Neurotoxic Symptoms Research Articles

Valacyclovir Induced Neurotoxicity, with Therapeutic Drug Monitoring, in a Hospital-Based Setting in the Netherlands.

Valacyclovir-induced neurotoxicity is a rare side effect. The aim of this study was to perform a retrospective analysis of patients with valacyclovir-induced neurotoxicity and establish valacyclovir plasma concentrations in a tertiary hospital between January 2018 and November 2022. In total 208 patients were identified with measured acyclovir concentrations, and the electronic health records of these patients were analysed. Based on the in- and exclusion criteria, 4 patents were identified in whom high plasma concentrations were linked to neurotoxicity. The first patient experienced balance and coordination problems, visual hallucinations, speaking difficulties and headaches. The second patient experienced a progressive decline of consciousness, resulting in coma. The third patient also experienced reduced consciousness and was found unconscious on the floor during the night. The fourth patient experienced vertigo after administration of acyclovir. Based on this study, neurotoxicity appears to be an underreported adverse effect of valacyclovir therapy in a hospital setting. This side effect may have a high impact on individuals as well as on the duration of hospitalization. In order to exclude valacyclovir as the cause, clinicians should consider requesting an acyclovir plasma concentration as standard hospital-based intervention whenever a patient experiences neurotoxic symptoms. Moreover, pharmacists and clinicians should be made better aware of the interaction between valacyclovir and cyclosporine and/or mycophenolic acid, in particular in elderly patients with impaired kidney function. Valaciclovir-induced neurotoxicity diagnosis is underreported.Accessible and frequent therapeutic drug monitoring (TDM) of valacyclovir is recommended.Interactions between valaciclovir and ciclosporin and/or mycophenolic acid, in particular in elderly patients with impaired kidney function, need a follow-up during hospitalization.

The Toxin Diversity, Cytotoxicity, and Enzymatic Activity of Cape Cobra (Naja nivea) Venom.

"True" cobras (genus Naja) are among the venomous snakes most frequently involved in snakebite accidents in Africa and Asia. The Cape cobra (Naja nivea) is one of the African cobras of highest medical importance, but much remains to be learned about its venom. Here, we used a shotgun proteomics approach to better understand the qualitative composition of N. nivea venom and tested its cytotoxicity and protease activity as well as its effect on intracellular Ca2+ release and NO synthesis. We identified 156 venom components representing 17 protein families, with the dominant ones being three-finger toxins, mostly of the short-chain type. Two-thirds of the three-finger toxin entries identified were assigned as cytotoxins, while the remainder were categorized as neurotoxins, including short-chain, long-chain, and ancestral three-finger toxins. We also identified snake venom metalloproteinases and members of CRISP, l-amino acid oxidase, and other families. Protease activity and its effect on intracellular Ca2+ release and NO synthesis were low. Phospholipase A2 activity was surprisingly high, despite this toxin family being marginally recovered in the analyzed venom. Cytotoxicity was relevant only at higher venom concentrations, with macrophage and neuroblastoma cell lines showing the lowest viability. These results are in line with the predominantly neurotoxic envenomation symptoms caused by Cape cobra bites. The present overview of the qualitatively complex and functionally intriguing venom of N. nivea may provide insights into the pathobiochemistry of this species' venom.

Potential neurotoxicity associated with methotrexate

This study aimed to elucidate the incidence and characteristics of neurotoxicity in patients receiving methotrexate (MTX) treatment. A retrospective analysis was performed using data from the electronic cohort database spanning from January 1990 to December 2021. This review focused on patients who manifested neurotoxic symptoms post-MTX therapy, excluding patients with peripheral neuropathy. Of the 498 individuals who received MTX, 26 (5.22%) exhibited neurotoxicity. Pediatric patients (< 18 years) accounted for 18 cases (7.44%), whereas adults (> 18 years) comprised eight cases (3.13%). The median onset age was 11 years (range 4–15) in the pediatric cohort and 39.5 years (range 19–67) in the adult cohort. A predominant male predisposition was noted (21 patients, 80.77%). The majority of patients (21, 80.77%) experienced neurotoxic effects following multiple MTX administrations. Modes of MTX delivery included intrathecal (37.0%), intravenous (22.2%), and combined routes (40.7%). Clinical presentations were predominantly encephalopathy (69.2%), followed by encephalomyelopathy (15.4%), myelopathy (11.5%), and polyradiculopathy (3.8%). Fourteen patients recovered (53.85%). Risk factors were male sex, pediatric age (particularly above 10 years), and administration route (intrathecal in adults and intravenous in pediatrics). Although infrequent, MTX-related neurotoxicity has a substantial impact on patient prognosis, with potential development following even a single dose. Its radiological resemblance to diverse neuropathologies, such as cerebral infarction and subacute combined degeneration, necessitates vigilant diagnostic scrutiny.

