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This paper analyses documents on health and disease among Chamorro people during and after 333 years (1565–1898) of the Spanish claim to and occupation of Guam. Here, a complex neurodegenerative di...

Purpose To reexamine the etiology of a unique retinal pathology (linear and vermiform sub-retinal tubular structures) described among subjects with and without neurodegenerative disease in former high-incidence foci of Western Pacific amyotrophic lateral sclerosis and parkinsonism-dementia complex (ALS/PDC) in Guam (USA) and the Kii peninsula of Honshu island (Japan). Methods Analysis of published and unpublished reports of 1) ALS/PDC and the retinal and cerebellar pathology associated therewith and 2) exogenous neurotoxic factors associated with ALS/PDC and the developing retina and cerebellum. Results ALS/PDC retinal and cerebellar pathology matches persistent retinal and cerebellar dysplasia found in laboratory animals given single in utero or postnatal systemic treatment with cycasin, the principal neurotoxic component in the seed of cycad plants traditionally used for food (Guam) or oral medicine (Kii-Japan), both of which have been linked to the human neurodegenerative disease. Conclusion ALS/PDC-associated retinal and cerebellar dysplasia could arise from in utero exposure to methylazoxymethanol, the genotoxic metabolite of cycasin that results from maternal ingestion of this azoxyglucoside. These results support the environmental toxic etiology of retinal and brain pathology in ALS/PDC.

In this announcement, we report the complete mitogenome of the vulnerable Crest-tailed Mulgara (Dasycercus cristicauda) (Krefft, 1867). The mitogenome was 17,085 bp in length and contained 13 protein-coding genes, two rRNA genes, 22 tRNAs and a 1583 bp variable control region (D-loop). The features of the D. cristicauda mitogenome are consistent with other vertebrate mitogenomes but, in contrast to other marsupials, appears to contain a functional tRNA-Lysine with a UUU anticodon. Phylogenetic analysis of available entire mitogenomes reveals it forms a cluster with other marsupials in the Dasyuromorphia order within the Australidelphian clade, being most closely related to the Northern Quoll and the Tasmanian Devil.

Lathyrism is a central motor system disorder recognized since antiquity resulting from prolonged dietary dependence on the grasspea (Lathyrus sativus). The neuropathology underlying the characteristic spastic paraparesis of lathyrism is sketchy. Described here is a landmark but little-known Spanish-language neuropathological study of two patients with lathyrism of recent onset. Due to erroneous interpretations of Filimonov's influential work in 1926, it was assumed that spastic paraparesis of lathyrism was explained by destruction of Betz's pyramidal cells in the motor cortex. Contrary to present understanding, Betz cells and anterior horn cells were preserved, and pathological findings dominated by myelin loss were largely limited to pyramidal tracts in the lumbar cord. Thickening of the adventitia of capillaries and arterioles, together with proliferation of perivascular astrocytes, was found along the length of the spinal cord. Oliveras de la Riva proposed that the segmental spinal pathology arose because distal regions of elongate pyramidal tract axons are distant from their trophic center in the motor cortex, a view not far from the current distal axonopathy concept of lathyrism. In addition, we review the historical circumstances of Filimonov's work in Russia, a summary of the epidemic of lathyrism in Spain following its Civil War (1936-1939), and some historical aspects of the Cajal Institute in Madrid, where Oliveras de la Riva's work was carried out under the supervision of Fernando de Castro, one of Cajal's favorite students.

The Ghost bat Macroderma gigas is a monotypic bat species that is endemic to northern Australia and named on the basis of the large size of its partially conjoined ears. It is the only carnivorous bat found in Australia and its conservation status is currently listed as Vulnerable. Here, we describe the complete mitochondrial genome of M. gigas and compare it to other vertebrates. The M. gigas circularized mitogenome was 16,661 bp and contained 13 protein-coding genes, two rRNA genes, 22 tRNAs and a control region (D-loop) of 1228 bp. Phylogenetic analysis of available entire mitogenomes reveals that Macroderma gigas is most closely related to the Indian false vampire bat Megaderma lyra in the family Megadermatidae (false vampire bats).

