CNS cell-derived exosome signatures as blood-based biomarkers of neurodegenerative diseases.

Molecular biomarkers require the reproducible capture of disease-associated changes and are ideally sensitive, specific and accessible with minimal invasiveness to patients. Exosomes are a subtype of extracellular vesicles that have gained attention as potential biomarkers. They are released by all cell types and carry molecular cargo that reflects the functional state of the cells of origin. These characteristics make them an attractive means of measuring disease-related processes within the central nervous system (CNS), as they cross the blood-brain barrier (BBB) and can be captured in peripheral blood. In this review, we discuss recent progress made toward identifying blood-based protein and RNA biomarkers of several neurodegenerative diseases from circulating, CNS cell-derived exosomes. Given the lack of standardized methodology for exosome isolation and characterization, we discuss the challenges of capturing and quantifying the molecular content of exosome populations from blood for translation to clinical use.

Predictors for the Differentiation between Glioblastoma, Primary Central Nervous System Lymphoma, and Metastasis in Patients with a Solitary Enhancing Intracranial Mass.

Introduction Differentiation between glioblastoma (GBM), primary central nervous system lymphoma (PCNSL), and metastasis is important in decision-making before surgery. However, these malignant brain tumors have overlapping features. This study aimed to identify predictors differentiating between GBM, PCNSL, and metastasis. Materials and Methods Patients with a solitary intracranial enhancing tumor and a histopathological diagnosis of GBM, PCNSL, or metastasis were investigated. All patients with intracranial lymphoma had PCNSL without extracranial involvement. Demographic, clinical, and radiographic data were analyzed to determine their associations with the tumor types. Results The predictors associated with GBM were functional impairment ( p = 0.001), large tumor size ( p < 0.001), irregular tumor margin ( p < 0.001), heterogeneous contrast enhancement ( p < 0.001), central necrosis ( p < 0.001), intratumoral hemorrhage ( p = 0.018), abnormal flow void ( p < 0.001), and hypodensity component on noncontrast cranial computed tomography (CT) scan ( p < 0.001). The predictors associated with PCNSL comprised functional impairment ( p = 0.005), deep-seated tumor location ( p = 0.006), homogeneous contrast enhancement ( p < 0.001), absence of cystic appearance ( p = 0.008), presence of hypointensity component on precontrast cranial T1-weighted magnetic resonance imaging (MRI; p = 0.027), and presence of isodensity component on noncontrast cranial CT ( p < 0.008). Finally, the predictors for metastasis were an infratentorial ( p < 0.001) or extra-axial tumor location ( p = 0.035), smooth tumor margin ( p < 0.001), and presence of isointensity component on cranial fluid-attenuated inversion recovery MRI ( p = 0.047). Conclusion These predictors may be used to differentiate between GBM, PCNSL, and metastasis, and they are useful in clinical management.

An extremely rare case of primary alveolar rhabdomyosarcoma in the central nervous system.

Background: Alveolar rhabdomyosarcoma (ARMS) shows a predilection for the peripheral extremities and is very rarely identified as a primary in the brain. Here, we report a case of ARMS with multiple lesions exclusively within the central nervous system (CNS). Case Description: A 20-year-old man presented to our hospital with a gradually increasing headache and disturbance of consciousness. Neuroimaging showed hydrocephalus and multiple tumor lesions, including in the brainstem and cerebellum, with uniform gadolinium enhancement on T1-weighted magnetic resonance imaging, as well as spinal cord seeding. Cerebrospinal fluid (CSF) analysis showed a slightly elevated cell count (6/µL; normal, <5/µL) and highly elevated protein (153 mg/dL). In addition, atypical cells were cytologically identified in the CSF. No other laboratory findings were abnormal. Emergency ventricular drainage was performed to control cerebral pressure, followed by a biopsy to confirm the diagnosis. Histological examination revealed a fascicular arrangement of oval cells with eosinophilic cytoplasm and tumor cells with pleomorphic nuclei and prominent nucleoli. Immunohistochemical studies showed negative results for glial fibrillary acidic protein and positive results for desmin and myogenin. In addition, molecular analysis revealed that this tumor had the H3F3A p.Lys28Met mutation and no paired box (PAX)3-forkhead box O1 (FOXO1) or PAX7-FOXO1 fusion genes. ARMS was, therefore, diagnosed. Chemotherapy and radiotherapy were subsequently initiated, but tumor growth could not be controlled, and the patient died 6 months after surgery. Conclusion: This report describes an extremely rare case of ARMS arising exclusively within the CNS.

