Unexpected Seizure Activity in the Setting of Lamotrigine Toxicity.

Lamotrigine, a widely utilized broad-spectrum anticonvulsant, is commonly prescribed for epilepsy management and bipolar mood disorders. Despite its extensive clinical usage, instances of lamotrigine overdose are underreported. Here, we present a case involving acute encephalopathy and seizure onset following an intentional lamotrigine overdose. This case underscores the importance of recognizing the potential clinical manifestations of lamotrigine toxicity, such as encephalopathy and seizures, emphasizing the necessity for vigilant management of patients receiving this medication.

Serofast status in syphilis: Pathogenesis to therapeutics.

Syphilis, a sexually transmitted infection caused by Treponema pallidum, has been experiencing a rise in prevalence in recent years. "Syphilis serofast" describes a unique serological reaction in patients with syphilis whose clinical symptoms have resolved following consistent anti-syphilitic therapy, but the non-Treponema pallidum antigen serologic test is still positive. Syphilis serofast is a risk factor for syphilis recurrence, neurosyphilis, and multisystem involvement. Considering the current lack of comprehensive knowledge about the epidemiological characteristics, pathogenesis, and therapies of syphilis serofast, we conducted an online search of research relating to syphilis serofast over the last twenty years. Previous research has shown that the pathogenesis of syphilis serofast is mainly related to clinical factors, immune factors, syphilis subtypes, and T.pallidum membrane protein repeat gene antigen. There are two distinct viewpoints on the treatment of serofast: no excessive treatment and active treatment. In addition, serofast patients also showed two clinical outcomes: syphilis recurrence and persistent serofast status. This article systematically reviews the related factors, treatment, and clinical outcomes of syphilis serofast, provides a theoretical basis for its research, diagnosis, and treatment, and helps clinicians develop a follow-up treatment management plan for syphilis serofast.

Treponema pallidum recombinant protein Tp0768 enhances the ability of HUVECs to promote neutrophil chemotaxis through TLR2/ER stress signaling pathway.

Neutrophils are essential cells involved in inflammation. However, the specific mechanism of neutrophil chemotaxis induced by Treponema Pallidum (T. pallidum) remains unknow. In this study, human umbilical vein endothelial cells (HUVECs) were utilized as target cells to investigate the expression levels of chemokines when stimulated with different concentrations of Tp0768(also known as TpN44.5 or TmpA, a T. pallidum infection dependent antigen). The results indicated that Tp0768 treatment enhanced neutrophil chemotaxis in HUVECs, which was closely associated with the expression levels of CXCL1(C-X-C Motif Chemokine Ligand 1), CXCL2(C-X-C Motif Chemokine Ligand 2), and CXCL8(C-X-C Motif Chemokine Ligand 8, also known as interleukin-8). At the same time, the results show that Toll Like Receptor 2 (TLR2) signaling pathway is activated and endoplasmic reticulum stress (ER stress) occurs. Furthermore, the findings revealed that the use of protein kinase RNA-like endoplasmic reticulum kinase (PERK) and Immunoglobulin-Regulated Enhancer 1 (IRE1) inhibitors reduced the expression levels of CXCL1, CXCL2, and CXCL8. Additionally, inhibiting TLR2 significantly decreased the expression levels of ER stress-related proteins (PERK and IRE1), CXCL1, CXCL2, and CXCL8. Consequently, neutrophil chemotaxis was significantly inhibited after treatment with TLR2, PERK, and IRE1 inhibitors. These findings shed light on the role of Tp0768 in enhancing neutrophil chemotaxis in endothelial cells, providing a foundation for further exploration of syphilis pathogenesis and offering a new direction for the diagnosis and treatment of T. pallidum infection.

Progression of unfolded protein response and ferroptosis in angiogenesis.

Angiogenesis is the growth of new blood vessels on preexisting ones. It is the outcome of a multifactorial effect involving several cells, which can be brought on by different stress reactions.The accumulation of unfolded proteins in the endoplasmic reticulum occurs when cells are stressed due to environmental changes, where physical or chemical stimuli induce endoplasmic reticulum stress, thereby activating the unfolded protein response (UPR), a homeostasis response designed to re-establish protein balance. Ferroptosis is a planned death of lipid peroxidation and anomalies in metabolism that is dependent on iron. Large concentrations of iron ions accumulate there, along with high concentrations of lipid peroxides and reactive oxygen species, all of which can contribute to the development of several diseases. Through the production of growth factors, adhesion factors, and inflammatory factors that trigger the start of angiogenesis, both UPR and Ferroptosis can be implicated in angiogenesis.To set the stage for further research on angiogenesis, this work concentrated on the effects of Ferroptosis and UPR on angiogenesis, respectively.

