motor Outcome of Subthalamic Nuclei Deep Brain Stimulation in Parkinson's Disease.

BACKGROUND: Previous studies have revealed the existence of electrode displacement during subthalamic nucleus deep brain stimulation (STN-DBS). However, the effect of electrode displacement on treatment outcomes is still unclear. In this study, we aimed to analyze the related factors of electrode displacement and assess postoperative electrode displacement in relation to the motor outcomes of STN-DBS. METHODS: A total of 88 patients aged 62.73 ± 6.35 years (55 males and 33 females) with Parkinson's disease undergoing STN-DBS, with comprehensive clinical characterization before and 1 month after surgery, were involved retrospectively and divided into a cross-incision group and cannula puncture group according to different dura opening methods. The electrode displacement, unilateral pneumocephalus volume percent (uPVP), and brain volume percent were estimated. RESULTS: A significant anterior and lateral electrode displacement was observed among all implanted electrodes after pneumocephalus absorption (p < 0.0001). The degree of electrode displacement was positively correlated with the uPVP (p = 0.005) and smaller in females than males (p = 0.0384). Electrode displacement was negatively correlated with motor improvement following STN-DBS in both on-medication and off-medication conditions (p < 0.05). Dural puncture reduced the uPVP (p < 0.0001) and postoperative electrode displacement (p = 0.0086) compared with dural incision. CONCLUSIONS: Electrode displacement had a negative impact on the therapeutic efficacy of STN-DBS. Opening the dura via cannula puncture is recommended to increase the accuracy of the lead implantation.

GRAIL gene knockout mice protect against aging-related and noise-induced hearing loss.

BACKGROUND: Hearing loss is a global health issue and its etiopathologies involve complex molecular pathways. The ubiquitin-proteasome system has been reported to be associated with cochlear development and hearing loss. The gene related to anergy in lymphocytes ( GRAIL ), as an E3 ubiquitin ligase, has not, as yet, been examined in aging-related and noise-induced hearing loss mice models. METHODS: This study used wild-type (WT) and GRAIL knockout (KO) mice to examine cochlear hair cells and synaptic ribbons using immunofluorescence staining. The hearing in WT and KO mice was detected using auditory brainstem response. Gene expression patterns were compared using RNA-sequencing to identify potential targets during the pathogenesis of noise-induced hearing loss in WT and KO mice. RESULTS: At the 12-month follow-up, GRAIL KO mice had significantly less elevation in threshold level and immunofluorescence staining showed less loss of outer hair cells and synaptic ribbons in the hook region compared with GRAIL WT mice. At days 1, 14, and 28 after noise exposure, GRAIL KO mice had significantly less elevation in threshold level than WT mice. After noise exposure, GRAIL KO mice showed less loss of outer hair cells in the cochlear hook and basal regions compared with WT mice. Moreover, immunofluorescence staining showed less loss of synaptic ribbons in the hook regions of GRAIL KO mice than of WT mice. RNA-seq analysis results showed significant differences in C-C motif chemokine ligand 19 ( CCL19 ), C-C motif chemokine ligand 21 ( CCL21 ), interleukin 25 ( IL25 ), glutathione peroxidase 6 ( GPX6 ), and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 1 ( NOX1 ) genes after noise exposure. CONCLUSION: The present data demonstrated that GRAIL deficiency protects against aging-related and noise-induced hearing loss. The mechanism involved needs to be further clarified from the potential association with synaptic modulation, inflammation, and oxidative stress.

An enigma of hypothyroidism and hyponatremia coexistence: a nationwide population-based retrospective study.