MRI-based radiomics signatures for preoperative prediction of Ki-67 index in primary central nervous system lymphoma.

PURPOSE: The aim of this study was to develop and validate radiomics signatures based on MRI for preoperative prediction of Ki-67 proliferative index (PI) expression in primary central nervous system lymphoma (PCNSL). METHODS: A total of 341 patients with PCNSL were retrospectively analyzed, including 286 patients in one center as the training set and 55 patients in another two centers as the external validation set. Radiomics features were extracted and selected from preoperative contrast-enhanced T1-weighted images, fluid attenuation inversion recovery to build radiomics signatures according to the Ki-67 PI. The predictive performances of the radiomics model were evaluated using four classifiers including random forest, K-Nearest Neighbors, Neural Network and Decision Tree. A combined model was built by incorporating radiomics signature, clinical variables and MRI radiological characteristics using multivariate logistic regression analysis, and a nomogram was established to predict the expression of Ki-67 individually. The predictive performances of the models were evaluated using area under receiver operating characteristic curve (AUC) and decision curve analysis (DCA). RESULTS: Radiomics signatures were independent predictors of the expression level of Ki-67 (OR: 2.523, P < 0.001). RF radiomics models had the highest accuracy (0.934 in the training set and 0.811 in the external validation set) and F1 Score (0.920 in the training set and 0.836 in the external validation set). The clinic-radiologic-radiomics nomogram showed better predictive performance with AUCs of 0.877(95 % CI: 0.837-0.918) in the training set and 0.866(95 % CI: 0.774-0.957) in the external validation set. The calibration curve and DCA demonstrated goodness-of-fit and improved benefits in clinical practice of the nomogram. CONCLUSIONS: Nomograms integrating MRI-based radiomics and clinical-radiological characteristics could effectively predict Ki-67 PI in primary PCNSL.

The Silent Masquerade: Clinical and Imaging Features of Asymptomatic Vitreoretinal Lymphoma.

PURPOSE: To report and characterize ocular features of asymptomatic vitreoretinal lymphoma (VRL) associated with primary central nervous system lymphoma (PCNSL), by examining clinical and multimodal imaging characteristics and comparing with symptomatic VRL. DESIGN: Retrospective cross-sectional study. METHODS: Patients with cytologically or molecularly confirmed VRL were included. Patients were classified into three groups: primary VRL (PVRL), symptomatic VRL associated with PCNSL (PCNSL-S), or asymptomatic VRL associated with PCNSL (PCNSL-AS). Data encompassing demographics, visual symptoms, visual acuity (VA), and imaging characteristics were collected. Cross-sectional analyses of quantitative and categorical variables among groups were performed with one-way ANOVA and multinomial linear regression analyses. RESULTS: The study included 104 eyes from 56 patients with VRL. Twenty-nine patients (52%) were diagnosed with PVRL, and 27 patients (48%) were diagnosed with VRL associated with PCNSL. Among these, 17 (63%) reported visual symptoms (PCNSL-S), whereas 10 (37%) were asymptomatic (PCNSL-AS). PCNSL-AS patients exhibited better VA than PVRL patients (0.11 vs. 0.76 LogMAR, p=0.04) and distinct clinical features, with lower rates of anterior segment involvement (odds ratio [OR]=0.02; 95% confidence interval [CI] 0.12-0.84; p<0.01) and vitritis (OR= 0.32; 95%CI 0.11-0.91; p=0.03). Subretinal infiltration was less common in PCNSL-AS cases compared to PVRL (OR= 0.14; 95%CI 0.02-1.11; p=0.06) and PCNSL-S (OR: 0.08; 95%CI 0.01-0.69 p=0.05) and was associated with worse VA (estimate=0.55 LogMAR; 95%CI 0.29-0.8; p<0.01). CONCLUSION: This study describes distinctive clinical and imaging features of asymptomatic VRL associated with PCNSL, characterized by better VA and less severe ocular involvement. The findings highlight the pivotal role of multimodal imaging in facilitating early detection of VRL in the staging of PCNSL. Future guidelines for PCNSL management should consider the necessity of diagnosing patients with asymptomatic VRL.