Crosstalk of ferroptosis and oxidative stress in infectious diseases.

Ferroptosis is a type of programmed cell death that pathogens can leverage to enhance their replication, transmission, and pathogenicity. Hosts typically combat pathogenic infections by utilizing oxidative stress as a defense mechanism. Nonetheless, some pathogens can trigger considerable oxidative stress while infecting, inducing an intense inflammatory response in the host's immune system and activating cell death. The process of ferroptosis is closely linked to oxidative stress, with their interaction exerting a substantial impact on the outcome of infectious diseases. This article presents an overview of the interrelated mechanisms of both Ferroptosis and oxidative stress in infectious diseases, identifying potential targets for treating such diseases in the context of their interaction.

First Report of Root Rot Caused by Pythium dissotocum on Tobacco in China.

Tobacco (Nicotiana tabacum L.) is an important economic crop that is widely grown around the world. Its annual production in China is estimated at 2.2 million tons (Berbec and Matyka 2020). Since 2022, a root rot disease was sporadically observed on tobacco seedlings on cultivar Yunyan 87 in cultivated tobacco fields in the Hunan province of China. A disease incidence of about 10% occurred across 48 ha of tobacco fields. The affected tobacco plants had slow and stunted growth with yellowing leaves. The roots turned grayish brown, decayed, and died. Diseased roots were collected from six fields and cut into small pieces (5 mm ×5 mm) from the edge of the rotted portions, and then sterilized with 70% ethanol for 10 s, 0.1% HgCl2 for 1 min, and washed in sterilized water three times. All the sterilized tissue were placed on potato dextrose agar (PDA) medium and cultured at 26 ℃ in the dark. About 3 days later, colonies with similar morphology were removed and sub-cultured on fresh PDA. A total of six strains were obtained from six tobacco samples. Strains were white and had radial growth on PDA. Hyphae were aseptate and the sporangia were filamentous. The oogonia were subglobose, smooth, 16.04 ± 0.25 µm (n=50) in diameter, and developed on unbranched stalks. The antheridia were barrel shaped and clavate. Oospores were globose, aplerotic or nearly plerotic, measuring 6.62 ± 0.33 µm (n=50). These morphological characteristics were consistent with the description of Pythium spp. (van der Plaats-Niterink 1981). For molecular identification, the internal transcribed spacer (ITS) region of rDNA and cytochrome c oxidase subunit I (Cox I) of a representative isolate, GF-3, were amplified and sequenced (GenBank accession nos. OR228424 for ITS and OR237556 for Cox I) using universal primers ITS1/ITS4 (White et al. 1990) and FM58/FM66, respectively (Villa et al. 2006). BLASTn analysis revealed that the ITS and Cox I sequences were 99.76 % (838/840 bp) and 99.85% (671/672 bp) identical to the corresponding sequences of P. dissotocum strain CBS 166.68 (AY598634.2) and UM982 (MT981147.1), respectively. A neighbor-joining phylogenetic tree based on the Cox I sequence showed that GF-3 grouped in the P. dissotocum branch. Based on morphological and molecular characteristics, GF-3 was identified to be P. dissotocum. For pathogenicity testing, four- to five-leaf-old healthy potted tobacco seedlings of the Yunyan 87 cultivar were inoculated with a zoospore suspension (1 × 105 zoospores/ml), which was induced on V8-juice medium. The zoospore suspension was introduced into the soil around plant roots and 10 mL of inoculum was used for each plant. In the control group, plants were inoculated with sterilized water. All of the treated plants were kept in humid chambers at 26°C under a 12 h/12 h photoperiod. The pathogenicity assays were performed twice, with each treatment having three replicated plants. After 5 days, tobacco seedlings inoculated with P. dissotocum showed symptoms resembling that observed in the field. However, the control plants remained healthy. Pythium dissotocum was re-isolated from the infected plants and identified by morphological and molecular methods, thus confirming Koch's postulates. Pythium dissotocum has been reported causing root rot in other plants, including hydroponic lettuce (McGehee et al. 2018) and spinach (Huo et al. 2020). Also, many Pythium species have recently been recovered from float-bed tobacco transplant production greenhouses (Zhang et al. 2022). However, to our knowledge, this is the first report of root rot on tobacco caused by P. dissotocum in China. Since this disease could greatly affect tobacco seedling establishment in the field, appropriate management strategies need to be developed to reduce further losses in tobacco planting fields.