Proteome analysis of toxic fractions of Moroccan cobra Naja haje venom using mass spectrometry

ABSTRACT Snake venoms constitute a complex blend of proteins and peptides, with their toxicity and pharmacological effects varying depending on their geographic origin. Naja haje, a venomous snake of significant medical importance in regions like Morocco and North Africa, can inflict severe pain, swelling, and neurotoxic symptoms upon biting. Without prompt medical intervention, these symptoms can rapidly worsen, potentially leading to fatal outcomes. Understanding the venom’s components is crucial for developing effective antivenom therapies. Specific antibodies that target the venom’s toxic elements are essential for neutralising its activity. Therefore, we conducted a proteomic analysis of these elements within Naja haje venom using gel filtration, HPLC, and mass spectrometry. Our findings identified eight fractions, among which fractions 5 and 6 exhibited notable toxicity, with fraction 5 resulting in mortality. Furthermore, we observed a prevalence of 3FTx, a diverse component in Naja venom, alongside short-chain neurotoxins such as short neurotoxin, cytotoxin, and muscarinic toxin-like proteins. Recognising these harmful elements is crucial for developing precise antivenom treatments. This investigation represents the first proteomic analysis of toxic fractions from Naja haje venom in Morocco, providing valuable insights into venom composition and aiding in the development of targeted therapies.

Ocular surface alterations in agricultural workers exposed to pesticides in Cundinamarca, Colombia

BackgroundThe cholinergic system regulates a variety of structures on the ocular surface and maintains homeostasis. Therefore, dysregulation of cholinergic activity could impact lacrimal and conjunctival function. Consequently, exposure of the ocular surface to chemical agents, including pesticides such as acetylcholinesterase inhibitors, which interact closely with the ocular surface and anterior segment, could affect ocular homeostasis. In this study, we assess alterations in the ocular surface in workers exposed to organophosphate pesticides. MethodsA cross-sectional study was conducted involving 39 participants (23 controls and 16 cases exposed to agrochemicals). The ocular surface of all subjects was assessed using the Schirmer test, TBUT, conjunctival impression cytology, and the Q16 neurotoxicity and ocular symptoms questionnaire by Donate. ResultsConjunctival hyperemia, impression cytology and Schirmer test were found to be altered in the workers exposed to cholinesterase inhibitor pesticides. ConclusionThese findings suggest that ocular surface alterations can be seen in organophosphate pesticide exposure, and that lacrimal hypersecretion could be an ocular biomarker for detecting pesticide effects before adverse clinical effects occur.

Il34 rescues metronidazole-induced impairment of spinal cord regeneration in zebrafish central nervous system.

Metronidazole (MTZ), a commonly used anti-infective drug in clinical practice, has also been employed as a prodrug in cell-targeted ablation systems in scientific research, exhibiting significant application value. However, it has been demonstrated that MTZ can induce neurotoxic symptoms to some extent during its use, and there is currently a lack of effective means to circumvent its toxicity in both clinical and research settings, which limits its application. Therefore, exploring the specific mechanisms underlying MTZ-induced neurotoxic symptoms and elucidating countermeasures will enhance the practical value of MTZ. In this study, using a zebrafish spinal cord injury regeneration model, we confirmed that MTZ neurotoxicity leads to impaired axon regeneration in the central nervous system. By overexpressing il34 in the central nervous system of zebrafish, we eliminated the inhibitory effect of MTZ on axonal regeneration and demonstrated that the pro-regenerative effect against MTZ neurotoxicity is not caused by excessive macrophages/microglia chemoattracted by interleukin 34(Il34). Transcriptome sequencing analysis and GO enrichment analysis of differentially expressed genes between groups revealed that Il34 may counteract MTZ neurotoxicity and promote spinal cord injury repair through biological processes that enhance cellular adhesion and cell location. In summary, our work uncovers a possible cause of MTZ neurotoxicity and provides a new perspective for eliminating MTZ toxicity.

