Exploration of the causal associations between circulating inflammatory proteins, immune cells, and neuromyelitis optica spectrum disorder: a bidirectional Mendelian randomization study and mediation analysis.

Background: An increasing body of research has demonstrated a robust correlation between circulating inflammatory proteins and neuromyelitis optica spectrum disorders (NMOSD). However, whether this association is causal or whether immune cells act as mediators currently remains unclear. Methods: We employed bidirectional two-sample Mendelian randomization (TSMR) analysis to examine the potential causal association between circulating inflammatory proteins, immune cells, and NMOSD using data from genome-wide association studies (GWAS). Five different methods for Mendelian randomization analyses were applied, with the inverse variance-weighted (IVW) method being the primary approach. Sensitivity analyses were further performed to assess the presence of horizontal pleiotropy and heterogeneity in the results. Finally, a two-step Mendelian randomization (MR) design was employed to examine the potential mediating effects of immune cells. Results: A notable causal relationship was observed between three circulating inflammatory proteins (CSF-1, IL-24, and TNFRSF9) and genetically predicted NMOSD. Furthermore, two immune cell phenotypes, genetically predicted CD8 on naive CD8+ T cells, and Hematopoietic Stem Cell Absolute Count were negatively and positively associated with genetically predicted NMOSD, respectively, although they did not appear to function as mediators. Conclusion: Circulating inflammatory proteins and immune cells are causally associated with NMOSD. Immune cells do not appear to mediate the pathway linking circulating inflammatory proteins to NMOSD.

Exploring causal correlations between systemic inflammatory cytokines and epilepsy: A bidirectional Mendelian randomization study.

BACKGROUND: Inflammation plays a role in the development and advancement of epilepsy, but the relationship between inflammatory cytokines and epilepsy is still not well understood. Herein, we use two-sample Mendelian randomization (MR) to examine the causal association between systemic inflammatory cytokines and epilepsy. METHODS: We conducted a bidirectional two-sample MR analysis based on genome-wide association study data of 41 serum cytokines from 8293 Finnish individuals with various epilepsy subtypes from the International League against Epilepsy Consortium. RESULTS: Our study showed that three inflammatory cytokines were associated with epilepsy, five were associated with generalized epilepsy, four were associated with focal epilepsy, one was associated with focal epilepsy-documented lesion negative, three were associated with juvenile absence epilepsy, one was associated with childhood absence epilepsy, two were associated with focal epilepsy-documented lesion other than hippocampal sclerosis, and two were associated with juvenile myoclonic epilepsy. Furthermore, the expression of systemic inflammatory cytokines was unaffected by genetically predicted epilepsy. CONCLUSION: This study suggested that several inflammatory cytokines are probably the factors correlated with epilepsy. Additional research is required to ascertain if these biomarkers have therapeutic potential to prevent or manage epilepsy.

Inflammatory cytokines and stroke and its subtypes: a genetic correlation and two-sample Mendelian randomization study.

Introduction: The causal relationship between inflammatory factors and stroke subtypes remains unclear. This study aimed to analyze the causal relationship between 41 inflammatory factors and these two factors using Mendelian randomization (MR). Methods: We performed a two-sample MR analysis to assess the causal effects of 41 inflammatory cytokines on stroke and its subtypes and conducted a genome-wide association study (GWAS) data. The inverse-variance weighted (IVW) method was adopted as the main MR method, and we performed a series of two-sample Mendelian randomizations and related sensitivity analyses. Results: The study indicated some suggestive evidences: using the IVW approach, we found that lower possible levels of IL-4 were positively associated with the occurrence of stroke (odds ratio [OR] = 0.93, 95% confidence interval [CI]: 0.88-0.99, p = 0.014), higher interleukin (IL)-1ß, IL-12p70 levels may be positively correlated with the occurrence of stroke (OR = 1.09, 95% CI: 1.01-1.18, p = 0.027; OR = 1.08, 95% CI: 1.02-1.15, p = 0.015). For IS, results showed that lower levels of IL-4, tumor necrosis factor-related apoptosis-inducing ligand were positively associated with the occurrence of possible ischemic stroke (IS) (OR = 0.92, 95% CI: 0.87-0.98, p = 0.006; OR = 0.95, 95% CI: 0.91-1.00, p = 0.031), higher levels of IL-1ß, IL-12p70 and vascular endothelial growth factor (VEGF) may be positively correlated with the occurrence of IS (OR = 1.09, 95% CI: 1.00-1.19, p = 0.042; OR = 1.07, 95% CI: 1.01-1.15, p = 0.035; OR = 1.06, 95% CI: 1.00-1.12, p = 0.034). Our findings suggest that decreased IL-17 levels could potentially be linked to a higher likelihood of intracerebral hemorrhage (ICH) (OR = 0.51, 95% CI: 0.28-0.93, p = 0.028). For subtypes of stroke, IS and ICH, higher levels of growth regulated oncogene-α, beta nerve growth factor, IL-18, macrophage colony-stimulating factor, and induced protein 10 upregulated the risk factors while lower levels of IL-2ra and IL-17 upregulated the risk factors. Conclusion: In summary, our research validated that inflammatory markers have a pivotal impact on the development of stroke and could potentially offer a fresh approach to treating this condition.