[Clinicopathologic characteristics and survival analysis of primary large B-cell lymphoma of the central nervous system].

Objective: To retrospectively analyze the clinical and pathologic characteristics, response to treatment, survival, and prognosis of patients with primary large B-cell lymphoma of the central nervous system (PCNSLBCL) . Methods: Clinical and pathologic data of 70 patients with PCNSLBCL admitted to Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine from December 2010 to November 2022 were collected for retrospective analysis. Survival analysis was performed using the Kaplan-Meier method and log-rank test, and prognosis analysis was conducted using the Cox proportional hazards model. Results: Among 70 patients with PCNSLBCL, complete remission (CRs) were achieved in 49 (70.0% ) and partial remission in 4 (5.7% ) after the first-line induction therapy; the overall remission rate was 75.7%. The 2-year progression-free survival (PFS) rate was 55.8% and the median progression-free survival (mPFS) time was 35.9 months, whereas the 2-year overall survival (OS) rate was 79.1% with a median OS time not reached. After CR induced by first-line therapy, cumulative incidence of relapse (CIR) was lower in patients who had received auto-HSCT than in those who had not received consolidation therapy (P=0.032), whose 2-year PFS rate was 54.4% and mPFS time was 35.9 months; comparatively, the 2-year PFS rate in patients having received oral maintenance of small molecule drugs reached 84.4% with a mPFS time of 79.5 months (P=0.038). Multivariant analysis demonstrated that Class 3 in the Memorial Sloan-Kettering Cancer Center (MSKCC) prognostic model is an independent adverse prognostic factor of OS in patients with PCNSLBCL (HR=3.127, 95% CI 1.057-9.253, P=0.039) . Conclusions: In patients with PCNSLBCL achieving CR after the first-line induction therapy, auto-HSCT as consolidation therapy would lead to a decreased CIR, and PFS time could be prolonged by oral maintenance of small molecule drugs. Class 3 MSKCC prognostic model is independently associated with poorer OS.

Corrigendum: Localization of hyperpolarization-activated cyclic nucleotide-gated channels in the vertebrate retinas across species and their physiological roles.

[This corrects the article DOI: 10.3389/fnana.2024.1385932.].

Cytology or Multiparameter Flow Cytometry Positivity in the Cerebrospinal Fluid Before Transplantation is Predictive of Poor Outcomes After Allotransplantation in Acute Myeloid Leukemia Patients.

INTRODUCTION: Central nervous system leukemia (CNSL) remains a serious complication in patients with acute myeloid leukemia (AML) and an ambiguous prognostic factor for those receiving allo-geneic hematopoiesis stem cell transplantation (allo-HSCT). It is unknown whether using more sensitive tools, such as multiparameter flow cytometry (MFC), to detect blasts in the cerebrospinal fluid (CSF) would have an impact on outcome. METHODS: We retrospectively analyzed the clinical outcomes of 1472 AML patients with or without cytology or MFC positivity in the CSF before transplantation. Abnormal CSF (CSF+) was detected via conventional cytology and MFC in 44 patients at any time after diagnosis. A control group of 175 CSF-normal (CSF-) patients was generated via propensity score matching (PSM) analyses according to sex, age at transplant, and white blood cell count at diagnosis. RESULTS: Compared to those in the CSF-negative group, the conventional cytology positive and MFC+ groups had comparable 8-year nonrelapse mortality (NRM) (4%, 4%, and 6%, p = 0.82), higher cumulative incidence of relapse (CIR) (14%, 31%, and 32%, p = 0.007), lower leukemia-free survival (LFS) (79%, 63%, and 64%, p = 0.024), and overall survival (OS) (83%, 63%, and 68%, p = 0.021), with no significant differences between the conventional cytology positive and MFC+ groups. Furthermore, multivariate analysis confirmed that CSF involvement was an independent factor affecting OS and LFS. CONCLUSION: Our results indicate that pretransplant CSF abnormalities are adverse factors independently affecting OS and LFS after allotransplantation in AML patients.

Diagnosis of pediatric central nervous system tumors using methylation profiling of cfDNA from cerebrospinal fluid.