Western Pacific amyotrophic lateral sclerosis (ALS) and parkinsonism-dementia complex (PDC), a prototypical neurodegenerative disease (tauopathy) affecting distinct genetic groups with common exposure to neurotoxic chemicals in cycad seed, has many features of Parkinson's and Alzheimer's diseases (AD), including early olfactory dysfunction. Guam ALS-PDC incidence correlates with cycad flour content of cycasin and its aglycone methylazoxymethanol (MAM), which produces persistent DNA damage (O(6)-methylguanine) in the brains of mice lacking O(6)-methylguanine methyltransferase (Mgmt(-/-)). We described in Mgmt(-/-)mice up to 7 days post-MAM treatment that brain DNA damage was linked to brain gene expression changes found in human neurological disease, cancer, and skin and hair development. This addendum reports 6 months post-MAM treatment- related brain transcriptional changes as well as elevated mitogen activated protein kinases and increased caspase-3 activity, both of which are involved in tau aggregation and neurofibrillary tangle formation typical of ALS-PDC and AD, plus transcriptional changes in olfactory receptors. Does cycasin act as a "slow (geno)toxin" in ALS-PDC?

This review examines the large body of toxicological and epidemiological information on human exposures to chlorpyrifos, with an emphasis on the controversial potential for chlorpyrifos to induce neurodevelopmental effects at low doses. The results of this review demonstrate that the use of urinary 3,5,6-trichlorpyridinol (TCPy), a metabolite of chlorpyrifos as a biomarker of nonoccupational exposure is problematic and may overestimate nonoccupational exposures to chlorpyrifos by 10-to 20-fold because of the widespread presence of both TCPy and chlorpyrifos-methyl in the food supply. Current "background" (nonoccupational) levels of exposure to chlorpyrifos are several orders of magnitude lower than those required to inhibit plasma cholinesterase activity, which is a more sensitive target than nervous system cholinesterase. However, several in vitro studies have identified putative neurodevelopmental mechanisms that are altered at concentrations of chlorpyrifos below those that inhibit cholinesterases. Although one human cohort study reported an association between maternal and cord blood chlorpyrifos levels and several measures of neurodevelopment, two other cohort studies that utilized urinary TCPy as a surrogate for chlorpyrifos exposure did not demonstrate an association. Although the weight of the scientific evidence demonstrates that current levels of chlorpyrifos exposure will not have any adverse effects on neurodevelopment that might result from inhibition of nervous system cholinesterases, several recent studies propose alternative mechanisms. Thus, further in vivo investigation on neurodevelopment in an appropriate animal model is needed; additional epidemiological studies may be warranted if a suitable, chlorpyrifos-exposed cohort can be identified and more rigorous measures of exposure are utilized.

Aspartame is a methyl ester of a dipeptide used as a synthetic nonnutritive sweetener in over 90 countries worldwide in over 6000 products. The purpose of this investigation was to review the scientific literature on the absorption and metabolism, the current consumption levels worldwide, the toxicology, and recent epidemiological studies on aspartame. Current use levels of aspartame, even by high users in special subgroups, remains well below the U.S. Food and Drug Administration and European Food Safety Authority established acceptable daily intake levels of 50 and 40 mg/kg bw/day, respectively. Consumption of large doses of aspartame in a single bolus dose will have an effect on some biochemical parameters, including plasma amino acid levels and brain neurotransmitter levels. The rise in plasma levels of phenylalanine and aspartic acid following administration of aspartame at doses less than or equal to 50 mg/kg bw do not exceed those observed postprandially. Acute, subacute and chronic toxicity studies with aspartame, and its decomposition products, conducted in mice, rats, hamsters and dogs have consistently found no adverse effect of aspartame with doses up to at least 4000 mg/kg bw/day. Critical review of all carcinogenicity studies conducted on aspartame found no credible evidence that aspartame is carcinogenic. The data from the extensive investigations into the possibility of neurotoxic effects of aspartame, in general, do not support the hypothesis that aspartame in the human diet will affect nervous system function, learning or behavior. Epidemiological studies on aspartame include several case-control studies and one well-conducted prospective epidemiological study with a large cohort, in which the consumption of aspartame was measured. The studies provide no evidence to support an association between aspartame and cancer in any tissue. The weight of existing evidence is that aspartame is safe at current levels of consumption as a nonnutritive sweetener.