A Chinese patient with POLR3A-related leukodystrophy: a case report and literature review.

Background: Leukodystrophies are hereditary white matter diseases characterized by genetic polymorphisms and considerable phenotypic variability. They can be classified into myelin and non-myelin malformations. These diseases are rare, affecting 1 out of 250,000-500,000 individuals and can manifest at any age. A subtype of leukodystrophy, associated with missense mutations in the RNA polymerase subunit III (POLR3A) gene, is inherited in an autosomal recessive manner. Case report: We report and analyse a case of a 34-year-old female who presented with ataxia. Magnetic Resonance Imaging (MRI) of the brain revealed demyelinating lesions in the white matter. Genetic testing identified the c.4044C > G and c.1186-2A > G variants in the POLR3A gene. The patient was diagnosed with hypomyelinating leukodystrophy type 7 and received neurotrophic and symptomatic supportive therapy. However, after 1 month of follow-up, there was no improvement in her symptoms. Conclusion: POLR3A-induced leukodystrophy is relatively rare and not well understood, making it challenging to diagnose and easy to overlook. The prognosis for this disease is generally poor, significantly impacting the quality of life of affected individuals. Currently, no cure is available for this condition, and treatment is limited to managing symptoms. Further research into new treatment methods for POLR3A-induced leukodystrophy is imperative to improve the quality of life and potentially extend the life expectancy of patients.

Effect of intranasal and oral administration of levetiracetam on the temporal and spatial distributions of SV2A in the KA-induced rat model of SE.

To investigate the effectiveness of nasal delivery of levetiracetam (LEV) on the distributions of synaptic vesicle protein 2 isoform A (SV2A) in epileptic rats with injection of kainic acid (KA) into amygdala. A total of 138 rats were randomly divided into four groups, including the Sham surgery group, the epilepsy group (EP), and the LEV oral administration (LPO) and nasal delivery (LND) groups. The rat intra-amygdala KA model of epilepsy was constructed. Pathological changes of rat brain tissue after status epilepticus (SE) were detected using haematoxylin and eosin staining. Expression of SV2A in rat hippocampus after SE was evaluated using the western blotting analysis. Expression and distribution of SV2A in rat hippocampus after SE were detected based on immunofluorescence staining. The EP group showed evident cell loss and tissue necrosis in the CA3 area of hippocampus, whereas the tissue damage in both LPO and LND groups was significantly reduced. Western blotting analysis showed that the expressions of SV2A in the hippocampus of both EP and LND groups were significantly decreased 1 week after SE, increased to the similar levels of the Sham group in 2 weeks, and continuously increased 4 weeks after SE to the level significantly higher than that of the Sham group. Results of immunofluorescence revealed largely the same expression patterns of SV2A in the CA3 area of hippocampus as those in the entire hippocampus. Our study revealed the same antiepileptic and neuronal protective effects by the nasal and oral administrations of LEV, without changing the expression level of SV2A.

The JAK-STAT Signaling Pathway in Epilepsy.