Pediatric central nervous system tumors remain challenging to diagnose. Imaging approaches do not provide sufficient detail to discriminate between different tumor types, while the histopathological examination of tumor tissue shows high inter-observer variability. Recent studies have demonstrated the accurate classification of central nervous system tumors based on the DNA methylation profile of a tumor biopsy. However, a brain biopsy holds significant risk of bleeding and damaging the surrounding tissues. Liquid biopsy approaches analyzing circulating tumor DNA show high potential as an alternative and less invasive tool to study the DNA methylation pattern of tumors. Here, we explore the potential of classifying pediatric brain tumors based on methylation profiling of the circulating cell-free DNA (cfDNA) in cerebrospinal fluid (CSF). For this proof-of-concept study, we collected cerebrospinal fluid samples from 19 pediatric brain cancer patients via a ventricular drain placed for reasons of increased intracranial pressure. Analyses on the cfDNA showed high variability of cfDNA quantities across patients ranging from levels below the limit of quantification to 40 ng cfDNA per milliliter of CSF. Classification based on methylation profiling of cfDNA from CSF was correct for 7 out of 20 samples in our cohort. Accurate results were mostly observed in samples of high quality, more specifically those with limited high molecular weight DNA contamination. Interestingly, we show that centrifugation of the CSF prior to processing increases the fraction of fragmented cfDNA to high molecular weight DNA. In addition, classification was mostly correct for samples with high tumoral cfDNA fraction as estimated by computational deconvolution (> 40%). In summary, analysis of cfDNA in the CSF shows potential as a tool for diagnosing pediatric nervous system tumors especially in patients with high levels of tumoral cfDNA in the CSF. Further optimization of the collection procedure, experimental workflow and bioinformatic approach is required to also allow classification for patients with low tumoral fractions in the CSF.

Risk factors for falls among hospitalized medical patients - A systematic review and meta-analysis.

OBJECTIVE: To identify and quantify risk factors for in-hospital falls in medical patients. DATA SOURCES: Six databases (MEDLINE, Embase, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, CINAHL, and Google Scholar) were systematically screened until April 11, 2023, to identify relevant articles. STUDY SELECTION: All titles and abstracts of the retrieved articles were independently screened by two researchers who also read the full texts of the remaining articles. Quantitative studies that assessed risk factors for falls among adult patients acutely hospitalized were included in the review. Publications that did not capture internal medicine patients or focused on other specific populations were excluded. DATA EXTRACTION: Information on study characteristics and potential risk factors were systematically extracted. Risk of bias was assessed using the Quality in Prognosis Studies (QUIPS) tool. PRISMA and MOOSE guidelines were followed for reporting. DATA SYNTHESIS: The main outcome was any in-hospital falls. Using a random-effects meta-analysis model, association measures for each risk factor reported in five or more studies were pooled. Separate analyses according to effect measure and studies adjusted for sex and age at least were performed. Of 5,067 records retrieved, 119 original publications from 25 countries were included. In conclusion, 23 potential risk factors were meta-analyzed. Strong evidence with large effect sizes was found for a history of falls (OR 2.54; 95% CI 1.63- 3.96; I2 91%), antidepressants (pooled OR 2.25; 95% confidence interval [95% CI] 1.92-2.65; I2 0%), benzodiazepines (OR 1.97; 95% CI 1.68-2.31; I2 0%), hypnotics-sedatives (OR 1.90; 95% CI 1.53-2.36; I2 46%), and antipsychotics (OR 1.61; 95% CI 1.33-1.95; I2 0%). Furthermore, evidence of associations with male sex (OR 1.22, 95% CI 0.99-1.50, I2 65%) and age (OR 1.17, 95% CI 1.02-1.35, I2 72%) were found, but effect sizes were small. CONCLUSIONS: The comprehensive list of risk factors, which specifies the strength of evidence and effect sizes, could assist in the prioritization of preventive measures and interventions.

Favorable efficacy and reduced acute neurotoxicity by antisense oligonucleotides with 2',4'-BNA/LNA with 9-(aminoethoxy)phenoxazine.