INTRODUCTION: Hypothyroidism is a rare and possible cause of hyponatremia. However, the clinical epidemiology and risk of mortality (ROM) when they coexist still remain elusive. OBJECTIVES: We assessed the epidemiology and ROM among index patients with coexisting hypothyroidism and hyponatremia via a national population database. PATIENTS AND METHODS: This retrospective cohort study utilized Taiwan's National Health Insurance program database. Distributions of definite sociodemographic factors were analyzed. The annual incidence among the overall group and sex-subgroups was investigated. In addition, potential factors influencing the ROM were also evaluated. RESULTS: Of 4,549,226 patients from 1998 to 2015, a total of 3,140 index patients with concurrent hypothyroidism and hyponatremia were analyzed. The incidence rate increased tenfold from 1998 to 2015; average annual incidence rate was 174. Among the total participants, 57.1% were women; mean age was 72.6 ± 14.7 years and 88.8% were aged > 55 years. Although average length of stay (LOS) was 13.1 ± 15.4 days, the mortality group had significantly longer LOS than that in the survival group (12.9 days vs 22.2 days). Old age, catastrophic illness, cardiac dysrhythmia, and low hospital hierarchy were independent predictors of hospital mortality. The optimal LOS cutoff value for ROM prediction was 16 days. Index patients with LOS > 16 days increased ROM by 2.3-fold. CONCLUSIONS: Coexistent hypothyroidism and hyponatremia is rare, although the incidence increased gradually. Factors influencing the ROM, such as old age, underlying catastrophic status, cardiac dysrhythmia, hospital hierarchy, and LOS should be considered in clinical care.

The clinical application of neuro-robot in the resection of epileptic foci: a novel method assisting epilepsy surgery.

During surgery for foci-related epilepsy, neurosurgeons face significant difficulties in identifying and resecting MRI-negative or deep-seated epileptic foci. Here, we present a neuro-robotic navigation system that is specifically designed for resection of MRI negative epileptic foci. We recruited 52 epileptic patients, and randomly assigned them to treatment group with either neuro-robotic navigation or conventional neuronavigation system. For each patient, in the neuro-robotic navigation group, we integrated multimodality imaging including MRI and PET-CT into the robotic workstation and marked the boundary of foci from the fused image. During surgery, this boundary was delineated by the robotic laser device with high accuracy, guiding resection for the surgeon. For deeply seated foci, we exploited the neuro-robotic navigation system to localize the deepest point with biopsy needle insertion and methylene dye application to locate the boundary of the foci. Our results show that, compared with the conventional neuronavigation, the neuro-robotic navigation system performs equally well in MRI positive epilepsy patients (ENGEL I ratio: 71.4% vs 100%, p = 0.255) systems and show better performance in patients with MRI-negative focal cortical dysplasia (ENGEL I ratio: 88.2% vs 50%, p = 0.0439). At present, there are no documented neurosurgery robots with similar function and application in the field of epilepsy. Our research highlights the added value of using neuro-robotic navigation systems in resection surgery for epilepsy, particularly in cases that involve MRI-negative or deep-seated epileptic foci.

RNF128 regulates neutrophil infiltration and myeloperoxidase functions to prevent acute lung injury.

Acute lung injury (ALI) is characterised by severe pulmonary inflammation, alveolar-capillary barrier disruption, and pulmonary oedema. Therefore, establishing effective therapeutic targets for ALI prevention is crucial. The present study reports a novel function of RNF128 in regulating LPS-induced ALI. Severe lung damage and increased immune cell infiltration were detected in RNF128-deficient mice. In vitro experiments revealed that RNF128 inhibits neutrophil activation by binding to myeloperoxidase (MPO) and reducing its levels and activity. Moreover, RNF128 regulates alveolar macrophage activation and neutrophil infiltration by interacting with TLR4, targeting it for degradation, and inhibiting NF-κB activation, hence decreasing pro-inflammatory cytokines. Our results demonstrate for the first time that RNF128 is a negative regulator of MPO and TLR4 in neutrophils and alveolar macrophages, respectively. However, AAV9-mediated RNF128 overexpression alleviated lung tissue damage and reduced inflammatory cell infiltration. Thus, RNF128 is a promising therapeutic candidate for pharmacological interventions in ALI.

Sleep outcomes and related factors in Parkinson's disease after subthalamic deep brain electrode implantation: a retrospective cohort study.

