Organochlorine pesticides and their markers of exposure in serum and urine of children from a nodding syndrome hotspot in northern Uganda, east Africa.

Nodding syndrome (NS) is a neurologic disorder of unknown etiology characterized by vertical head nodding that has affected children aged 5-18 years in East Africa. Previous studies have examined relationships with biological agents (e.g., nematodes, measles, and fungi), but there is limited data on the possible contributions of neurotoxic environmental chemicals frequently used as pesticides/insecticides to the development and progression of this disorder. We examined the levels of persistent organochlorine pesticides (OCPs) in children (5-18 years old) from Kitgum District, Northern Uganda. These children previously lived in internally displaced people's (IDP) camps, where they were exposed to various health risks, including contaminated food and water. Exposure to OCPs through contaminated food and water is postulated here as a potential contributor to NS etiology. We analyzed serum (n = 75) and urine (n = 150) samples from children diagnosed with NS, and from seizure-free household controls (HC), and community controls (CC). Samples were extracted using solid-phase extraction (SPE) and extracts were analyzed for OCPs using gas chromatography with a triple quadrupole mass spectrometry (GC-MS/MS). Mean levels of total (∑) ∑OCPs in serum samples from NS, HC and CC subjects were 23.3 ± 2.82, 21.1 ± 3.40 and 20.9 ± 4.24 ng/mL, respectively, while in urine samples were 1.86 ± 1.03, 2.83 ± 1.42, and 2.14 ± 0.94 ng/mL, respectively. Correlation and linear regression analysis indicated that potential markers for ∑hexachlorocyclohexanes (HCHs), ∑chlordane compounds (CHLs), ∑endosulfan and ∑dichlorodiphenyltrichloroethanes (DDTs) were γ-HCH, heptachlor-exo-epoxide, endosulfan-α and p,p'-DDD in NS cases while in controls were α -HCH, heptachlor, endosulfan-α and p,p'-DDE, respectively. Since, in some instances, higher OCP levels were found in controls vs. NS cases, we conclude that exposure to organochlorine pesticides is unlikely to be associated with the etiology of NS.

Standardized immunological assays for assessing COVID-19 vaccines by the CEPI-Centralized Laboratory Network.

The CEPI Centralized Laboratory Network implemented key steps in the transfer and monitoring of the developed immunological SARS-CoV-2 assays to ensure standardization across all the facilities of the network. This comprehensive evaluation reinforces the reliability of the generated data and establishes a solid foundation for a standardized approach, enabling precise inter-laboratory comparisons and contributing to the overall integrity of our network's clinical results. Herein, we will provide a brief elaboration on the specific measures and procedures implemented to standardize the transfer of assays across our network.

Introducing the Role of Genotoxicity in Neurodegenerative Diseases and Neuropsychiatric Disorders.

Decades of research have identified genetic and environmental factors involved in age-related neurodegenerative diseases and, to a lesser extent, neuropsychiatric disorders. Genomic instability, i.e., the loss of genome integrity, is a common feature among both neurodegenerative (mayo-trophic lateral sclerosis, Parkinson's disease, Alzheimer's disease) and psychiatric (schizophrenia, autism, bipolar depression) disorders. Genomic instability is associated with the accumulation of persistent DNA damage and the activation of DNA damage response (DDR) pathways, as well as pathologic neuronal cell loss or senescence. Typically, DDR signaling ensures that genomic and proteomic homeostasis are maintained in both dividing cells, including neural progenitors, and post-mitotic neurons. However, dysregulation of these protective responses, in part due to aging or environmental insults, contributes to the progressive development of neurodegenerative and/or psychiatric disorders. In this Special Issue, we introduce and highlight the overlap between neurodegenerative diseases and neuropsychiatric disorders, as well as the emerging clinical, genomic, and molecular evidence for the contributions of DNA damage and aberrant DNA repair. Our goal is to illuminate the importance of this subject to uncover possible treatment and prevention strategies for relevant devastating brain diseases.

Cramp-Fasciculation Syndrome Associated with Natural and Added Chemicals in Popular Food Items.