Epilepsy is defined as spontaneous recurrent seizures in the brain. There is increasing evidence that inflammatory mediators and immune cells are involved in epileptic seizures. As more research is done on inflammatory factors and immune cells in epilepsy, new targets for the treatment of epilepsy will be revealed. The Janus kinase-signal transducer and transcriptional activator (JAKSTAT) signaling pathway is strongly associated with many immune and inflammatory diseases, At present, more and more studies have found that the JAK-STAT pathway is involved in the development and development of epilepsy, indicating the JAK-STAT pathway's potential promise as a target in epilepsy treatment. In this review, we discuss the composition, activation, and regulation of the JAK-STAT pathway and the relationship between the JAK-STAT pathway and epilepsy. In addition, we summarize the common clinical inhibitors of JAK and STAT that we would expect to be used in epilepsy treatment in the future.

The pathogenesis of blepharospasm.

Blepharospasm is a focal dystonia characterized by involuntary tetanic contractions of the orbicularis oculi muscle, which can lead to functional blindness and loss of independent living ability in severe cases. It usually occurs in adults, with a higher incidence rate in women than in men. The etiology and pathogenesis of this disease have not been elucidated to date, but it is traditionally believed to be related to the basal ganglia. Studies have also shown that this is related to the decreased activity of inhibitory neurons in the cerebral cortex caused by environmental factors and genetic predisposition. Increasingly, studies have focused on the imbalance in the regulation of neurotransmitters, including dopamine, serotonin, and acetylcholine, in blepharospasm. The onset of the disease is insidious, and the misdiagnosis rate is high based on history and clinical manifestations. This article reviews the etiology, epidemiological features, and pathogenesis of blepharospasm, to improve understanding of the disease by neurologists and ophthalmologists.

Association of HLA Alleles with Antiepileptic Drug-Induced Mild Cutaneous Reactions: A Case-Control Study of a Northeast Han Chinese Population.

Background: Human leukocyte antigen (HLA) is associated with drug-induced cutaneous adverse reactions, including antiepileptic drugs (AEDs). HLA gene polymorphism has a regional discrepancy, and it is therefore important to study it in different populations. Objective: To investigate the role of HLA in AED-induced mild cutaneous adverse drug reactions (cADRs) in a Northeast Han Chinese population. Methods: A case-control study was performed in the First Hospital of Jilin University between August 2016 and March 2017. In total, 26 patients with mild cADRs induced by AEDs and 23 AED-tolerant control patients were included. Sequence-based typing (SBT) was used to detect HLA-A and HLA-B genotypes. Differences in genotype frequencies between groups were assessed using Fisher's exact test. Results: In the mild cADRs group, 22 patients (84.6%) presented with maculopapular exanthema (MPE) and four patients (15.4%) presented with an isolated itch. The median duration between the AED exposure and cADRs was 7.5 days (IQR, 3 - 14 days). We failed to find statistically significant differences in HLA alleles between the cADRs group and the control group when considering all the drugs included in our study together or when considering oxcarbazepine (OXC), carbamazepine (CBZ), and levetiracetam (LEV) alone (P > 0.05). Conclusions: Our findings indicated that there was no correlation between HLA alleles and AED-induced mild cADRs in the Northeast Han Chinese population.

Parthanatos participates in glutamate-mediated HT22 cell injury and hippocampal neuronal death in kainic acid-induced status epilepticus rats.

AIMS: Epileptic seizures or status epilepticus (SE) can cause hippocampal neuronal death, which has detrimental effects. Parthanatos, a new form of programmed cell death, is characterized by hyperactivation of poly (ADP-ribose) polymerase-1 (PARP-1), excessive synthesis of poly ADP-ribose polymer, mitochondrial depolarization, and nuclear translocation of apoptosis-inducing factor, observed in various neurodegenerative disorders but rarely reported in epilepsy. We aimed to investigate whether parthanatos participates in the mechanism of seizure-induced hippocampal neuronal death. METHODS: Glutamate-mediated excitotoxicity cell model was used to study the mechanism of seizure-induced cell injury. Injection of kainic acid into the amygdala was used to establish the epileptic rat model. Corresponding biochemical tests were carried out on hippocampal tissues and HT22 cells following indicated treatments. RESULTS: In vitro, glutamate time-dependently induced HT22 cell death, accompanied by parthanatos-related biochemical events. Pretreatment with PJ34 (PARP-1 inhibitor) or small interfering RNA-mediated PARP-1 knockdown effectively protected HT22 cells against glutamate-induced toxic effects and attenuated parthanatos-related biochemical events. Application of the antioxidant N-acetylcysteine (NAC) rescued HT22 cell death and reversed parthanatos-related biochemical events. In vivo, PJ34 and NAC afforded protection against SE-induced hippocampal neuronal damage and inhibited parthanatos-related biochemical events. CONCLUSION: Parthanatos participates in glutamate-induced HT22 cell injury and hippocampal neuronal damage in rats following epileptic seizures. ROS might be the initiating factor during parthanatos.