Background: Subthalamic nucleus deep brain stimulation (STN-DBS) improves sleep qualities in Parkinson's disease (PD) patients; however, it remains elusive whether STN-DBS improves sleep by directly influencing the sleep circuit or alleviates other cardinal symptoms such as motor functions, other confounding factors including stimulation intensity may also involve. Studying the effect of microlesion effect (MLE) on sleep after STN-DBS electrode implantation may address this issue. Objective: To examine the influence of MLE on sleep quality and related factors in PD, as well as the effects of regional and lateral specific correlations with sleep outcomes after STN-DBS electrode implantation. Study Design: Case-control study; Level of evidence, 3. Data Sources and Methods: In 78 PD patients who underwent bilateral STN-DBS surgery in our center, we compared the sleep qualities, motor performances, anti-Parkinsonian drug dosage, and emotional conditions at preoperative baseline and postoperative 1-month follow-up. We determined the related factors of sleep outcomes and visualized the electrodes position, simulated the MLE-engendered volume of tissue lesioned (VTL), and investigated sleep-related sweet/sour spots and laterality in STN. Results: MLE improves sleep quality with Pittsburgh Sleep Quality Index (PSQI) by 13.36% and Parkinson's Disease Sleep Scale-2 (PDSS-2) by 17.95%. Motor (P = 0.014) and emotional (P = 0.001) improvements were both positively correlated with sleep improvements. However, MLE in STN associative subregions, as an independent factor, may cause sleep deterioration (r = 0.348, P = 0.002), and only the left STN showed significance (r = 0.327, P = 0.004). Sweet spot analysis also indicated part of the left STN associative subregion is the sour spot indicative of sleep deterioration. Conclusion: The MLE of STN-DBS can overall improve sleep quality in PD patients, with a positive correlation between motor and emotional improvements. However, independent of all other factors, the MLE in the STN associative subregion, particularly the left side, may cause sleep deterioration.

KDELC2 Upregulates Glioblastoma Angiogenesis via Reactive Oxygen Species Activation and Tumor-Associated Macrophage Proliferation.

Glioblastoma is notorious for its rapid progression and neovascularization. In this study, it was found that KDEL (Lys-Asp-Glu-Leu) containing 2 (KDELC2) stimulated vasculogenic factor expression and induced human umbilical vein endothelial cell (HUVEC) proliferation. The NLRP3 inflammasome and autophagy activation via hypoxic inducible factor 1 alpha (HIF-1α) and mitochondrial reactive oxygen species (ROS) production was also confirmed. The application of the NLRP3 inflammasome inhibitor MCC950 and autophagy inhibitor 3-methyladenine (3-MA) indicated that the above phenomenon activation correlated with an endothelial overgrowth. Furthermore, KDELC2 suppression decreased the endoplasmic reticulum (ER) stress factors' expression. The ER stress inhibitors, such as salubrinal and GSK2606414, significantly suppressed HUVEC proliferation, indicating that ER stress promotes glioblastoma vascularization. Finally, shKDELC2 glioblastoma-conditioned medium (CM) stimulated TAM polarization and induced THP-1 cells to transform into M1 macrophages. In contrast, THP-1 cells co-cultured with compensatory overexpressed (OE)-KDELC2 glioblastoma cells increased IL-10 secretion, a biomarker of M2 macrophages. HUVECs co-cultured with shKDELC2 glioblastoma-polarized THP-1 cells were less proliferative, demonstrating that KDELC2 promotes angiogenesis. Mito-TEMPO and MCC950 increased caspase-1p20 and IL-1ß expression in THP-1 macrophages, indicating that mitochondrial ROS and autophagy could also interrupt THP-1-M1 macrophage polarization. In conclusion, mitochondrial ROS, ER stress, and the TAMs resulting from OE-KDELC2 glioblastoma cells play important roles in upregulating glioblastoma angiogenesis.

New dimension on potential factors of successful pediatric peripheral intravenous catheterization.