Cramp-fasciculation syndrome (CFS) is a rare and benign neuromuscular disorder that may initially masquerade as motor neuron disease/amyotrophic lateral sclerosis. While CFS may have a familial disposition, we report on cases associated with high consumption of popular food items. One set of patients reversibly experienced acute onset of headache, flushing, muscle stiffness and fasciculations following the consumption of umami-flavored food containing a large concentration of monosodium glutamate. A second group of patients consuming food derived from lupin seed developed acute cholinergic toxicity, CFS, and, with chronic intake, significant, self-limiting, but incompletely reversible upper and lower motor neuron deficits. While these cases may improve our knowledge about the possible causes of CFS, our series also demonstrates that excessive consumption of some popular foods is not harmless. This warrants further research on their safety at all stages of human development from a neurological point of view.

Screening tools to evaluate the neurotoxic potential of botanicals: building a strategy to assess safety.

AREAS COVERED: This paper outlines the selection of NAMs, including in vitro assays using primary rat cortical neurons, zebrafish embryos, and Caenorhabditis elegans. These assays aim to assess neurotoxic endpoints such as neuronal activity and behavioral responses. Microelectrode array recordings of rat cortical neurons provide insights into the impact of botanical extracts on neuronal function, while the zebrafish embryos and C. elegans assays evaluate neurobehavioral responses. The paper also provides an account of the selection of botanical case studies based on expert judgment and existing neuroactivity/toxicity information. The proposed battery of assays will be tested with these case studies to evaluate their utility for neurotoxicity screening. EXPERT OPINION: The complexity of botanicals necessitates the use of multiple NAMs for effective neurotoxicity screening. This paper discusses the evaluation of methodologies to develop a robust framework for evaluating botanical safety, including complex neuronal models and key neurodevelopmental process assays. It aims to establish a comprehensive screening framework.

Nodding syndrome: A role for environmental biotoxins that dysregulate MECP2 expression?

Nodding syndrome is an epileptic encephalopathy associated with neuroinflammation and tauopathy. This initially pediatric brain disease, which has some clinical overlap with Methyl-CpG-binding protein 2 (MECP2) Duplication Syndrome, has impacted certain impoverished East African communities coincident with local civil conflict and internal displacement, conditions that forced dependence on contaminated food and water. A potential role in Nodding syndrome for certain biotoxins (freshwater cyanotoxins plus/minus mycotoxins) with neuroinflammatory, excitotoxic, tauopathic, and MECP2-dysregulating properties, is considered here for the first time.

Corrected speciation and gyromitrin content of false morels linked to ALS patients with mostly slow-acetylator phenotypes.

A case-control study of sporadic amyotrophic lateral sclerosis (ALS) in a mountainous village in the French Alps discovered an association of cases with a history of eating wild fungi (false morels) collected locally and initially identified and erroneously reported as Gyromitra gigas. Specialist re-examination of dried specimens of the ALS-associated fungi demonstrated they were members of the G. esculenta group, namely G. venenata and G. esculenta, species that have been reported to contain substantially higher concentrations of gyromitrin than present in G. gigas. Gyromitrin is metabolized to monomethylhydrazine, which is responsible not only for the acute oral toxic and neurotoxic properties of false morels but also has genotoxic potential with proposed mechanistic relevance to the etiology of neurodegenerative disease. Most ALS patients had a slow- or intermediate-acetylator phenotype predicted by N-acetyltransferase-2 (NAT2) genotyping, which would increase the risk for neurotoxic and genotoxic effects of gyromitrin metabolites.

Neurological patients confronting climate change: A potential role for the glymphatic system and sleep.

Interest in the health consequences of climate change (global warming, heatwaves) has increased in the neurological community. This review addresses the impact of elevated ambient temperatures and heatwaves on patients with neurological and mental health disorders, including multiple sclerosis, synucleinopathies, dementia, epilepsies, mental health, and stroke. Patients with such conditions are highly vulnerable during heatwaves because of functional disorders affecting sleep, thermoregulation, autonomic system reactivity, mood, and cognitive ability. Several medications may also increase the risk of heatstroke. Special attention is devoted to the involvement of common underlying mechanisms, such as sleep and the glymphatic system. Disease prevention and patient care during heatwaves are major issues for caregivers. Beyond the usual recommendations for individuals, we favor artificially induced acclimation to heat, which provides preventive benefits with proven efficacy for healthy adults.

Heatwaves and human sleep: Stress response versus adaptation.