An increasing number of antisense oligonucleotides (ASOs) have been approved for clinical use. However, improvements of both efficacy and safety in the central nervous system (CNS) are crucial for the treatment with CNS diseases. We aimed to overcome the crucial issues by our development of various gapmer ASOs with a novel nucleoside derivative including a 2',4'-BNA/LNA with 9-(aminoethoxy)phenoxazine (BNAP-AEO). The various gapmer ASOs with BNAP-AEO were evaluated for thermal stability, in vitro and in vivo efficacy, and acute CNS toxicity. Thermal stability analysis of the duplexes with their complementary RNAs showed that ASOs with BNAP-AEO had a higher binding affinity than those without BNAP-AEO. In vitro assays, when transfected into neuroblastoma cell lines, demonstrated that ASOs with BNAP-AEO, had a more efficient gene silencing effect than those without BNAP-AEO. In vivo assays, involving intracerebroventricular injections into mice, revealed ASOs with BNAP-AEO potently suppressed gene expression in the brain. Surprisingly, the acute CNS toxicity in mice, as assessed through open field tests and scoring systems, was significantly lower for ASOs with BNAP-AEO than for those without BNAP-AEO. This study underscores the efficient gene-silencing effect and low acute CNS toxicity of ASOs incorporating BNAP-AEO, indicating the potential for future therapeutic applications.

Corticosteroid-free adalimumab-cyclophosphamide combination therapy for acute phase neuro-Behçet's disease: a case report.

Neuro-Behçet's disease (NBD) represents a significant complication of Behçet's syndrome, potentially leading to elevated mortality and disability rates. The standard treatment for parenchymal NBD typically entails administering high-dose corticosteroids to prompt rapid-onset effects, coupled with immunosuppressants to prevent subsequent relapses. A 48-year-old male with NBD presented with progressively worsening dysarthria over 9 months. This patient experienced increased intraocular pressure while using glucocorticoids, which worsened his pre-existing glaucoma. The patient had a prior diagnosis of NBD and presented with progressive dysarthria over a period of nine months, leading to a brain magnetic resonance imaging (MRI) scan. The brain MRI revealed multifocal punctate high signal intensities in the left frontoparietal area, insula, and basal ganglia. Instead of the standard steroid pulse therapy, the patient received adalimumab-cyclophosphamide combination as an alternative induction therapy. Subsequent serial brain MRI scans exhibited no emergence of new lesions, and the patient remained devoid of clinical relapses even after 17 months from the commencement of induction treatment. Adalimumab-cyclophosphamide combination could be used as a corticosteroid-free induction strategy for NBD. Further investigations are warranted to establish the most suitable combination regimen.

Differentiation between primary central nervous system lymphomas and gliomas according to pharmacokinetic parameters derived from dynamic contrast-enhanced magnetic resonance imaging.

Purpose: It is difficult to differentiate between primary central nervous system lymphoma and primary glioblastoma due to their similar MRI findings. This study aimed to assess whether pharmacokinetic parameters derived from dynamic contrast-enhanced MRI could provide valuable insights for differentiation. Methods: Seventeen cases of primary central nervous system lymphoma and twenty-one cases of glioblastoma as confirmed by pathology, were retrospectively analyzed. Pharmacokinetic parameters, including Ktrans, Kep, Ve, and the initial area under the Gd concentration curve, were measured from the enhancing tumor parenchyma, peritumoral parenchyma, and contralateral normal parenchyma. Statistical comparisons were made using Mann-Whitney U tests for Ve and Matrix Metallopeptidase-2, while independent samples t-tests were used to compare pharmacokinetic parameters in the mentioned regions and pathological indicators of enhancing tumor parenchyma, such as vascular endothelial growth factor and microvessel density. The pharmacokinetic parameters with statistical differences were evaluated using receiver-operating characteristics analysis. Except for the Wilcoxon rank sum test for Ve, the pharmacokinetic parameters were compared within the enhancing tumor parenchyma, peritumoral parenchyma, and contralateral normal parenchyma of the primary central nervous system lymphomas and glioblastomas using variance analysis and the least-significant difference method. Results: Statistical differences were observed in Ktrans and Kep within the enhancing tumor parenchyma and in Kep within the peritumoral parenchyma between these two tumor types. Differences were also found in Matrix Metallopeptidase-2, vascular endothelial growth factor, and microvessel density within the enhancing tumor parenchyma of these tumors. When compared with the contralateral normal parenchyma, pharmacokinetic parameters within the peritumoral parenchyma and enhancing tumor parenchyma exhibited variations in glioblastoma and primary central nervous system lymphoma, respectively. Moreover, the receiver-operating characteristics analysis showed that the diagnostic efficiency of Kep in the peritumoral parenchyma was notably higher. Conclusion: Pharmacokinetic parameters derived from dynamic contrast-enhanced MRI can differentiate primary central nervous system lymphoma and glioblastoma, especially Kep in the peritumoral parenchyma.

