PYRIDINE-2-ALDOXIME METHIODIDE—A Valuable Agent for Phosphate Poisoning

Phosphate insecticide use is increasing as is concomitant human poisoning. Home insecticide bomb as well as agricultural, crop contamination and suicidal exposure are noted.Clinical poisoning may be chronic and severe. It may follow long exposure or short exposure with heavy dosages. Manifestations are those of excessive cholinergic activity.Adequate laboratory means for early, rapid diagnosis and screen testings are available.PAM is a valuable agent for this type of poisoning and is a much more adequate and complete antidote than atropine. It is available (under certain restrictive conditions presently). It is being widely used elsewhere in the world but with limited education and use in this country. Morbidity and mortality continue at a rate that could probably be corrected.Case reports, describing the use of this antidote in our hands, are included.Government and industry responsibility as well as physician education must be more clearly defined in prevention, recognition and treatment in what is often a life threatening situation.     

Polymorphism of metabolic genes and susceptibility to occupational chronic manganism

In this study we investigated genetic polymorphisms of five metabolizing genes and their association with occupational chronic manganism. We recruited 49 patients with chronic manganism and 50 unrelated healthy control subjects who were welders and ferromanganese smelters and occupationally exposed to manganese dust and fume in the same workshops from three metallurgical industries. The controls were matched to the cases by sex, age, cigarette and alcohol intake, as well as the manganese exposure duration. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to genotype the cytochrome P450 2D6L gene (CYP2D6L) and the NAD(P)H:quinone oxidoreductase gene (NQO1). Allele-specific PCR was used to detect the cytochrome P450 1A1 gene (CYP1A1), and the glutathione-S-transferase mu and theta genes (GSTM and GSTT). The frequency of polymorphic alleles, a mutation of CYP2D6L, was significantly lower in patients with chronic manganism (16.3%) than in controls (29.0%). Individuals with the homozygote polymorphism (L/L) of CYP2D6 had a 90% decreased risk of chronic manganism compared with the wild-type (Wt/Wt) (odds ratio =0.10, 95% confidence interval = 0.01-0.82). A significant association between the CYP2D6 genotype subgroup and the latency of chronic manganese poisoning was also found. Patients who had homozygous (L/L) or heterozygous (Wt/L) mutant alleles developed manganism an average of 10 years later than those who were homozygous wildtype (Wt/Wt). However, the allele and genotype frequencies of CYP1A1 and NQO1 genes were distributed similarly in cases and controls. In addition, no difference in the frequencies of GSTM1 and GSTT1 null genotypes were observed between cases and controls. The results suggest that CYP2D6L gene polymorphism might influence susceptibility to manganese-induced neurotoxicity. However, because of limited sample size, our results should be validated in large-scale studies.     

Manganese is highly effective in protecting cells from cadmium intoxication

Cadmium poisoning results in cell death. Although several intracellular pathways have been identified in this response, transport systems responsible for cadmium entry into cells remain poorly understood and controversial. Here, we analyzed the effects of several divalent cations on cadmium toxicity in different cell types. We found that zinc, previously reported as a protective agent against cadmium poisoning, is actually much less efficient than manganese. We show that manganese dramatically reduces cadmium intake, and that this is associated with the inhibition of our recently reported sustained activation of ERK, characteristic of cadmium intoxication. Finally, we show that this inhibition of cadmium entry and ERK-sustained activation perfectly correlates with a high cellular resistance to cadmium exposure. Our results, together with previously published data, support the idea that the yet to be characterized manganese transporter system(s) may be responsible for cadmium entry into cells.     

Polymorphism of metabolic genes and susceptibility to occupational chronic manganism