The World Meteorological Organization considers a heatwave as "a period of statistically unusual hot weather persisting for a number of days and nights". Accompanying the ongoing global climate change, sharp heatwave bouts occur worldwide, growing in frequency and intensity, and beginning earlier in the season. Heatwaves exacerbate the risk of heat-related illnesses, hence human morbidity and mortality, particularly in vulnerable elderly and children. Heat-related illnesses present a continuum from normothermic (prickly heat, heat edema, heat cramps, heat tetany) to hyperthermic syndromes (from heat syncope and heat exhaustion to lethal heat stroke). Heat stroke may occur through passive heating and/or exertional exercise. "Normal sleep", such as observed in temperate conditions, is altered during heatwaves. Brisk excessive heat bouts shorten and fragment human sleep. Particularly, deep N3 sleep (formerly slow-wave sleep) and REM sleep are depleted, such as in other stressful situations. The resultant sleep loss is deleterious to cognitive performance, emotional brain function, behavior, and susceptibility to chronic health conditions and infectious diseases. Our group has previously demonstrated that sleep constitutes an adaptive mechanism during climatic heat acclimatization. In parallel, artificial heat acclimation procedures have been proposed in sports and military activities, and for the elderly. Other preventive actions should be considered, such as education and urban heat island cooling (vegetation, white paint), thus avoiding energy-hungry air conditioning.

Environmental neurology: Concepts and short history of an interdisciplinary approach to etiology, treatment and prevention.

Environmental Neurology (EN), a sub-discipline of Neurology and Neurological Sciences, favors an interdisciplinary collaboration allowing a holistic approach to understanding the impact of environmental factors on the nervous system and their relationship with neurological diseases. Several examples of diseases and conditions show the large scope of subjects addressed by EN. The EN sub-discipline focuses on both individual and population issues thus joining patient care and public health, respectively. Neuropathogenesis is addressed by several major questions: How do the environment and nervous system interact? Which exogenous factors can trigger neurological disease? When, where and how do they act? What are the therapeutic implications, and how can these disorders be controlled or prevented. To answer such questions, we address the incentive for, philosophy of and methods developed by EN, which seeks to safeguard Brain Health and, thus, the quality of life.

New clues to the elusive aetiology of nodding syndrome.

Nodding syndrome is a paediatric epileptic encephalopathy of unknown aetiology that affects children in impoverished communities of Eastern Africa subject to internal displacement. Set in southcentral South Sudan, where nodding syndrome first surfaced circa 1990, an important new study of recent-onset cases of nodding syndrome examined parasitic, bacterial, viral, immune-mediated, metabolic and nutritional factors associated with the brain disease. Infection with the nematode Mansonella perstans, but not with Onchocerca volvulus, was the most prominent finding in nodding syndrome cases versus controls. While M. perstans is unlikely to be causal of nodding syndrome, investigation of the freshwater habitats, where insect-to-human transmission of the filarial larvae takes place, may reveal a clue as to the aetiology of this neurodegenerative disease. The culpable environmental agent(s) must be able to induce neuroinflammation and tau pathology preferentially in infants and children.

Endemic parkinsonism: clusters, biology and clinical features.

The term 'endemic parkinsonism' refers to diseases that manifest with a dominant parkinsonian syndrome, which can be typical or atypical, and are present only in a particular geographically defined location or population. Ten phenotypes of endemic parkinsonism are currently known: three in the Western Pacific region; two in the Asian-Oceanic region; one in the Caribbean islands of Guadeloupe and Martinique; and four in Europe. Some of these disease entities seem to be disappearing over time and therefore are probably triggered by unique environmental factors. By contrast, other types persist because they are exclusively genetically determined. Given the geographical clustering and potential overlap in biological and clinical features of these exceptionally interesting diseases, this Review provides a historical reference text and offers current perspectives on each of the 10 phenotypes of endemic parkinsonism. Knowledge obtained from the study of these disease entities supports the hypothesis that both genetic and environmental factors contribute to the development of neurodegenerative diseases, not only in endemic parkinsonism but also in general. At the same time, this understanding suggests useful directions for further research in this area.

Association of N-nitrosodimethylamine exposure with cognitive impairment based on the clues of mice and humans.