Multiomics provides insights into the succession of microbiota and metabolite during plant leaf fermentation.

The quality of fermented plant products is closely related to microbial metabolism. Here, the associations of bacterial communities, metabolites, and functional genes were explored using multi-omics techniques based on plant leaf fermentation systems. The results showed significant changes in the structure of the microbial community, with a significant decrease in Firmicutes and a significant increase in Proteobacteria. In addition, the concentration of metabolites with antibacterial, antioxidant and aroma properties increased significantly, enhancing the quality of the fermented plant leaves. Integrated macrogenomic and metabolomic analyses indicated that amino acid metabolism could be key metabolic pathway affecting fermentation quality. Actinobacteria, Proteobacteria, Firmicutes were actively involved in tyrosine metabolism (ko00350) and phenylalanine metabolism (ko00360), and are presumed to be the major groups responsible for synthesizing growth and flavor compounds. This study emphasized the important role of microorganisms in the changes of metabolites during the fermentation of plant leaves.

Investigation of the immune escape mechanism of Treponema pallidum.

BACKGROUND: Syphilis is a chronic sexually transmitted disease caused by Treponema pallidum subspecies pallidum (T. pallidum), which is a public health problem that seriously affects human health worldwide. T. pallidum is characterized by early transmission and immune escape and is therefore termed an "invisible pathogen". METHODS: This review systematically summarizes the host's innate and adaptive immune responses to T. pallidum infection as well as the escape mechanisms of T. pallidum. PURPOSE: To lay the foundation for assessing the pathogenic mechanism and the systematic prevention and treatment of syphilis. CONCLUSION: The immune escape mechanism of T. pallidum plays an important role in its survival. Exploring the occurrence and development of these mechanisms has laid the foundation for the development of syphilis vaccine.

Treponema pallidum lipoprotein Tp0768 promotes the migration and adhesion of THP-1 cells to vascular endothelial cells through stress of the endoplasmic reticulum and the NF-κB/HIF-1α pathway.

Endothelial cell injury is a key factor in the spread of infection and pathogenicity of Treponema pallidum. The migration and adhesion reaction mediated by T. pallidum lipoprotein plays an important role. This study aimed to systematically explore the migration and adhesion effect of T. pallidum lipoprotein Tp0768 and its molecular mechanism. Stimulating vascular endothelial cells with Tp0768 increased the expression of ICAM-1, MCP-1, and IL-8. Moreover, it promoted the migration and adhesion of THP-1 cells to vascular endothelial cells. Our results revealed that Tp0768 promoted the THP-1 cells migrating and adhering to vascular endothelial cells by the PERK and IRE-1α pathways of endoplasmic reticulum (ER) stress. We further demonstrated that the inhibition of the NF-κB pathway and the downregulation of hypoxia-inducible factor 1 alpha (HIF-1α) reduced the mRNA levels of ICAM-1, MCP-1, and IL-8 induced by Tp0768. Also, the adhesion rate of THP-1 cells to endothelial cells decreased. After inhibiting ER stress, NF-κB p65 nuclear translocation was weakened, and the mRNA level of HIF-1α was also significantly downregulated. Our results indicated that T. pallidum lipoprotein Tp0768 promoted the migration and adhesion of THP-1 cells to vascular endothelial cells through ER stress and NF-κB/HIF-1α pathway.

Endoplasmic Reticulum Stress and Oxidative Stress in Inflammatory Diseases.

Endoplasmic reticulum (ER) stress and oxidative stress (OS) are often related states in cells as part of normal physiology but more frequently manifested in the pathophysiology of many diseases, particularly diseases involving acute or chronic inflammation. In this study, we reviewed recent findings about the role of ER stress and OS in the pathogenesis of inflammatory diseases.