BACKGROUND: Peripheral intravenous catheterization (PIVC) is pivotal to pediatric medical care; however, it is a challenging technique for pediatricians, and the parameters affecting successful pediatric PIVC establishment have not been fully investigated. METHODS: This prospective observational study collected data from pediatric patients aged less than 18 years who required PIVC. The participants were categorized into five groups for subgroup analysis: newborn, infant, toddler, pre-school, and student (children and adolescent). Data on demography, biochemistry, and PIVC executors were examined to elucidate the most powerful factors affecting the success of PIVC. RESULTS: A total of 935 peripheral venous cannulations conducted within 1 year were studied. Age-subgroup analysis showed the highest failure rate (FR) of PIVC in the infant group (18.4%). No significant difference in BMI standard deviation score was noted among the groups (p-value = 0.430). Compared with those for the success group, more attempts, longer completion time, and more medical staff were needed for the failure group (all p-values < 0.05). A high serum procalcitonin level was correlated with an increased FR (p-value = 0.016). In addition, the success rate was positively associated with the seniority of the operators, except for the 3-year experienced R3 group (93.5%) showing a higher success rate than the 4-year experienced CR group (84.2%). CONCLUSIONS: Difficulty in setting up PIVC was the greatest in infants and even greater than that in newborns. Even though seniority was a cardinal factor in successful PIVC, a high FR was still noted despite the lack of continuous and steady practice.

Sex modulates the outcome of subthalamic nucleus deep brain stimulation in patients with Parkinson's disease.

There are many documented sex differences in the clinical course, symptom expression profile, and treatment response of Parkinson's disease, creating additional challenges for patient management. Although subthalamic nucleus deep brain stimulation is an established therapy for Parkinson's disease, the effects of sex on treatment outcome are still unclear. The aim of this retrospective observational study, was to examine sex differences in motor symptoms, non-motor symptoms, and quality of life after subthalamic nucleus deep brain stimulation. Outcome measures were evaluated at 1 and 12 months post-operation in 90 patients with Parkinson's disease undergoing subthalamic nucleus deep brain stimulation aged 63.00 ± 8.01 years (55 men and 35 women). Outcomes of clinical evaluations were compared between sexes via a Student's t-test and within sex via a paired-sample t-test, and generalized linear models were established to identify factors associated with treatment efficacy and intensity for each sex. We found that subthalamic nucleus deep brain stimulation could improve motor symptoms in men but not women in the on-medication condition at 1 and 12 months post-operation. Restless legs syndrome was alleviated to a greater extent in men than in women. Women demonstrated poorer quality of life at baseline and achieved less improvement of quality of life than men after subthalamic nucleus deep brain stimulation. Furthermore, Hoehn-Yahr stage was positively correlated with the treatment response in men, while levodopa equivalent dose at 12 months post-operation was negatively correlated with motor improvement in women. In conclusion, women received less benefit from subthalamic nucleus deep brain stimulation than men in terms of motor symptoms, non-motor symptoms, and quality of life. We found sex-specific factors, i.e., Hoehn-Yahr stage and levodopa equivalent dose, that were related to motor improvements. These findings may help to guide subthalamic nucleus deep brain stimulation patient selection, prognosis, and stimulation programming for optimal therapeutic efficacy in Parkinson's disease.

Deep brain stimulation of the nucleus basalis of Meynert modulates hippocampal-frontoparietal networks in patients with advanced Alzheimer's disease.