We describe three novel species of piroplasms, each from a distinct host species within the Macropodoidea, in Western Australia; namely, Setonix brachyurus (Quoy & Gaimard, 1830), Macropus fuliginosus (Desmarest, 1817) (Macropodidae) and Bettongia penicillata (Gray, 1837) (Potoroidae). The light-microscopic appearance of organisms in blood films was typical of the Piroplasmida. Phylogenetic analyses of partial 18S rRNA gene sequences revealed that isolates from three marsupial species form reciprocally monophyletic clades within the Theileriidae, and each have a relatively high level of divergence (3.6 to 7.4%) from each other. The distinct molecular differences indicate these organisms should be regarded as separate, novel species which we designate Theileria brachyuri sp. nov., Theileria fuliginosa sp. nov., and Theileria penicillata sp. nov.

Gulf War veterans were given pyridostigmine bromide (PB) tablets to enhance the therapeutic effect of antidotes to nerve agents in the event of exposure. The goal of this research is to examine whether combined exposure to PB and sarin (agent GB) is more neurotoxic to sensitive surrogate animals, mice and chickens, than if given separately. Scoping trials were performed to establish appropriate dose-response ranges for sarin and control chemicals. IC50 values were determined in chickens and mice for in vitro inhibition of acetylcholinesterase (AChE) and neuropathy target esterase (NTE). The results indicated PB neither inhibits NTE nor does it spare sarin's inhibition of AChE. Chick embryo nerve cells in vitro showed more inhibition of AChE activity and no faster recovery when PB treatment was followed by DFP treatment than the other way around. Experiments on chickens also indicated that PB treatment did not inhibit NTE and that it crossed the blood brain barrier inhibiting brain AChE although to a lesser extent than it inhibited blood cholinesterases. Other experiments determined multiple dose levels in chickens for sarin and DFP that inhibited80% of NTE, considered a threshold for triggering organophosphate-induced delayed neuropathy.

The causes and the mechanisms of neuronal death in Alzheimer's disease are not elucidated, although some new insights have been proposed over the past years, including free-radical toxicity, beta-amyloid toxicity, excitotoxicity, and disturbed cellular calcium metabolism. Some authors have also pointed out that apoptosis could play a role in neuronal degeneration, but it is still largely debated. Here, we review some recent data linking the induction of experimental neuronal apoptosis in vitro and the molecular pathology of the tau protein and amyloid precursor protein (APP). In cultures exposed to mild glutamate toxicity, tau mRNA expression, not beta-actin, is enhanced in stressed neurons. The Guam cycad toxin metabolite methylazoxymethanol also produces an increase of tau gene transcription that exacerbates changes induced by glutamate. In serum-deprived cultures or glutamate-exposed cultures, neurons committed to apoptosis have a reduced tau gene expression, whereas resistant neurons display a stable or even augmented tau mRNA expression accompanied by a persistent tau phosphorylation near serine 202. In the same conditions, stressed neurons produce membrane blebbings strongly immunopositive for APP and putative amyloidogenic fragments that are subsequently released in the extracellular space. Experimental apoptosis in neurons can recapitulate tau and APP modifications that could be associated with a selective vulnerability and a progression of cellular degeneration along the neuronal network.

Environmental chemicals involved in the etiology of human neurodegenerative disorders are challenging to identify. Described here is research designed to determine the etiology and molecular pathogenesis of nerve cell degeneration in two little known corticomotoneuronal diseases with established environmental triggers. Both conditions are toxic-nutritional disorders dominated by persistent spastic weakness of the legs and degeneration of corresponding corticospinal pathways. Lathyrism, a disease caused by dietary dependence on grass pea (Lathyrus sativus), is mediated by a stereospecific plant amino acid (beta-N-oxalylamino-L-alanine) that serves as a potent agonist at the (RS)-alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA) subclass of neuronal glutamate receptors. A neurologically similar disorder, konzo ("tied legs"), is found among protein-poor African communities that rely for food on cyanogen-containing cassava roots. Thiocyanate, the principal metabolite of cyanide, is an attractive etiologic candidate for konzo because it selectively promotes the action of glutamate at AMPA receptors. Studies are urgently needed to assess the health effects of cassava and other cyanogenic plants, components of which are widely used as food.

(1980). The Enlarging View of Hexacarbon Neurotoxicity. CRC Critical Reviews in Toxicology: Vol. 7, No. 4, pp. 279-356.