Quantitative Study on Human Error in Emergency Activities of Road Transportation Leakage Accidents of Hazardous Chemicals.

The emergency rescue process of road transportation leakage accidents involving hazardous chemicals is complex and includes various emergency activities. A quantitative study of human errors in emergency activities is conducive to seeking the focus of the emergency rescue process. To quantitatively analyze human error in emergency activities during the emergency rescue process of road transportation leakage accidents of hazardous chemicals, sequentially timed events plotting (STEP) and the cognitive reliability and error analysis method (CREAM), were used. First, STEP was used to analyze six laws, regulations and standards, as well as 54 accident cases, to derive 24 emergency activities in the emergency rescue process. Then, CREAM was used to analyze and obtain the probability of human error for each emergency activity. Two high error level emergency activities, five medium error level emergency activities, and seventeen low error level emergency activities were identified after the human error levels of the emergency activities were classified. The results show that two emergency activities, the initial handling of the accident, and cleanup of the leakage site, should be prioritized in the emergency rescue process of road transportation leakage accidents of hazardous chemicals.

Responses of the bacterial community of tobacco phyllosphere to summer climate and wildfire disease.

Both biotic and abiotic factors continually affect the phyllospheric ecology of plants. A better understanding of the drivers of phyllospheric community structure and multitrophic interactions is vital for developing plant protection strategies. In this study, 16S rRNA high-throughput sequencing was applied to study how summer climatic factors and bacterial wildfire disease have affected the composition and assembly of the bacterial community of tobacco (Nicotiana tabacum L.) phyllosphere. Our results indicated that three time series groups (T1, T2 and T3) formed significantly distinct clusters. The neutral community model (NCM) and beta nearest taxon index (betaNTI) demonstrated that the overall bacterial community assembly was predominantly driven by stochastic processes. Variance partitioning analysis (VPA) further showed that the complete set of the morbidity and climatic variables together could explain 35.7% of the variation of bacterial communities. The node numbers of the molecular ecological networks (MENs) showed an overall uptrend from T1 to T3. Besides, Pseudomonas is the keystone taxa in the MENs from T1 to T3. PICRUSt2 predictions revealed significantly more abundant genes of osmoprotectant biosynthesis/transport in T2, and more genes for pathogenicity and metabolizing organic substrate in T3. Together, this study provides insights into spatiotemporal patterns, processes and response mechanisms underlying the phyllospheric bacterial community.

Integrated signaling system under endoplasmic reticulum stress in eukaryotic microorganisms.

The endoplasmic reticulum (ER) is a multifunctional organelle, which is crucial for correct folding and assembly of secretory and transmembrane proteins. Perturbations of ER function can cause ER stress. ER stress can activate the unfolded protein response (UPR) to cope with the accumulation of misfolded proteins and protein toxicity. UPR is a coordination system that regulates transcription and translation, leading to the recovery of ER homeostasis or cell death. However, cells have an integrated signaling system to cope with ER stress, which helps cells to restore and balance their ER function. The main components of this system are ER-associated degradation (ERAD), autophagy, hypoxia signaling, and mitochondrial biogenesis. If the balance cannot be restored, the imbalance will lead to cell death or apoptosis, or even to a series of diseases. In this review, a series of activities to restore the homeostasis of cells during ER stress are discussed. KEY POINTS: • Endoplasmic reticulum (ER) plays a key role in the biological process of cells. • Perturbations of ER function can cause ER stress, including the ER overload response (EOR), sterol-regulated cascade reaction, and the UPR. • Cells have an integrated signaling system (ERAD, autophagy, hypoxia signaling, and mitochondrial biogenesis) to cope with the adverse impact caused by ER stress.

A Randomized Controlled Trial of SGS-742, a γ-aminobutyric acid B (GABA-B) Receptor Antagonist, for Succinic Semialdehyde Dehydrogenase Deficiency.

