Cellular and Molecular Mechanisms Mediating Methylmercury Neurotoxicity and Neuroinflammation.

Methylmercury (MeHg) toxicity is a major environmental concern. In the aquatic reservoir, MeHg bioaccumulates along the food chain until it is consumed by riverine populations. There has been much interest in the neurotoxicity of MeHg due to recent environmental disasters. Studies have also addressed the implications of long-term MeHg exposure for humans. The central nervous system is particularly susceptible to the deleterious effects of MeHg, as evidenced by clinical symptoms and histopathological changes in poisoned humans. In vitro and in vivo studies have been crucial in deciphering the molecular mechanisms underlying MeHg-induced neurotoxicity. A collection of cellular and molecular alterations including cytokine release, oxidative stress, mitochondrial dysfunction, Ca2+ and glutamate dyshomeostasis, and cell death mechanisms are important consequences of brain cells exposure to MeHg. The purpose of this review is to organize an overview of the mercury cycle and MeHg poisoning events and to summarize data from cellular, animal, and human studies focusing on MeHg effects in neurons and glial cells. This review proposes an up-to-date compendium that will serve as a starting point for further studies and a consultation reference of published studies.

Effect of exposure to staphylococcus aureus, particulate matter, and their combination on the neurobehavioral function of mice.

Neurotoxicity in Kunming mice caused by Staphylococcus aureus (S. aureus) and Particulate matter (PM) as individual matter and mixtures was studied in this paper. Male Kunming mice were instilled intratracheally with PM at doses of 0.2mg/mouse and S. aureus at doses of 5.08×106 CFU/mouse as individual matter and mixtures two times at 5-day intervals. Morris water maze (MWM) test was performed during the exposure experiment. One day following the exposure experiment, the expression of neurotrophins, neurotransmitters, cholinergic system enzymes, oxidative damage levels, and pro-inflammatory cytokines (TNF-α, IL-1ß) in the brain of mice were determined. Combined treatment of PM and S. aureus led to significant increment of escape latency at day 6, 8, and 10. Oxidative stress levels, and pro-inflammatory cytokines were affected significantly by S. aureus and PM as individual matter and mixtures. Meanwhile, Glu contents were increased significantly in S. aureus group, ChAT levels were decreased significantly in PM group, combined treatment of PM and S. aureus led to significant concentration reduction of AChE. Treatment of S. aureus or PM- S. aureus combination also led to significant concentration reduction of BDNF. Results showed that combined treatment of PM and S. aureus induced damage on physique and motor function, as well as impairment on learning and memory capacity of mice. Oxidative damage, abnormal metabolism of neurotransmitters and cholinergic system enzymes, and the alternation of neurotrophins and pro-inflammatory cytokines expression might be the possible mechanisms for PM - S. aureus -induced neurotoxicity.

Recruitment of septin cytoskeletal proteins by botulinum toxin A protease determines its remarkable stability.

Proteolytic cleavage of synaptosomal-associated protein 25 by the light chain of botulinum neurotoxin type A (LCA) results in a blockade of neurotransmitter release that persists for several months in motor neurons. The L428A/L429A mutation in LCA is known to significantly shorten both the proteolytic and neuroparalytic effects of the neurotoxin in mice. To elucidate the cellular mechanism for LCA longevity, we studied the effects of L428A/L429A mutation on the interactome, localization and stability of LCA expressed in cultured neuronal cells. Mass spectrometry analysis of the LCA interactome showed that the mutation prevented the interaction of LCA with septins. The wild-type LCA was concentrated in plasma-membrane-associated clusters, colocalizing with septins-2 and septin-7, which accumulated in these clusters only in the presence of LCA. The L428A/L429A mutation decreased co-clustering of LCA and septins and accelerated proteasomal and non-proteasomal degradation of LCA. Similarly, the impairment of septin oligomerization by forchlorfenuron or silencing of septin-2 prevented LCA interaction and clustering with septins and increased LCA degradation. Therefore, the dileucine-mediated LCA-septin co-clustering is crucial for the long-lasting stabilization of LCA-related proteolytic and presumably neuroparalytic activity.

Clinical and radiologic features of encephalopathy during 2011 E coli O111 outbreak in Japan.