A 19-year longitudinal assessment of gyromitrin-containing (Gyromitra spp.) mushroom poisonings in Michigan

Mushroom poisonings are common in the United States. Gyromitrin (acetaldehyde N-methyl-N-formylhydrazone) is a clinically significant mycotoxin primarily associated with the lorchel (i.e. the false morel) Gyromitra esculenta. Resemblance between ‘true and false morels’ has resulted in misidentification of Gyromitra spp. as edible and sought after Morchella spp., resulting in toxicity. Despite literature evidence outlining toxic sequalae, Gyromitra spp. mushrooms are commonly consumed and prepared for culinary purposes. Classic clinical teachings emphasize significant neurotoxicity, including seizures, associated with ingestion of gyromitrin-containing mushrooms, stemming from gyromitrin's terminal metabolite monomethylhydrazine. We performed a longitudinal descriptive review of the clinical toxicity associated with ingestion of mushroom species known or suspected to contain gyromitrin in cases reported to the Michigan Poison & Drug Information Center between January 1, 2002, to December 31, 2020. Our 19-year descriptive case series of gyromitrin-containing mushroom ingestions reported to our Center demonstrated a preponderance of gastrointestinal signs and symptoms, including hepatotoxicity. Of 118 identified cases, 108 (91.5%) of the reported ingestions involved Gyromitra esculenta. The most frequent clinical findings associated with symptomatic ingestions (n = 83) were the aforementioned gastrointestinal symptoms (n = 62; 74.7%). Neurological symptoms were less frequent (n = 22, 26.5%) while hepatotoxicity occurred in fewer patients (n = 14; 16.9%). Of symptomatic patients, most were treated with symptomatic and supportive care (n = 58; 70%). Pyridoxine was used in a total of seven patients (n = 7; 8.4%) with either hepatotoxicity or neurotoxicity. Medical outcomes ranged from minor to major, with no reported deaths. Patient presentations (i.e. GI vs. neurotoxic symptoms) following ingestion of gyromitrin-containing mushrooms may be highly variable and multifactorial, owing to differences in dose ingested, geographical distribution, genetic variability of both patient and mushroom species, and species-specific differences in toxin composition. Future research warrants species-level identification of ingested gyromitrin-containing mushrooms and investigating the contribution of genetic polymorphisms to differences in clinical toxidromes.

Dietary acrylamide disrupts the functioning of the biological clock

Acrylamide (ACR) is a known carcinogen and neurotoxin. It is chronically consumed in carbohydrate-rich snacks processed at high temperatures. This calls for systematic research into the effects of ACR intake, best performed in an experimental model capable of detecting symptoms of its neurotoxicity at both high and low doses. Here, we study the influence of 10 µg/g (corresponding to the concentrations found in food products) and, for comparison, 60, 80 and 110 µg/g dietary ACR, on the fruit fly Drosophila melanogaster. We show that chronic administration of ACR affects lifespan, activity level and, most importantly, the daily and circadian pattern of locomotor activity of Drosophila. ACR-treated flies show well-defined and concentration-dependent symptoms of ACR neurotoxicity; a reduced anticipation of upcoming changes in light conditions and increased arrhythmicity in constant darkness. The results suggest that the rhythm-generating neural circuits of their circadian oscillator (biological clock) are sensitive to ACR even at low concentrations if the exposure time is sufficiently long. This makes the behavioural readout of the clock, the rhythm of locomotor activity, a useful tool for studying the adverse effects of ACR and probably other compounds.