N-nitrosodimethylamine (NDMA) is an environmental and food contaminant, but limited data to concern whether NDMA has adverse effects on the brain. This study first determined the concentration of NDMA in foods from aquaculture markets in Shenzhen, then analyzed the effects on C57BL/6 mice and further evaluated on the urine samples of elderly Chinese residents with normal cognition (NC, n = 144), cognitive decline (CD, n = 116) and mild cognitive impairment (MCI, n = 123). The excessive rate of NDMA in foods was 3.32% (27/813), with a exceeding range of 4.78-131.00 µg/kg. Behavioral tests showed that 60 days treatment of mice with 3 mg/kg NDMA reduced cognitive performance. Cognitive impairment in human was significantly associated with sex, educational levels, length of residence in Shenzhen, household registration, passive smoking, rice, fresh vegetables, bacon products. NDMA was detected in 55.4% (212/383) of urine samples, with a median concentration of 0.23 µg/L (1.20 × 10 -7-157.39 µg/L). The median concentration for NC, CD and MCI were 0.32, 0.27, and 0 µg/L, respectively. The urinary NDMA concentration had a strong negative correlation with cognitive impairment (Kendall's Tau-b = -0.89, P = 0.024). The median estimated daily intake (EDI) of NDMA was determined to be 6.63 ng/kg-bw/day. Taken together, there appears to be an association between NDMA and human and murine cognition, which provides a new clue to Alzheimer's disease (AD).

Lathyrism in Spain: Lessons from 68 publications following the 1936-39 Civil War.

After the end of the Spanish Civil War (1936-1939), an estimated 1,000 patients presented with lathyrism due to their excessive and prolonged consumption of grasspea (Lathyrus sativus L.) against the backdrop of poverty, drought, and famine. Based on 68 scientific communications between 1941 and 1962 by qualified medical professionals, the disease emerged in different geographical locations involving selective populations: (1) farmers from extensive areas of central Spain, traditionally producers and consumers of grasspea; (2) immigrants in the industrial belt of Catalonia and in the Basque Country, areas with little or no production of grasspea, which was imported from producing areas; (3) workers in Galicia, an area where the legume is neither produced nor consumed, who were seasonally displaced to high-production areas of grasspea in Castille; and (4) inmates of overcrowded postwar Spanish prisons. Original reports included failed attempts by Carlos Jiménez Díaz (1898-1967) to induce experimental lathyrism, the neuropathology of lathyrism in early stages of the disease in two patients, as reported by Carlos Oliveras de la Riva (1914-2007), and the special susceptibility of children to develop a severe form of lathyrism after relatively brief periods of consumption of the neurotoxic seed of L. sativus. In the Spanish Basque Country, L. cicera L. (aizkol) was cultivated exclusively as animal fodder. Patients who were forced to feed on this plant developed unusual manifestations of lathyrism, such as axial myoclonus and severe neuropsychiatric disorders, unknown in other regions of the country and previously unreported. The postwar epidemic of lathyrism in Spain represents the most extensively studied outbreak of this self-limiting but crippling upper motor neuron disease.

Empirical landscape genetic comparison of single nucleotide polymorphisms and microsatellites in three arid-zone mammals with high dispersal capacity.

Landscape genetics is increasingly transitioning away from microsatellites, with single nucleotide polymorphisms (SNPs) providing increased resolution for detecting patterns of spatial-genetic structure. This is particularly pertinent for research in arid-zone mammals due to challenges associated with unique life history traits, such as boom-bust population dynamics and long-distance dispersal capacities. Here, we provide a case study comparing SNPs versus microsatellites for testing three explicit landscape genetic hypotheses (isolation-by-distance, isolation-by-barrier, and isolation-by-resistance) in a suite of small, arid-zone mammals in the Pilbara region of Western Australia. Using clustering algorithms, Mantel tests, and linear mixed effects models, we compare functional connectivity between genetic marker types and across species, including one marsupial, Ningaui timealeyi, and two native rodents, Pseudomys chapmani and P. hermannsburgensis. SNPs resolved subtle genetic structuring not detected by microsatellites, particularly for N. timealeyi where two genetic clusters were identified. Furthermore, stronger signatures of isolation-by-distance and isolation-by-resistance were detected when using SNPs, and model selection based on SNPs tended to identify more complex resistance surfaces (i.e., composite surfaces of multiple environmental layers) in the best-performing models. While we found limited evidence for physical barriers to dispersal across the Pilbara for all species, we found that topography, substrate, and soil moisture were the main environmental drivers shaping functional connectivity. Our study demonstrates that new analytical and genetic tools can provide novel ecological insights into arid landscapes, with potential application to conservation management through identifying dispersal corridors to mediate the impacts of ongoing habitat fragmentation in the region.