We examined safety, tolerability, and efficacy of SGS-742, a γ-aminobutyric acid B (GABA-B) receptor antagonist, in patients with succinic semialdehyde dehydrogenase deficiency. This was a single-center randomized, double-blind crossover phase II clinical trial of SGS-742 versus placebo in patients with succinic semialdehyde dehydrogenase deficiency. Procedures included transcranial magnetic stimulation and the Adaptive Behavior Assessment Scale. Nineteen subjects were consented and enrolled; the mean age was 14.0 ± 7.5 years and 11 (58%) were female. We did not find a significant effect of SGS-742 on the Adaptive Behavior Assessment Scale score, motor threshold, and paired-pulse stimulation. The difference in recruitment curve slopes between treatment groups was 0.003 (P = .09). There was no significant difference in incidence of adverse effects between drug and placebo arms. SGS-742 failed to produce improved cognition and normalization of cortical excitability as measured by the Adaptive Behavior Assessment Scale and transcranial magnetic stimulation. Our data do not support the current use of SGS-742 in succinic semialdehyde dehydrogenase deficiency.Trial registry number NCT02019667. Phase 2 Clinical Trial of SGS-742 Therapy in Succinic Semialdehyde Dehydrogenase Deficiency. https://clinicaltrials.gov/ct2/show/NCT02019667.

Multi-system Monitoring for Identification of Seizures, Arrhythmias and Apnea in Conscious Restrained Rabbits.

Patients with ion channelopathies are at a high risk of developing seizures and fatal cardiac arrhythmias. There is a higher prevalence of heart disease and arrhythmias in people with epilepsy (i.e., epileptic heart.) Additionally, cardiac and autonomic disturbances have been reported surrounding seizures. 1:1,000 epilepsy patients/year die of sudden unexpected death in epilepsy (SUDEP). The mechanisms for SUDEP remain incompletely understood. Electroencephalograms (EEG) and electrocardiograms (ECG) are two techniques routinely used in the clinical setting to detect and study the substrates/triggers for seizures and arrhythmias. While many studies and descriptions of this methodology are in rodents, their cardiac electrical activity differs significantly from humans. This article provides a description of a non-invasive method for recording simultaneous video-EEG-ECG-oximetry-capnography in conscious rabbits. As cardiac electrical function is similar in rabbits and humans, rabbits provide an excellent model of translational diagnostic and therapeutic studies. In addition to outlining the methodology for data acquisition, we discuss the analytical approaches for examining neuro-cardiac electrical function and pathology in rabbits. This includes arrhythmia detection, spectral analysis of EEG and a seizure scale developed for restrained rabbits.

Recombinant Treponema pallidum protein Tp0768 promotes proinflammatory cytokine secretion of macrophages through ER stress and ROS/NF-κB pathway.

In response to danger signals, macrophages rapidly produce many inflammatory cytokines that trigger the cascade release of inflammatory mediators, leading to tissue damage, which is an important cause of clinical manifestations of syphilis at all stages. However, we still know very little about the specific mechanism of this process. Tp0768 is an infection-stage-dependent antigen that plays an important role in the infection of Treponema pallidum. In this study, we demonstrated that Tp0768 stimulation of macrophages can cause IL-1ß, IL-6, and IL-8 mRNA expression levels to increase in a dose- and time-dependent manner. Further research showed that Tp0768 activated ER stress and the ROS/NF-κB pathway in macrophages. Inhibition of ER stress and the ROS/NF-κB pathway inhibited the expression of IL-1ß, IL-6, and IL-8 induced by Tp0768. In addition, pretreatment with a PERK pathway inhibitor significantly reduced the expression of the NF-κB and JNK pathways, while also downregulating the expression of IL-1ß, IL-6, and IL-8. Tp0768 stimulation can activate IRE1α/XBP-1 signaling and participate in the induction of inflammatory cytokines through the JNK pathway. These findings indicate that Tp0768 promotes the secretion of proinflammatory cytokines IL-1ß, IL-6, and IL-8 by macrophages through ER stress and the ROS/NF-κB pathway, which are also involved in the activation of the NF-κB and JNK pathways that are induced by the PERK pathway and activation of IRE1α/XBP-1 signaling. KEY POINTS: • This study found for the first time that the recombinant Treponema pallidum protein Tp0768 promotes the production of IL-1ß, IL-6, and IL-8 by macrophages through ER stress. • Recombinant Treponema pallidum protein Tp0768 regulates the ROS/NF-κB pathway through ER stress. • ER stress-related pathway PERK induces the expression of IL-1ß, IL-6, and IL-8 by activating the NF-κB pathway and the JNK pathway. • IRE1α can induce the splicing of XBP-1mRNA and activate the JNK pathway.