A smartphone-based fluorescent biosensor with metal-organic framework biocomposites and cotton swabs for the rapid determination of tetrodotoxin in seafood

BackgroundTetrodotoxin (TTX) is a potent neurovirulent marine biotoxin that is present in puffer fish and certain marine animals. It is capable of causing severe neurotoxic symptoms and even death when consumed through contaminated seafood. Due to its high toxicity, developing an effective assay for TTX determination in seafood has significant benefits for food safety and human health. Currently, it remains challenging to achieve on-site determination of TTX in seafood. To facilitate mass on-site assays, more affordable technologies utilizing accessible equipment that require no skilled personnel are needed. ResultsA smartphone-based portable fluorescent biosensor is proposed for TTX determination by using metal-organic framework (MOF) biocomposites and cotton swabs. Oriented antibody (Ab)-decorated and fluorescent quantum dot (QD)-loaded MOF biocomposites (QD@MOF*Ab) are rapidly synthesized for binding targets and fluorescent responses by utilizing the tunability of zinc-based MOF. Moreover, facile Ab-immobilized household cotton swabs are utilized as TTX capture tools. TTX forms sandwich immune complexes with QD@MOF*Ab probes, achieving signal amplification. These probes are excited by a portable device to generate bright fluorescent signals, which can be detected by the naked eye, and TTX quantitative results are obtained using a smartphone. When observed with the naked eye, the limit of detection (LOD) is 0.4 ng/mL, while intelligent quantitation presents an LOD of 0.13 ng/mL at logarithmic concentrations of 0.2–400 ng/mL. SignificanceThis biosensor is convenient to use, and an easy-to-operate analysis is completed within 15 min, thus demonstrating excellent performance in terms of detection speed and portability. Furthermore, it successfully determines TTX contents in puffer fish and clam samples, demonstrating its potential for monitoring seafood. Herein, this work provides a favorable rapid sensing platform that is easily portable.

Urgent administration of antivenom following proven krait bites in Southeast Asia irrespective of neurotoxic symptoms.

Urgent administration of antivenom following proven krait bites in Southeast Asia irrespective of neurotoxic symptoms.

Critical flicker fusion in patients with epilepsy under antiseizure medication.

Critical flicker frequency (CFF) and flicker frequency (FF) are used as indicators for the neurotoxic adverse events of drugs in pharmacology. In this pilot study, we investigated whether patients with epilepsy (PWE) treated with various antiseizure medications (ASM) had significantly different CFFs compared with healthy controls. In addition, we investigated the appropriateness of CFF as an objective measurement tool in PWE who reported adverse events according to the adverse event profile (AEP). Patients receiving regular antiseizure treatment at our center, along with healthy controls, were included in this study. Clinical neurotoxic symptoms, AEP scores, and serum ASM levels were assessed in the PWE group. We used a CFF device that produced a red-black, green-black, blue-black, or white-black flicker. CFF and FF were compared between PWE and healthy controls. In PWE, the correlation of alterations in CFF and FF with AEP results and through ASM serum concentrations was calculated. A total of 33 PWE and 20 healthy controls participated in the study. Except for two light modalities, CFF and FF were significantly reduced in PWE compared with controls. CFF and FF did not differ significantly between PWE with AEP scores >44 points and those with lower scores. CFF and FF levels did not correlate with changes in AEP scores, serum concentrations, or doses. CFF and FF distinguished PWE with ASM from healthy controls. No clinically relevant differentiation was detected in the heterogenous PWE group. To investigate whether CFF and FF may serve as subtle indicators of neurotoxicity or specific modes of action, additional studies are needed in more homogenous PWE groups.