OBJECTIVE: To elucidate the clinical and radiologic features and analyze factors associated with neurologic outcomes of encephalopathy secondary to Shiga toxin-producing Escherichia coli (STEC) O111. METHODS: We reviewed medical records and neuroimaging in 22 patients with neurologic symptoms among 86 with STEC O111 infection. RESULTS: Twenty-one (6 males and 15 females, 10 children and 11 adults) of the 22 patients were diagnosed with encephalopathy. All patients with encephalopathy also presented with hemolytic-uremic syndrome. Five patients died, from day 1 to 6 months (days 1-5 in 4 patients), due to progressive encephalopathy with severe cerebral edema observed in neuroimaging (4 patients). Fifteen of the 16 surviving patients clinically recovered completely. Statistical analysis revealed differences between patients with poor (n = 6) and good (n = 15) outcomes in the interval from hemolytic-uremic syndrome presentation to encephalopathy, creatinine levels, and the methylprednisolone administration ratio. CONCLUSION: We note a high incidence of encephalopathy in the Toyama STEC O111 outbreak. All fatal cases resulted from progressive encephalopathy. Methylprednisolone pulse therapy represents a possible therapeutic choice. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that methylprednisolone pulse therapy increases the probability of a good outcome for patients with encephalopathy associated with STEC O111.

Investigation of encephalopathy caused by Shiga toxin 2c-producing Escherichia coli infection in mice.

A large outbreak of Shiga toxin (Stx)-producing enteroaggregative Escherichia coli (EAEC) O104:H4 occurred in northern Germany. From this outbreak, at least 900 patients developed hemolytic uremic syndrome (HUS), resulting in more than 50 deaths. Thirty percent of the HUS patients showed encephalopathy. We previously established a mouse model with encephalopathy associated with blood brain barrier (BBB) damage after oral infection with the Shiga toxin (Stx) 2c-producing Escherichia coli O157: H- strain E32511 (E32511). In this model, we detected high expression of the Stx receptor synthase enzyme, glycosphingolipid globotriaosylceramide (Gb3) synthase, in endothelial cells (ECs) and neurons in the reticular formation of the medulla oblongata by in situ hybridization. Caspase-3 was activated in neurons in the reticular formation of the medulla oblongata and the anterior horn of the spinal cord. Astrocytes (ASTs) were activated in the medulla oblongata and spinal cord, and a decrease in aquaporin 4 around the ECs suggested that BBB integrity was compromised directly by Stx2c or through the activation of ASTs. We also report the effectiveness of azithromycin (AZM) in our model. Moreover, AZM strongly inhibited the release of Stx2c from E32511 in vitro.

Intracerebroventricular Shiga toxin 2 increases the expression of its receptor globotriaosylceramide and causes dendritic abnormalities.

Neurological damage caused by intoxication with Shiga toxin (Stx) from enterohemorrhagic Escherichia coli is the most unrepairable and untreatable outcome of Hemolytic Uremic Syndrome, and occurs in 30% of affected infants. In this work intracerebroventricular administration of Stx2 in rat brains significantly increased the expression of its receptor globotriaosylceramide (Gb(3)) in neuronal populations from striatum, hippocampus and cortex. Stx2 was immunodetected in neurons that expressed Gb(3) after intracerebroventricular administration of the toxin. Confocal immunofluorescence of microtubule-associated protein 2 showed aberrant dendrites in neurons expressing increased Gb(3). The pro-apoptotic Bax protein was concomitantly immunodetected in neurons and other cell populations from the same described areas including the hypothalamus. Confocal immunofluorescence showed that Gb(3) colocalized also with glial fibrillary acidic protein only in reactive astrocytic processes, and not in vehicle-treated normal ones. Rats showed weight variation and motor deficits as compared to controls. We thus suggest that Stx2 induces the expression of Gb(3) in neurons and triggers neuronal dysfunctions.

Acute encephalopathy of Bacillus cereus mimicking Reye syndrome.

We present an 11-year-old boy diagnosed as having acute encephalopathy and liver failure with the underlying condition of a metabolic dysfunction. He developed convulsions and severe consciousness disturbance following gastroenteritis after the ingestion of some fried rice. He showed excessive elevation of transaminases, non-ketotic hypoglycemia and hyperammonemia, which were presumed to reflect a metabolic dysfunction of the mitochondrial beta-oxidation, and he exhibited severe brain edema throughout the 5th hospital day. He was subjected to mild hypothermia therapy for encephalopathy, and treated with high-dose methylprednisolone, cyclosporine and continuous hemodiafiltration for liver failure, systemic organ damage and hyperammonemia. The patient recovered with the sequela of just mild intelligence impairment. In this case, Bacillus cereus, producing emetic toxin cereulide, was detected in a gastric fluid specimen, a stool specimen and the fried rice. It was suggested that the cereulide had toxicity to mitochondria and induced a dysfunction of the beta-oxidation process. The patient was considered as having an acute encephalopathy mimicking Reye syndrome due to food poisoning caused by cereulide produced by B. cereus.