Multiple intracranial tuberculomas in an elderly patient: A central nervous system tuberculosis case in the emergency department.

A 67-year-old male presented to the emergency department with a 7-day history of fever, malaise, myalgia, headache, and a seizure episode. Physical examination showed stable vital signs but a fever. Laboratory tests indicated leukocytosis, anemia, thrombocytosis, and elevated inflammatory markers. Imaging revealed multiple intracranial lesions, and cerebrospinal fluid analysis confirmed the presence of acid-fast bacilli. The patient responded well to anti-tuberculosis therapy, showing significant clinical improvement within 8 weeks.

A Case of Klebsiella pneumoniae infection.

INTRODUCTION: In recent years, hypervirulent Klebsiella pneumoniae (hvKp) has attracted increasing attention. It usually causes liver abscesses, which spread through the bloodstream to other parts such as the eyes, brain, lungs. 5.5% of all paroxysmal sympathetic hyperactivity syndrome are associated with infection, hydrocephalus, brain tumors, and some unknown causes. Younger patients with focal lesions of the brain parenchyma are at higher risk of paroxysmal sympathetic hyperactivity (PSH). CASE PRESENTATION: This case report details the clinical features of Klebsiella pneumoniae diagnosed in a healthy individual. In addition to liver abscesses, bacteremia, and hyperglycemia, there are also brain abscesses, hernias, and postoperative paroxysmal sympathetic hyperactivity, an unexpected association between diseases or symptoms. The patient stabilized after comprehensive treatment, including early drainage of abscesses, rapid pathogen diagnosis, and timely and appropriate antibiotics. At a two-month follow-up, no signs of infection recurrence were noted, and the patient regained neurological function and could participate in regular physical activity. DISCUSSION: Symptoms of Klebsiella pneumoniae infection usually appear gradually, and misdiagnosis is common. When young patients suddenly develop high fever and abscess at a particular site, Klebsiella pneumoniae infection should be considered routine. Paroxysmal sympathetic hyperactivity syndrome caused by infection is rare, but a clinical score (PSH assessment measure, PSH-AM score) should be performed when clinical features appear. Early diagnosis and treatment can improve the prognosis.

The Emerging Role of Immune Checkpoint Blockade for the Treatment of Lung Cancer Brain Metastases.

Lung cancer has the highest incidence of brain metastases (BM) among solid organ cancers. Traditionally whole brain radiation therapy has been utilized for non-small-cell lung cancer (NSCLC) BM treatment, although stereotactic radiosurgery has emerged as the superior treatment modality for most patients. Highly penetrant central nervous system (CNS) tyrosine kinase inhibitors have also shown significant CNS activity in patients harboring select oncogenic drivers. There is emerging evidence that patients without oncogene-driven tumors derive benefit from the use of immune checkpoint inhibitors (ICIs). The CNS activity of ICIs have not been well studied given exclusion of patients with active BM from landmark trials, due to concerns of inadequate CNS penetration and activity. However, studies have challenged the idea of an immune-privileged CNS, given the presence of functional lymphatic drainage within the CNS and destruction of the blood brain barrier by BM. An emerging understanding of the interactions between tumor and CNS immune cells in the BM tumor microenvironment also support a role for immunotherapy in BM treatment. In addition, posthoc analyses of major trials have shown improved intracranial response and survival benefit of regimens with ICIs over chemotherapy (CT) alone for patients with BM. Two prospective phase 2 trials evaluating pembrolizumab monotherapy and atezolizumab plus CT in patients with untreated NSCLC BM also demonstrated significant intracranial responses. This review describes the interplay between CNS immune cells and tumor cells, discusses current evidence for ICI CNS activity from retrospective and prospective studies, and speculates on future directions of investigation.

Repellency, toxicity, and physiological actions of low molecular weight basic amines in mosquitoes.