Pupil size change in agricultural workers exposed to pesticides

ABSTRACT Clinical relevance Pupil size evaluation using clinical examination may be important for detecting and monitoring individuals at risk of neurotoxic effects from chemical exposure, as it may enable early intervention and the implementation of preventive measures. Background This work aimed to investigate the association between pesticide exposure and pupil size. Pupil size is regulated by muscarinic and nicotinic receptors, and it is well-established that common pesticide chemicals disrupt this regulation. Methods Twenty agricultural workers exposed to pesticides, and twenty participants not exposed, underwent visual screening, and pupil size evaluation under mesopic and photopic conditions. Additionally, signs of neurotoxicity and pesticide exposure in both groups were evaluated using the modified version of the neurotoxic symptoms questionnaire (Q16) and measuring cholinesterase (AChE) levels in blood, respectively. Results Agricultural workers exposed to pesticides had a score indicating medium–high level of neurotoxicity (49.85 (SD ± 8.94)) which was significantly higher (t (36) = 7.659, p ≤ 0.0001) than non-exposed participants who had low levels of neurotoxicity (27.25 SD ± 8.86). There was a significant difference in pupil size (mm) under mesopic (t (19) 4.42 p = 0.003) and scotopic (t (19) 4.63, p = 0.0002) conditions between the two groups. Additionally, there was a significant difference in AChE blood levels (t (19) 2.94 p = 0.008) between exposed and non-exposed participants, indicating that exposed workers had low levels of this enzyme (average exposed group 3381 U/L (SD ± 1306)) compared to the non-exposed group (average non-exposed group 4765 U/L (SD ± 1300)). A significant negative correlation between AChE levels, years of exposure, and pupil size was found. The latter finding importantly showed that smaller pupils are associated with the accumulation of acetylcholine or a decrease in the activity of the enzyme AChE. Conclusion Pupil size of agricultural workers exposed to pesticides can be abnormal and is associated with neurotoxicity as indicated by symptomatology and cholinesterase levels. Evaluation of pupil size may be useful for clinically detecting neurotoxicity.

Comprehensive analysis and novel insights into the efficacy of polymyxin B sulfate in the treatment of sepsis caused by carbapenem-resistant gram-negative bacteria.

To investigate and analyze the clinical efficacy and safety of polymyxin B sulfate in the treatment of carbapenem-resistant gram-negative bacteria (CR-GNB) in sepsis; in order to provide reference for the clinical diagnosis, treatment and prognosis evaluation of sepsis. The clinical data of 76 patients with CR-GNB sepsis treated with polymyxin B sulfate combined with an anti-infection regimen in the First Affiliated Hospital of Gannan Medical University from January 2020 to February 2024 were retrospectively studied. To analyze and discuss the clinical characteristics, results of the bacterial culture and drug sensitivity, clinical efficacy and prognosis of CR-GNB patients, efficacy comparison of different doses of polymyxin B sulfate treatment regimens, efficacy comparison of different combination regimens based on polymyxin B sulfate, changes in clinical indexes before and after treatment of polymyxin B sulfate, adverse drug reactions and adverse events of polymyxin B sulfate were investigated. A total of 76 patients with CR-GNB sepsis were included in this study, with 55 males and 21 females, with an average age of 59.86 years old, 44 of which were (57.89%) were > 60 years old. All patients included in this study were treated with polymyxin B based combination therapy, 49 cases (64.47%) received the two-drug combination regimen, 27 cases (35.53%) received the three-drug or more combination regimen, and all the patients had the above treatment followed by systematic symptomatic supportive treatment. Patients in this study received polymyxin B for an average of (8.6±4.3) days, there were 60 (78.95%) patients with effective clinical treatment, and 49 patients (64.47%) achieved pathogen (bacterial) clearance of infection. Twenty-two cases (28.95%) died within 28 days, 31 cases (40.79%) died within 90 days, and the remaining 23 cases (30.26%) survived. There were statistically significant differences in the therapeutic effective rates and bacterial clearance rates among different courses of treatment or different initial doses of polymyxin B (all P < 0.05). Moreover, there were significant differences in APACHE II score, WBC, NE, HGB, platelet count, albumin, NT-proBNP and CRP before and after polymyxin B treatment (all P < 0.001). In this study, 7 cases (9.21%) developed drug-related kidney injury, which recovered or decreased below the pre-medication level after discontinuation or dose adjustment and infection control. Skin darkening (melanin deposition) occurred in 5 cases (6.58%), and the above patients basically returned to normal several months after withdrawal of the drug, but there was still a certain degree of skin pigmentation. Meanwhile, 3 cases (3.95%) had neurotoxic reactions, mainly manifested as numbness at the extremities, and the neurotoxic symptoms were improved after reducing the dosage. Accordingly, there was no statistically significant difference in the prognosis of CR-GNB sepsis patients between different age and gender groups (all P > 0.05), while the treatment course and dosage of polymyxin B had statistically significant effects on the prognosis of CR-GNB sepsis patients (all P < 0.05). A Polymyxin B sulfate based combination regimen is an effective choice for CR-GNB sepsis, which can maximize the survival and prognosis benefits of sepsis patients.