Epilepsy Associated With Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Episodes.

Objectives: The present study explored the clinical characteristics and prognostic factors of epilepsy in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). Methods: Thirty-four MELAS patients were included in the present study. They were diagnosed by clinical characteristics, genetic testing, muscle biopsy, and retrospective analysis of other clinical data. The patients were divided into three groups according to the effects of treatment after at least 2 years of follow-up. Results: Epilepsy was more common in male MELAS patients than in females (20/14). The age of onset ranged from 0.5 to 57 years, with an average of 22.6 years. Patients with epilepsy and MELAS had various forms of seizures. Focal seizures were the most common type affecting 58.82% of patients, and some patients had multiple types of seizures. The abnormal EEG waves were mainly concentrated in the occipital (69.57%), frontal (65.22%) and temporal lobes (47.83%). Overall, the prognosis of patients with epilepsy and MELAS was poor. Poor prognosis was associated with brain atrophy (P = 0.026), status epilepticus (P < 0.001), and use of anti-seizure medications with high mitochondrial toxicity (P = 0.015). Interpretation: Avoiding the application of anti-seizure medications with high mitochondrial toxicity, controlling seizures more actively and effectively, and delaying the occurrence and progression of brain atrophy as much as possible are particularly important to improve the prognosis of patients with MELAS and epilepsy.

The Role of ASIC1a in Epilepsy: A Potential Therapeutic Target.

BACKGROUND: Epilepsy represents one of the most common brain diseases among humans. Tissue acidosis is a common phenomenon in epileptogenic foci. Moreover, its role in epileptogenesis remains unclear. Acid-sensing ion channel-1a (ASIC1a) represents a potential way to assess new therapies. ASIC1a, mainly expressed in the mammalian brain, is a type of protein-gated cation channel. It has been shown to play an important role in the pathological mechanism of various diseases, including stroke, epilepsy, and multiple sclerosis. METHODS: Data were collected from Web of Science, Medline, PubMed, through searching for these keywords: "Acid-sensing ion channels 1a" or "ASIC1a" and "epilepsy" or "seizure". RESULTS: The role of ASIC1a in epilepsy remains controversial; it may represent a promising therapeutic target of epilepsy. CONCLUSION: This review is intended to provide an overview of the structure, trafficking, and molecular mechanisms of ASIC1a in order to elucidate the role of ASIC1a in epilepsy further.

Molecular phenotype discordance between primary and synchronous metastatic lesions of breast cancer and its determinant role in guiding treatment decisions: a case report.

Molecular phenotype discordance between primary and metastatic tumors exists in a small proportion of breast cancer (BC) patients with accessible synchronous metastases. Reduced therapeutic effect and delays in treatment can occur when decisions on systemic therapy are determined by ignoring the differences in tumor type. Here we report a 54-year-old post-menopausal locally advanced BC patient, who showed no tumor response following routine treatment which included targeting anti-HER2, based on the phenotype of primary tumor (Luminal B, HER2-positive), during neoadjuvant therapy. However, following a secondary biopsy of the metastatic subclavian lymph node, a distinct pathological feature (Triple-negative) was revealed; chemotherapy was adjusted accordingly and resulted in a positive tumor response. Various subclones within primary and metastatic lesions were identified which might be attributed to tumor heterogeneity and in turn resulting in the phenotypic discordance in the receptor status. The patient died due to tumor progression related to triple-negative-featured lung metastasis, with overall survival time of 26.4 months. This study strengthens the value of concurrent biopsies of both primary and synchronous metastatic lesions in BC patients, and provides a reference for treating this kind of tumor when discordance in the molecular phenotype is observed.

Calibration and measurement performance analysis for a spectral band charge-coupled-device-based pyrometer.