Isolation of Salmonella enterica serotype Isangi from a suspected case of enteric encephalopathy.

Nontyphoidal salmonella species are thought to be potentially infectious to humans and many are documented to cause human diseases. We isolated S. Isangi from the blood of a 30-year-old man with complaints of diarrhoea, fever, and altered sensorium. The serotype of the isolate was confirmed at National Salmonella Centre (Vet.), Division of Bacteriology and Mycology, Indian Veterinary Research Institute, Izzatnagar, India. The isolate was not an extended spectrum beta-lactamase (ESBL) producer and the patient responded well to ceftriaxone. We reviewed the literature concerning infections caused by salmonella; however, did not find any report related to S. Isangi infection in human beings from India.

Neuropsychological exploration of alleged mold neurotoxicity.

Cognitive and emotional correlates of toxic mold exposure and potential dose-response effects for both outcomes were investigated. Self-reported length of exposure, time since last exposure, and serum immunoglobulin (IgG) levels were assessed. Despite CNS complaints often seen with mold exposed individuals, overall results did not uncover concomitant cognitive deficits suggested in previous studies or a significant reduction in intellectual functioning. Fewer subjects were excluded as result of failing effort/motivation assessment than expected. Correlations of IgG and cognitive function are discussed. A dose-effect for self-reported length of exposure and cognitive outcome was not seen. The sample's overall Minnesota Multiphasic Personality Inventory II (MMPI-2) profile indicated elevations on scales 1, 2, 3, 7 and 8. MMPI-2 clinical scales 1 and 3 were significantly correlated with length of exposure. The MMPI-2 may be sensitive to increasing physical and emotional sequelae as length of exposure increases. A potential subgroup of cognitively impaired outliers within mold exposure litigants is explored. Limitations of self-reported and objective measurements for mold exposure and exploratory statistical methodology are discussed.

Toxic shock syndrome toxin-1 challenges the neuroprotective functions of the choroidal epithelium and induces neurotoxicity.

To probe encephalopathy pathogenesis during toxic shock syndrome (TSS), we investigated the fate of bloodborne TSS toxin-1 (TSST-1) as it moves through the choroid plexus epithelium that forms the main blood-cerebrospinal fluid (CSF) barrier and the effect that TSST-1 has on choroidal barrier properties and on cultured neuronal cell viability. TSST-1 showed a slow, diffusional movement across a cellular model of the blood-CSF barrier but did not compromise the integrity of the barrier. Relevant to the acute symptoms of TSS, a combination of human leukocytes and the toxin induced a decrease in CSF clearance of the pyrogenic prostaglandin E(2) (PGE(2)). The direct effects that TSST-1 had on primary cortical neuron cultures and a neuronal cell line involved elevated caspase 3/7 levels, which correlated with an increase in neuronal cell death. The results of the present study suggest that TSST-1 can affect the brain, by inducing both an intracerebral increase in PGE(2) concentration and caspase-dependent neuronal death, which are possibly relevant to long-term intoxication.

Aspergillus clavatus tremorgenic neurotoxicosis in cattle fed sprouted grains.

Beef and dairy cattle from four different herds in southern and central Queensland fed hydroponically-produced sprouted barley or wheat grain heavily infested with Aspergillus clavatus developed posterior ataxia with knuckling of fetlocks, muscular tremors and recumbency, but maintained appetite. A few animals variously had reduced milk production, hyperaesthesia, drooling of saliva, hypermetria of hind limbs or muscle spasms. Degeneration of large neurones was seen in the brain stem and spinal cord grey matter. The syndrome was consistent with A clavatus tremorgenic mycotoxicosis of ruminants. The cases are the earliest known to be associated with this fungus in Australia. They highlight a potential hazard of hydroponic fodder production systems, which appear to favour A clavatus growth on sprouted grain, exacerbated in some cases by equipment malfunctions that increase operating temperatures.