Study on SH-SY5Y autophagy inhibition and apoptosis induced by methanol extract of Zanthoxylum armatum DC. based on mTOR signal pathway

Abstract Background Zanthoxylum armatum DC. (ZADC) is a novel food raw material resource, offering both edible and medicinal properties. Recent research has unveiled the toxic nature of ZADC, particularly its close association with the nervous system. In a prior study, we observed that administering methanol extract of Zanthoxylum armatum DC. (MZADC) to rats via gavage at a dose of 1.038 g/kg resulted in various neurotoxicity symptoms, including excessive salivation, reduced mobility, unsteady gait, muscle twitching, and altered respiratory rates. Materials and methods We conducted cell-based research to assess the safety of ZADC and elucidate its potential toxic mechanism. In addition, we used experimental methods such as Cell Counting Kit-8, Western blot, and Flow cytometry to detect cytotoxicity in SH-SY5Y cells after intervention with MZADC. Results Following exposure of SY-SY5Y cells with MZADC, a substantial decline in cell viability was observed, accompanied by a concentration-dependent increase in intracellular reactive oxygen species (ROS) levels. Additionally, MZADC induced cellular oxidative stress, leading to elevated malonic dialdehyde (MDA) and superoxide dismutase (SOD) concentrations while decreasing glutathione (GSH) levels. Furthermore, MZADC induced apoptosis at varying doses (20, 40, and 60 μg/mL), and this effect was associated with increased Caspase-3, Bax expressions, and reduced Bcl2 and Bcl2/Bax expressions. In addition, the investigation revealed that MZADC induced autophagy inhibition in SH-SY5Y cells by activating the mTOR signaling pathway, resulting in a decrease in LC3II/LCI and Beclin-1, while increasing p-mTOR/mTOR, p62. Conclusion Consequently, this study suggests that MZADC triggers the mTOR pathway through oxidative stress in SH-SY5Y cells, ultimately leading to apoptosis. Understanding the toxicity mechanisms associated with ZADC can offer a valuable theoretical and experimental basis for its development and utilization.

A Life-Threatening Neurotoxicity in Bungarus Candidus Snake Bite: A Case Report

Background: Bungarus Candidus, a snake inducing severe neurotoxic symptoms. Case: A 31-year-old female presented to the emergency department with complaints of pain in the whole body, limb weakness, shortness of breath after being bitten by a snake. Neurological examination, ptosis of both eyelids was found with normal movement of the eyeballs. Muscle strength in all extremities is 4 followed by decreased physiological reflexes. There are fang marks in the form of 2 slightly swollen and reddened black dots on the left foot. During observation, the patient had decreased consciousness, severe shortness of breath with desaturation without any signs of shock. Other clinical revealed bilateral dilated pupils, dysphonia, dysarthria, and muscle strength that was difficult to assess. The patient was intubated and subsequently admitted to the ICU. The patient regained consciousness but still had difficulty opening his eyes and weak muscle strength on the 2nd of ICU. The patient's condition improved on the 5th of ICU, extubating was performed and transferred to the non-ICU. The treatment obtained included 17 vials of SABU, analgesics, antibiotics, anticholinesterase, and anticholinergic. The patient was discharged after 11 days of hospitalization. Discussion: The neurotoxicity of snake venom is related to mechanisms of neuromuscular transmission blockade, pre-synaptic and post-synaptic. Bungarus Candidus has a peculiar type of toxin, candoxin that acts by inhibiting nicotinic acetylcholine receptors at the postsynaptic site. Recognition of symptoms and management interventions in snakebite cases are critical to patient outcomes and survival.