Commercial charge-coupled device (CCD) cameras are used widely in industrial applications. This paper uses a commercial CCD camera to develop a spectral band CCD-based pyrometer. To improve the calibration accuracy, a thermometry model based on the extended effective wavelength is introduced to describe the pyrometer. The Tikhonov regularization method is employed to acquire the stabilized solutions for the model parameters considering their sensitivities to the perturbations in the calibration data. Therefore, the relationships between the temperature measurement performances and the system parameters, namely, the electron gain and F-number, are analyzed in terms of the temperature measurement range and sensitivity. Meanwhile, the error and uniformity of the temperature measurements are also investigated using a blackbody furnace. The experimental results show that the temperature measurement range for the designed pyrometer is 800-1203 °C, in which the sensitivity is 0.4906-35.64 °C-1 and the average relative error and non-uniformity of the temperature measurements are 2.5‰ and 1.36%, respectively.

Disseminated histoplasmosis in primary Sjögren syndrome: A case report.

BACKGROUND: Sjögren syndrome (SS) is a chronic and systemic autoimmune disease characterized by lymphocytic infiltration of the exocrine glands. And histoplasmosis is an invasive mycosis caused by the saprophytic dimorphic fungus H. capsulatum. In patients with primary SS (PSS), disseminated histoplasmosis (DH) is extremely rare. CASE SUMMARY: We report a 37-year-old female patient admitted to our hospital with exacerbating fatigue, somnolence, and pancytopenia as the main symptoms. She was eventually diagnosed with DH based on pancytopenia, splenomegaly, and findings of bone marrow smears. The atypical clinical symptoms made the diagnosis process more tortuous. Unfortunately, she died of respiratory failure on the day the diagnosis was confirmed. CONCLUSION: We present a rare and interesting case of DH in a PSS patient. This case updates the geographic distribution of histoplasmosis in China, and expands the clinical manifestations of DH in PSS, highlighting the significance of constantly improving the understanding of PSS with DH.

A Challenging Diagnosis of Atypical Glut1-DS: A Case Report and Literature Review.

Glucose transporter type 1 deficiency syndrome (Glut1-DS) is a rare neurometabolic disorder caused by mutations of the SLC2A1 gene. Paroxysmal exercise-induced dyskinesia is regarded as a representative symptom of Glut1-DS. Paroxysmal non-kinesigenic dyskinesia is usually caused by aberrations of the MR1 and KCNMA1 genes, but it also appears in Glut1-DS. We herein document a patient with Glut1-DS who suffered first from paroxysmal exercise-induced dyskinesia and subsequently paroxysmal non-kinesigenic dyskinesia and experienced a recent worsening of symptoms accompanied with a low fever. The lumbar puncture result showed a decreased glucose concentration and increased white blood cell (WBC) count in cerebrospinal fluid (CSF). The exacerbated symptoms were initially suspected to be caused by intracranial infection due to a mild fever of <38.0°C, decreased CSF glucose, and increased CSF WBC count. However, the second lumbar puncture result indicated a decreased glucose concentration and normal WBC count in CSF with no anti-infective agents, and the patient's symptoms were not relieved apparently. The continuous low glucose concentration attracted our attention, and gene analysis was performed. According to the gene analysis result, the patient was diagnosed with Glut1-DS finally. This case indicates that the complex paroxysmal dyskinesia in Glut1-DS may be confusing and pose challenges for accurate diagnosis. Except intracranial infection, Glut1-DS should be considered as a differential diagnosis upon detection of a low CSF glucose concentration and dyskinesia. The case presented here may encourage clinicians to be mindful of this atypical manifestation of Glut1-DS in order to avoid misdiagnosis.

Seizure characteristics, treatment, and outcome in autoimmune synaptic encephalitis: A long-term study.