BACKGROUND: Deep brain stimulation (DBS) of the nucleus basalis of Meynert (NBM) has shown potential for the treatment of mild-to-moderate Alzheimer's disease (AD). However, there is little evidence of whether NBM-DBS can improve cognitive functioning in patients with advanced AD. In addition, the mechanisms underlying the modulation of brain networks remain unclear. This study was aimed to assess the cognitive function and the resting-state connectivity following NBM-DBS in patients with advanced AD. METHODS: Eight patients with advanced AD underwent bilateral NBM-DBS and were followed up for 12 months. Clinical outcomes were assessed by neuropsychological examinations using the Mini-Mental State Examination (MMSE) and Alzheimer's Disease Assessment Scale. Resting-state functional magnetic resonance imaging and positron emission tomography data were also collected. RESULTS: The cognitive functioning of AD patients did not change from baseline to the 12-month follow-up. Interestingly, the MMSE score indicated clinical efficacy at 1 month of follow-up. At this time point, the connectivity between the hippocampal network and frontoparietal network tended to increase in the DBS-on state compared to the DBS-off state. Additionally, the increased functional connectivity between the parahippocampal gyrus (PHG) and the parietal cortex was associated with cognitive improvement. Further dynamic functional network analysis showed that NBM-DBS increased the proportion of the PHG-related connections, which was related to improved cognitive performance. CONCLUSION: The results indicated that NBM-DBS improves short-term cognitive performance in patients with advanced AD, which may be related to the modulation of multi-network connectivity patterns, and the hippocampus plays an important role within these networks. TRIAL REGISTRATION: ChiCTR, ChiCTR1900022324. Registered 5 April 2019-Prospective registration. https://www.chictr.org.cn/showproj.aspx?proj=37712.

The effect of age and disease duration on the efficacy of subthalamic nuclei deep brain stimulation in Parkinson's disease patients.

BACKGROUND: Previous studies have reported the effects of age and disease duration on the efficacy of subthalamic nuclei deep brain stimulation (STN-DBS) of Parkinson's disease (PD) patients. However, available data involving these issues are not consistent. In particular, the effect of age and disease duration on the initial efficacy of STN-DBS has not been established. METHODS: A total of 51 patients with PD treated with bilateral STN-DBS were involved in the present study. They received clinical symptom evaluation during the preoperative, initial, and chronic stages of surgery. The correlations between age when undergoing surgery/age at disease onset/disease duration and outcomes of STN-DBS were measured. RESULTS: The preoperative levodopa response was negatively associated with age. During the initial stage, the age when undergoing surgery and age at disease onset were negatively correlated with the effect on bradykinesia, with better symptom control of general symptoms in long-term disease patients. Similarly, patients with an early time of surgery and disease onset and long-term disease duration showed better control of bradykinesia and axial symptoms at the chronic stage. Furthermore, a long-term disease duration and early disease onset benefited from an increase of therapeutic efficacy in general, rigid, and axial symptoms with STN-DBS after a long period. Nevertheless, patients with late disease onset achieved a better relief of stigma. CONCLUSION: Age and disease durations played a unique role in controlling the symptoms of PD patients treated with STN-DBS. These results may contribute to patient selection and adjustments of expectations of surgery, based on the age, disease duration, and different symptoms.

Generation and analysis of pseudohypoaldosteronism type II knock-in mice caused by a nonsense KLHL3 mutation in the Kelch domain.

Mutations in the Kelch-like 3 (KLHL3) gene are the most common cause of inherited pseudohypoaldosteronism type II (PHAII) featuring thiazide-sensitive hypertension and hyperkalemic metabolic acidosis. Although Klhl3R528H/+ knock-in (KI) mice carrying a missense mutation in the Kelch repeat domain have been reported, nonsense KLHL3 mutations in the same domain that cause PHAII have not been fully investigated in vivo. We generated and analyzed Klhl3 KI mice harboring a nonsense W523X mutation (corresponding to the human KLHL3 W470X mutation). Both heterozygous and homozygous Klhl3W523X/+ KI mice exhibited typical PHAII with low-renin hypertension, hyperkalemia with reduced renal potassium excretion, and hyperchloremic metabolic acidosis. Their kidney tissues showed the presence of Klhl3 mRNA and increased Klhl3 protein levels along with enhanced downstream Wnk1/4-Spak/Osr1-N(k)cc phosphorylation. Increased protein expression of total Spak, phosphor(p-)Spak, total Ncc, and p-Ncc from urinary extracellular vesicles (uEVs) also confirmed the activation of the Wnk-mediated Ncc pathway. In vitro studies showed that the human KLHL3 W470X mutation resulted in increased KLHL3 protein stability and disrupted its binding affinity for WNK1/4, leading to the attenuated degradation and increased abundance of total WNKs. In conclusion, nonsense Klhl3W523X/+ mice recapitulating PHAII phenotypes exhibit Klhl3 protein stability, abrogating its binding to Wnks, with enhanced Ncc expression in the kidney tissue and even in uEVs. Activation of the WNK-mediated Na+ -Cl- co-transporter reiterated the in vivo pathogenic role of nonsense KLHL3 mutations in PHAII.