Long-term sustained release Poly(lactic-co-glycolic acid) microspheres of asenapine maleate with improved bioavailability for chronic neuropsychiatric diseases.

Schizophrenia and bipolar disorder are severe chronic neuropsychiatric diseases, affecting hundreds of millions of people worldwide. Asenapine maleate (ASM) has been demonstrated as a safe and effective therapeutic agent under twice-daily administration. However, lower compliance is observed when patients are treated with ASM, which significantly limits its application in schizophrenia and bipolar disorder. Moreover, the low bioavailability of ASM caused by first-pass metabolism and poor aqueous solubility also impairs the treatment effect. A formulation of ASM with the property of long-term sustained release and improved bioavailability can be a solution to overcome these weaknesses. In this article, we prepared ASM-loaded poly(lactic-co-glycolic acid) (ASM-PLGA) microspheres through different techniques, including emulsification-solvent evaporation (ESE), Shirasu porous glass membrane emulsification (SPG-ME), and microfluidic method. In vitro and in vivo assessments demonstrated that uniform-sized microspheres generated by the microfluidic process sustainably released ASM throughout 40-days, showing low burst release and significantly improved bioavailability. The results suggest that ASM-PLGA microspheres prepared by the microfluidic method provide an efficient strategy to enhance the drug exposure of ASM as the treatment of chronic neuropsychiatric diseases. It is also evident that this microfluidic strategy has the potential to construct with other drugs, establishing long-acting formulations.

Crosstalk between ER stress, NLRP3 inflammasome, and inflammation.

Endoplasmic reticulum stress (ERS) is a protective response to restore protein homeostasis by activating the unfolded protein response (UPR). However, UPR can trigger cell death under severe and/or persistently high ERS. The NLRP3 inflammasome is a complex of multiple proteins that activates the secretion of the proinflammatory cytokine IL-1ß in a caspase-1-dependent manner to participate in the regulation of inflammation. The NLRP3 inflammasome involvement in ERS-induced inflammation has not been completely described. The intersection of ERS with multiple inflammatory pathways can initiate and aggravate chronic diseases. Accumulating evidence suggests that ERS-induced activation of NLRP3 inflammasome is the pathological basis of various inflammatory diseases. In this review, we have discussed the networks between ERS and NLRP3 inflammasome, with the view to identifying novel therapeutic targets in inflammatory diseases. KEY POINTS: • Endoplasmic reticulum stress (ERS) is an important factor for the activation of the NLRP3 inflammasomes that results in pathological processes. • ERS can activate the NLRP3 inflammasome to induce inflammatory responses via oxidative stress, calcium homeostasis, and NF-κB activation. • The interactions between ERS and NLRP3 inflammasome are associated with inflammation, which represent a potential therapeutic opportunity of inflammatory diseases.

Identification of key genes and pathways in syphilis combined with diabetes: a bioinformatics study.

We noticed that syphilis patients seem to be more susceptible to diabetes and the lesions often involve the kidneys, but the pathogenesis is not yet completely understood. In this study, microarray analysis was performed to investigate the dysregulated expressed genes (DEGs) in rabbit model of syphilis combined with diabetes. A total of 1045 genes were identified to be significantly differentially expressed, among which 571 were up-regulated and 474 were down-regulated (≥ 2.0fold, p < 0.05). Using the database visualization and integration discovery for the Kyoto Encyclopedia of Gene and Genome (KEGG) pathway enrichment analysis. The downregulated DEGs were significantly enriched for biosynthesis of antibiotics, carbon metabolism and protein digestion, while the upregulated DEGs were mainly enriched for cancer and PI3K-Akt signaling pathway. Molecular Complex Detection (MCODE) plugins were used to visualize protein-protein interaction (PPI) network of DEGs and Screening for hub genes and gene modules. ALB, FN1, CASP3, MMP9, IL8, CTGF, STAT3, IGF1, VCAM-1 and HGF were filtrated as the hub genes according to the degree of connectivity from the PPI network. To the best of our knowledge, this study is the first to comprehensively identify the expression patterns of dysregulated genes in syphilis combined with diabetes, providing a basis for revealing the underlying pathogenesis of syphilis combined with diabetes and exploring the goals of therapeutic intervention.