BACKGROUND: This study investigated the behavioral responses and toxicity of three basic amines: 1-methylpiperazine, 1-methylpyrrolidine, and triethylamine (TEA), compounds suggested previously to be anosmic in vapor exposures to caged mosquitoes. RESULTS: These compounds showed repellency of Aedes aegypti mosquitoes, followed by flightlessness, knockdown, and paralysis, all increasing with exposure time and dosage. Electrophysiological experiments showed a blocking effect on nerve discharge of the Drosophila melanogaster larval central nervous system (CNS) with little evidence of hyperexcitation. Blockage of voltage-gated (Kv2) potassium channel currents under patch clamp occurred at similar concentrations. Involvement of K+ channels in the action of basic amines was supported by behavior and CNS recordings of a Shaker Kv1 mutant exposed to TEA, where instead of blockage, a hyperexcitation of nerve firing was observed. Experiments on cockroach leg mechanoreceptors demonstrated neuronal excitation and on mosquito antennae strong electroantennogram (EAG) signals with an augmentation of blank air responses after a single puff of basic amine. CONCLUSIONS: The neurophysiological effects of basic amines are consistent with K+ channel block, whereas the antennal EAG response was not obviously associated with anosmia. The low-dose effects of basic amines appear to be repellency and bradykinesia. Overall, the findings provide key insights into the mechanisms underlying the biological activity of basic amines. © 2024 Society of Chemical Industry.

Unleashing the Neurotherapeutic Potential: The Crucial Role of miR-206-3p in Facilitating Hsp90aa1-Mediated Central Nervous System Injuries During Heat Stroke.

This study aims to explore the molecular mechanisms of miR-206-3p in regulating Hsp90aa1 and its involvement in the central nervous system (CNS) injury in heat stroke. Weighted gene co-expression network analysis (WGCNA) was performed on the GSE64778 dataset of heat stroke to identify module genes most closely associated with disease characteristics. Through the selection of key genes and predicting upstream miRNAs using RNAInter and miRWalk databases, the regulatory relationship between miR-206-3p and Hsp90aa1 was determined. Through in vitro experiments, various methods, including bioinformatics analysis, dual-luciferase reporter gene assay, RIP experiment, and RNA pull-down experiment, were utilized to validate this regulatory relationship. Furthermore, functional experiments, including CCK-8 assay to test neuron cell viability and flow cytometry to assess neuron apoptosis levels, confirmed the role of miR-206-3p. Transmission electron microscopy, real-time quantitative PCR, DCFH-DA staining, and ATP assay were employed to verify neuronal mitochondrial damage. Heat stroke rat models were constructed, and mNSS scoring and cresyl violet staining were utilized to assess neural functional impairment. Biochemical experiments were conducted to evaluate inflammation, brain water content, and histopathological changes in brain tissue using H&E staining. TUNEL staining was applied to detect neuronal apoptosis in brain tissue. RT-qPCR and Western blot were performed to measure gene and protein expression levels, further validating the regulatory relationship in vivo. Bioinformatics analysis indicated that miR-206-3p regulation of Hsp90aa1 may be involved in CNS injury in heat stroke. In vivo, animal experiments demonstrated that miR-206-3p and Hsp90aa1 co-localized in neurons of the rat hippocampal CA3 region, and with prolonged heat stress, the expression of miR-206-3p gradually increased while the expression of Hsp90aa1 gradually decreased. Further in vitro cellular mechanism validation and functional experiments confirmed that miR-206-3p could inhibit neuronal cell viability and promote apoptosis and mitochondrial damage by targeting Hsp90aa1. In vivo, experiments confirmed that miR-206-3p promotes CNS injury in heat stroke. This study revealed the regulatory relationship between miR-206-3p and Hsp90aa1, suggesting that miR-206-3p could regulate the expression of Hsp90aa1, inhibit neuronal cell viability, and promote apoptosis, thereby contributing to CNS injury in heat stroke.

Cardiac autonomic response to acute painful stimulus in individuals with chronic neck pain: A case-control study.

PURPOSE: Characterize heart rate and cardiac autonomic response to painful stimulus on neck pain. METHODS: Twenty-five individuals with neck pain and 25 healthy subjects were included. Heart rate variability and heart rate were assessed in the conditioned pain modulation test at pretest rest, during testing and in recovery. Heart rate variability indices were obtained using linear and nonlinear methods. RESULTS: No significant differences were observed between groups regarding heart rate and the linear methods (p > 0.05). However, significant difference was observed between groups regarding nonlinear methods (standard deviation of the instantaneous variability of beat-to-beat interval variability, p = 0.005) CONCLUSIONS: Individuals with chronic neck pain showed autonomic responses similar to those of their healthy counterparts during the conditioning stimulus.