OBJECTIVES: The objective of this study was to report seizure characteristics, long-term outcome, and potential factors associated with persistent seizures in patients with autoimmune synaptic encephalitis (ASE). METHOD: Clinical data and courses of 52 patients with ASE who presented with seizures at the Department of Neurology of the First Hospital of Jilin University from January 2015 to August 2017 were reviewed. Seizure outcomes were assessed with a median follow-up duration of 30 months (8-40 months). RESULTS: Most patients (71.2%) presented with seizure at initial consultation; focal to bilateral tonic-clonic seizures (50.0%) were the most common type. The temporal lobe (73.5%) was the prominent region of seizure origin, which was incident with hippocampal lesions on magnetic resonance imaging (MRI) in 62.1% of the patients. Status epilepticus, subclinical seizures, and nonepileptic events were observed in 28.9%, 36.8%, and 28.9% of the patients, respectively. Twenty-seven out of the 43 followed-up patients (62.8%) exhibited seizure remission after initial immunotherapy. Others (37.2%) developed persistent seizures to different extents. Six out of 9 patients experienced additional seizure freedom because of antiepileptic drugs (AEDs); however, the seizures of the other three patients, with serious conditions, showed poor response. Patients with anti-N-methyl-d-aspartate receptor antibodies had a lower risk of developing persistent seizures than those with anti-leucine-rich glioma-inactivated 1 (LGI1) or anti-γ-aminobutyric acid receptor type B receptor (GABABR) antibodies (P = 0.001). CONCLUSIONS: A complex of clinical and subclinical seizures, and nonepileptic events characterize ASE. Patients with anti-LGI1 or anti-GABABR antibodies have a higher risk of developing persistent seizures; AEDs are suitable for achieving additional seizure freedom, but not for patients with serious conditions. A few patients present with super-refractory epilepsy despite multiple treatments.

Familial Hemiplegic Migraine Type 3 (FHM3) With an SCN1A Mutation in a Chinese Family: A Case Report.

Familial hemiplegic migraine (FHM) is a rare, monogenic, autosomal dominant subtype of migraine, in which three genes, CACNA1A, ATP1A2, and SCN1A, are currently known to be involved. The familial hemiplegic migraine type 3 (FHM3) is seldom caused by mutations in SCN1A. Here, we report a rare case of an SCN1A mutation leading to FHM3 in a Chinese family. This case report describes a 62-year-old female patient that was admitted to our clinic. She presented with recurrent attacks of hemiplegic migraine. Her symptoms were first suspicious of a transient ischemic attack (TIA), but they were eventually diagnosed as FHM with a c.4495T>C mutation being found in the SCN1A gene. This case highlights that when a patient presents at the clinic with TIA symptoms associated with migraine, the diagnosis of an FHM should be considered and a genetic test is indicated. The identification of SCN1A gene mutations may help us to further understand the FHM pathophysiology.

First-line treatment of apatinib in elderly patient of advanced gastric carcinoma: A case report of NGS-driven targeted therapy.

Gastric carcinoma (GC) is a common gastrointestinal malignancy with high incidence and mortality worldwide, and most patients are diagnosed in the late stages of disease. Palliative chemotherapy provides a survival benefit for patients with inoperable advanced GC. However, elderly patients who are unable to tolerate chemotherapy had worse prognosis due to lack of effective treatment. Herein we reported a Chinese elderly GC patient using next generation sequencing (NGS)-based tumor DNA analysis. Valuable gene variants of vascular endothelial growth factor (VEGF) A gene amplification were detected. Additionally, a novel NOTCH1-BPHL fusion has been identified. He received antiangiogenic drug apatinib and showed both good clinical and radiographic response, but eventually died of non-cancer related cause, with progression free survival time (PFS) and overall survival time (OS) up to 9.53 months. This was the first GC case with apatinib usage as first-line treatment under the guidance of NGS gene profiling.

The c-Jun N-terminal kinase signaling pathway in epilepsy: activation, regulation, and therapeutics.

Epilepsy affects approximately 50-70 million people worldwide and 30-40% of patients do not benefit from medication. Therefore, it is necessary to identify novel targets for epileptic treatments. c-Jun N-terminal kinase (JNK) is a member of the mitogen-activated protein kinase (MAPK) family that activates diverse substrates, such as transcriptional factors, adaptor proteins, and signaling proteins, and has a wide variety of functions in both physiological and pathological conditions. The excessive activation of JNK is found not only in the acute phase of epilepsy, but also in the chronic phase, which potentiates it as a promising target in epilepsy control. In this review, we discuss the activation of the JNK pathway in epilepsy and its role in neuronal death, astrocyte activation, and mossy fiber sprouting (MFS) based on recent updates. Finally, we briefly introduce the current agents that target JNK signaling to control epilepsy.