Ban Cough Syrup 2022 Review

The contamination of cough syrups manufactured in Haryana was recently reported. The four cough and cold syrups so contaminated as to be banned by the WHO are Promethazine Oral Solution, Kofexmalin Baby Cough Syrup, Makoff Baby Cough Syrup, and Magrip N Cold Syrup. India-made cough and cold syrups are "potentially linked with acute kidney injuries and 70 children`s deaths" and will be distributed in The Gambia in 2022. According to the WHO, diethylene glycol and ethylene glycol are toxic to humans when consumed and can be fatal. This incident includes the prevalent proportion of cases with neurotoxic signs and symptoms

Assessing Neurobehavioral Alterations Among E-waste Recycling Workers in Hong Kong

BackgroundE-waste workers in Hong Kong are handling an unprecedented amount of e-waste, which contains various neurotoxic chemicals. However, no study has been conducted to evaluate the neurological health status of e-waste workers in Hong Kong. This study aimed to evaluate the prevalence of neurobehavioral alterations and to identify the vulnerable groups among Hong Kong e-waste workers. MethodsWe recruited 109 Hong Kong e-waste workers from June 2021 to September 2022. Participants completed standard questionnaires and wore a GENEActiv accelerometer for seven days. Pittsburgh Sleep Quality Index and Questionnaire 16/18 (Q16/18) were used to assess subjective neurobehavioral alterations. The GENEActiv data generated objective sleep and circadian rhythm variables. Workers were grouped based on job designation and entity type according to the presumed hazardous level. Unconditional logistic regression models measured the associations of occupational characteristics with neurobehavioral alterations after adjusting for confounders. ResultsWhile dismantlers/repairers and the workers in entities not funded by the government were more likely to suffer from neurotoxic symptoms in Q18 (adjusted odds ratio: 3.18 [1.18–9.39] and 2.77 [1.10–7.46], respectively), the workers from self-sustained recycling facilities also have poor performances in circadian rhythm. Results also showed that the dismantlers/repairers working in entities not funded by the government had the highest risk of neurotoxic symptoms compared to the lowest-risk group (i.e., workers in government-funded companies with other job designations). ConclusionThis timely and valuable study emphasizes the importance of improving the working conditions for high-risk e-waste workers, especially the dismantlers or repairers working in facilities not funded by the government.

Blood RNA-sequencing analysis in acrylamide-induced neurotoxicity and depressive symptoms in rats.

Acrylamide (ACR) is a by-product of the Maillard reaction, which occurs when food reacts at high temperatures. Occupational exposure is a risk factor for chronic ACR toxicity. ACR may cause neurotoxicity and depressive symptoms with high concentration in the blood; however, the underlying mechanism remains unknown. We showed the rats developed neurotoxic symptoms after being fed with ACR for 28 days, such as reduced activity and hind limb muscle weakness. We investigated whether ACR exposure causes gene expression differences by blood RNA sequencing and analyzed the differential expression of depressive symptoms-associated genes. The result indicated that IFN-γ the key regulator of neurotoxicity and depressive symptoms was induced by ACR. ACR induced the ubiquitin-mediated proteolysis pathway and JAK/STAT pathways gene expression. ACR upregulated the expression of IFN-γ, inducing neuroinflammation and neurotoxicity. ACR also upregulated the expression of JAK2, STAT1, PI3K, AKT, IκBα, UBE2D4, NF-κB, TNF-α, and iNOS in rat brain tissues and Neuro-2a cells. Thus, IFN-γ induction by ACR may induce depressive symptoms, and the ubiquitin-mediated proteolysis pathway and JAK/STAT pathways may involve in ACR neurotoxicity and depressive symptoms.

Peptide toxins that target vertebrate voltage-gated sodium channels underly the painful stings of harvester ants

Harvester ants (genus Pogonomyrmex) are renowned for their stings which cause intense, long-lasting pain, and other neurotoxic symptoms in vertebrates. Here, we show that harvester ant venoms are relatively simple and composed largely of peptide toxins. One class of peptides is primarily responsible for the long-lasting local pain of envenomation via activation of peripheral sensory neurons. These hydrophobic, cysteine-free peptides potently modulate mammalian voltage-gated sodium (NaV) channels, reducing the voltage threshold for activation and inhibiting channel inactivation. These toxins appear to have evolved specifically to deter vertebrates.