Protection-Free Strategy for the Synthesis of Boro-Depsipeptides in Aqueous Media under Microwave-Assisted Conditions.

In this report, 19 boron-containing depsipeptides were synthesized via microwave-assisted Passerini three-component reaction (P-3CR) in an aqueous environment. The linker-free DAHMI fluorescent tagging approach was used on selected boron-containing compounds to study the relationship between their structures and their level of cellular uptake of HEK293 cells. The biological data retrieved from the DAHMI experiments indicated that while the structures of tested compounds may be highly similar, their bio-distribution profile could be vastly distinctive. The reported optimized one-pot synthetic strategy along the linker-free in vitro testing protocol could provide an efficient platform to accelerate the development of boron-containing drugs.

Seed-Based Connectivity Prediction of Initial Outcome of Subthalamic Nuclei Deep Brain Stimulation.

Subthalamic nuclei deep brain stimulation (STN-DBS) is a well-established treatment for Parkinson's disease (PD). Some studies have confirmed the long-term efficacy is associated with brain connectivity; however, whether the initial outcome is associated with brain connectivity and efficacy of prediction based on these factors has not been well investigated. In the present study, a total of 98 patients were divided into a training set (n = 78) and a test set (n = 20). The stimulation and medication responses were calculated based on the motor performance. The functional and structural connectomes were established based on a public database and used to measure the association between stimulation response and brain connectivity. The prediction of initial outcome was achieved via a machine learning algorithm-support vector machine based on the model established with the training set. It was found that the initial outcome of STN-DBS was associated with functional/structural connectivities between the volume of tissue activated and multiple brain regions, including the supplementary motor area, precentral and frontal areas, cingulum, temporal cortex, and striatum. These factors could be used to predict the initial outcome, with an r value of 0.4978 (P = 0.0255). Our study demonstrates a correlation between a specific connectivity pattern and initial outcome of STN-DBS, which could be used to predict the initial outcome of DBS.

Predict initial subthalamic nucleus stimulation outcome in Parkinson's disease with brain morphology.

AIM: Subthalamic nucleus deep brain stimulation (STN-DBS) has been reported to be effective in treating motor symptoms in Parkinson's disease (PD), which may be attributed to changes in the brain network. However, the association between brain morphology and initial STN-DBS efficacy, as well as the performance of prediction using neuroimaging, has not been well illustrated. Therefore, we aim to investigate these issues. METHODS: In the present study, 94 PD patients underwent bilateral STN-DBS, and the initial stimulation efficacy was evaluated. Brain morphology was examined by magnetic resonance imaging (MRI). The volume of tissue activated in the motor STN was measured with MRI and computed tomography. The prediction of stimulation efficacy was achieved with a support vector machine, using brain morphology and other features, after feature selection and hyperparameter optimization. RESULTS: A higher stimulation efficacy was correlated with a thicker right precentral cortex. No association with subcortical gray or white matter volumes was observed. These morphological features could estimate the individual stimulation response with an r value of 0.5678, an R2 of 0.3224, and an average error of 11.4%. The permutation test suggested these predictions were not based on chance. CONCLUSION: Our results indicate that changes in morphology are associated with the initial stimulation motor response and could be used to predict individual initial stimulation-related motor responses.