Toxic mold and mycotoxins in neurotoxicity cases: Stachybotrys, Fusarium, Trichoderma, Aspergillus, Penicillium, Cladosporium, Alternaria, Trichothecenes.

Presented is the argument that psychologists and neuropsychologists have no scientific basis for rendering opinions about causation given the current state of the literature. The critical question is whether in a residence or office inhalation of mold spores or mold metabolites, including mycotoxins, causes neuropsychological impairment or mental and emotional disorders. There has not been sufficient research to support such conclusions. Nonetheless, in the context of litigation, speculative opinions are rendered in lieu of scientifically well-founded conclusions. Resources for recognizing and coping with pseudoscientific arguments are suggested.

The neurological significance of abnormal natural killer cell activity in chronic toxigenic mold exposures.

Toxigenic mold activities produce metabolites that are either broad-spectrum antibiotics or mycotoxins that are cytotoxic. Indoor environmental exposure to these toxigenic molds leads to adverse health conditions with the main outcome measure of frequent neuroimmunologic and behavioral consequences. One of the immune system disorders found in patients presenting with toxigenic mold exposure is an abnormal natural killer cell activity. This paper presents an overview of the neurological significance of abnormal natural killer cell (NKC) activity in chronic toxigenic mold exposure. A comprehensive review of the literature was carried out to evaluate and assess the conditions under which the immune system could be dysfunctionally interfered with leading to abnormal NKC activity and the involvement of mycotoxins in these processes. The functions, mechanism, the factors that influence NKC activities, and the roles of mycotoxins in NKCs were cited wherever necessary. The major presentations are headache, general debilitating pains, nose bleeding, fevers with body temperatures up to 40 degrees C (104 degrees F), cough, memory loss, depression, mood swings, sleep disturbances, anxiety, chronic fatigue, vertigo/dizziness, and in some cases, seizures. Although sleep is commonly considered a restorative process that is important for the proper functioning of the immune system, it could be disturbed by mycotoxins. Most likely, mycotoxins exert some rigorous effects on the circadian rhythmic processes resulting in sleep deprivation to which an acute and transient increase in NKC activity is observed. Depression, psychological stress, tissue injuries, malignancies, carcinogenesis, chronic fatigue syndrome, and experimental allergic encephalomyelitis could be induced at very low physiological concentrations by mycotoxin-induced NKC activity. In the light of this review, it is concluded that chronic exposures to toxigenic mold could lead to abnormal NKC activity with a wide range of neurological consequences, some of which were headache, general debilitating pains, fever, cough, memory loss, depression, mood swings, sleep disturbances, anxiety, chronic fatigue, and seizures.

[Clinical and microbiological features of acute enteric mixed infection caused by Hafnia alvei and rotavirus]. / Kliniko-mikrobiologicheskie osobennosti ostroi kishechnoi mikst-infektsii, vyzvannoi bakteriiami Hafnia alvei i rotavirusom.

The data obtained in the clinical and laboratory study of 72 hospitalized patients with acute enteric infection are presented. The observed outbreak was caused by H. alvei producing heat-stable enterotoxin. The role of this etiological agent is also confirmed by simultaneous occurrence of the disease after using the same foodstuff, a short incubation period, the severity of the course of the disease with pronounced symptoms of neurotoxicosis, a high detection rate of H. alvei in material taken from patients at the acute period of the disease, rapid disappearance of this agent in the period of convalescence and a pronounced rise in the titer of specific antibodies to H. alvei in the dynamics of the disease. At the same time in the feces of 8 patients rotavirus antigen was detected, which, in combination with residual catarrhal phenomena, hyperemia and granularity of the pharynx, yellow stool, was indicative of the simultaneous circulation of rotavirus among these patients.

Progress in clinical neurosciences: sepsis-associated encephalopathy: evolving concepts.

Systemic sepsis commonly produces brain dysfunction, sepsis-associated encephalopathy, which can vary from a transient, reversible encephalopathy to irreversible brain damage. The encephalopathy in the acute phase clinically resembles many metabolic encephalopathies: a diffuse disturbance in cerebral function with sparing of the brain stem. The severity of the encephalopathy, as reflected in progressive EEG abnormalities, often precedes then parallels dysfunction in other organs. Recent research has revealed a number of potentially important, non-mutually exclusive, mechanisms that have therapeutic implications.