Gene-Edited Universal CD7 Chimeric Antigen Receptor T Cells for Pediatric T-Cell Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma

Background: T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL) are highly aggressive T-lineage malignancies characterized by an infiltration of immature T cells in the bone marrow (BM) and peripheral blood (PB) or extramedullary organ involvements. Effective treatments were elusive, and the long-term survival of patients with refractory/relapsed (R/R) T-ALL/LBL remains poor despite allogeneic hematopoietic stem cell transplantation (allo-HSCT). CAR-T therapies for T-cell malignancies remain underdeveloped due to the shared antigenicity between normal and malignant T cells. CD7 is highly expressed on the surface of T-ALL/LBL T cells and is considered a viable CAR-T therapeutic target. However, CD7-targeting immunotherapies may be compromised by T-cell fratricide and extermination. And one of the biggest challenges with autologous CAR-T cell therapy is to isolate a sufficient number of healthy T cells from malignant T cells. Thus, clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR9-associated protein 9 (Cas9)-mediated gene ablation has been used to produce universal CD7-targeted CAR T cells (UCD7-CAR) from suitable healthy donors that no longer express CD7 and TCR. In vitro killing tests, animal tests, and phase 1 clinical trials have preliminarily verified the efficacy and safety of universal CD7 CAR-T cells. Here we investigated the safety and efficacy of the universal CD7 CAR-T therapy in phase 2 clinical trial(NCT05454241) for pediatric R/R T-ALL/LBL patients. Aims: To investigate the efficacy and safety of the universal CD7 CAR-T therapy for pediatric R/R T-ALL/LBL patients. Methods: Patients over three years of age whose disease failed ≥ 2 lines of therapies and had ≥ 80% CD7 expression were eligible, including those who relapsed within 12 months after complete response or relapsed more than 12 months after complete response and failed to achieve remission induced by one or more courses of standard treatment; and patients with recurrence after hematopoietic stem cell transplantation. A lymphodepletion regimen was administered to all patients using fludarabine (30 mg/m2 per day) and cyclophosphamide (500 mg/m2 per day) for three consecutive days (day -5 to day -3) before CAR-T infusion. Patients received one single infusion of UCD7-CAR T cells at a median dose of 2.0×10^6/kg. Consolidative allo-HSCT after remission was allowed after day 28 after UCD7-CART infusion at the discretion of the physician and patient preference. All surviving patients were followed until July 15, 2023; the median follow-up was 109 days (54 to 117 days). Results: Five eligible children, 1 with r/r T-LBL and 4 with r/r T-ALL, were enrolled between December 2022 and April 2023 (Table 1). The median age of the patients was 5 (4-11) years. One girl(Patient 04) had a history of allo-HSCT before enrollment. Patients were heavily pretreated with a median of 3(2-6) lines of therapies. At registration, the median proportion of blasts in 4 T-ALL patients was 47.275% (6.0%-56.0%) in BM by FCM along with CNS(n=2) or testis(n=1) involvement. In contrast, 1 T-LBL patient(patient 02) did not have BM blasts but with bulky mediastinal masses ≥7 cm in diameter. All five patients had no or mild CRS (no CRS, n=1; grade 1, n=3; grade 2, n=1), and most(n=4) did not show symptoms of neurotoxicity. Patient 04, who received a prior allo-HSCT approximately seven months before CAR-T therapy, had a Herpes virus 6 (HHV-6B) encephalitis on day 17 after CAR-T infusion, but no GVHD was observed. On day 28, 4 of 5 (80.0%) patients who had BM involvement achieved MRD-negative complete remission (CR; n=2) or CR with incomplete hematologic recovery (CRi; n=2); but patient 02 with bulky mediastinal masses did not have an obvious response. Until the cutoff date, patient 04 still kept a sustained MRD negative CR; patient 05 relapsed again 49 days after CAR-T infusion, and the other three patients received a subsequent allo-UCBT with a CR state. All the children are still alive. Conclusion:UCD7-CAR T therapy is a safe and highly effective pediatric T-ALL/LBL treatment. More patients and longer follow-ups are needed for validation.