In this study we investigated genetic polymorphisms of five metabolizing genes and their association with occupational chronic manganism. We recruited 49 patients with chronic manganism and 50 unrelated healthy control subjects who were welders and ferromanganese smelters and occupationally exposed to manganese dust and fume in the same workshops from three metallurgical industries. The controls were matched to the cases by sex, age, cigarette and alcohol intake, as well as the manganese exposure duration. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to genotype the cytochrome P450 2D6L gene (CYP2D6L) and the NAD(P)H:quinone oxidoreductase gene (NQO1). Allele-specific PCR was used to detect the cytochrome P450 1A1 gene (CYP1A1), and the glutathione-S-transferase mu and theta genes (GSTM and GSTT). The frequency of polymorphic alleles, a mutation of CYP2D6L, was significantly lower in patients with chronic manganism (16.3%) than in controls (29.0%). Individuals with the homozygote polymorphism (L/L) of CYP2D6 had a 90% decreased risk of chronic manganism compared with the wild-type (Wt/Wt) (odds ratio =0.10, 95% confidence interval = 0.01-0.82). A significant association between the CYP2D6 genotype subgroup and the latency of chronic manganese poisoning was also found. Patients who had homozygous (L/L) or heterozygous (Wt/L) mutant alleles developed manganism an average of 10 years later than those who were homozygous wildtype (Wt/Wt). However, the allele and genotype frequencies of CYP1A1 and NQO1 genes were distributed similarly in cases and controls. In addition, no difference in the frequencies of GSTM1 and GSTT1 null genotypes were observed between cases and controls. The results suggest that CYP2D6L gene polymorphism might influence susceptibility to manganese-induced neurotoxicity. However, because of limited sample size, our results should be validated in large-scale studies.     

Manganese exposure is cytotoxic and alters dopaminergic and GABAergic neurons within the basal ganglia

Manganese is an essential nutrient, integral to proper metabolism of amino acids, proteins and lipids. Excessive environmental exposure to manganese can produce extrapyramidal symptoms similar to those observed in Parkinson's disease (PD). We used in vivo and in vitro models to examine cellular and circuitry alterations induced by manganese exposure. Primary mesencephalic cultures were treated with 10–800 μM manganese chloride which resulted in dramatic changes in the neuronal cytoskeleton even at subtoxic concentrations. Using cultures from mice with red fluorescent protein driven by the tyrosine hydroxylase (TH) promoter, we found that dopaminergic neurons were more susceptible to manganese toxicity. To understand the vulnerability of dopaminergic cells to chronic manganese exposure, mice were given i.p. injections of MnCl₂ for 30 days. We observed a 20% reduction in TH-positive neurons in the substantia nigra pars compacta (SNpc) following manganese treatment. Quantification of Nissl bodies revealed a widespread reduction in SNpc cell numbers. Other areas of the basal ganglia were also altered by manganese as evidenced by the loss of glutamic acid decarboxylase 67 in the striatum. These studies suggest that acute manganese exposure induces cytoskeletal dysfunction prior to degeneration and that chronic manganese exposure results in neurochemical dysfunction with overlapping features to PD.     

Bovine besnoitiosis and its effect on the male reproductive system

Besnoitia besnoiti and several species of the genus have been reported in a variety of domestic and wild animals in many parts of the world (1, 2, 3, 4, 5). Cutaneous besnoitiosis in cattle has been described as a serious skin condition characterized by painful swellings, alopecia and thickening of the skin (6). It is a chronic, debilitating and occasionally fatal disease with both cutaneous and systemic manifestations (6, 7, 8). Besnoitia cysts and lesions have been observed in the testes, epididymes and blood vessels of bulls (9). The possibility of abortion in cows and sterility in bulls with besnoitiosis has been reported (6). Spontaneous clinical besnoitiosis in cattle with accompanying systemic manifestations has not been fully documented, and the effect of scrotal besnoitiosis on spermatogenesis in bulls has not been previously reported in Nigeria. Case report : Outbreaks of babesiosis, heartwater and suspected cutaneous besnoitiosis were observed in a government farm in the Kano State of Nigeria in March, 1979. The cattle population was over 1500, consisting of exotic (Bos taurus ) and indigenous (Bos indicus ) breeds and their crosses. Clinical Examination : All stages of clinical besnoitiosis were initially observed in 14 bulls and 1 cow in a period of 4 months. The farm was visited bi-weekly for 1 year, during which time 58 bulls and 2 cows showed the lesions. Most of the animals affected with this disease were 3-way crosses of Australian Draughtmaster x Rahaji x Niger Azwak (DM x Rh x AZ). Table 1 summarises the distribution of clinicial cases of besnoitiosis.     

MANGANESE-INDUCED BEHAVIORAL DYSFUNCTION AND ITS NEUROCHEMICAL MECHANISM IN GROWING MICE

Abstract— Suckling mice were exposed to manganese from birth indirectly through their mothers and then directly through drinking water after weaning. The growth and development of these mice and their age-matched controls were almost identical. Motor activity of offspring measured at 30-day intervals showed a significant increase at 60 and 90 days in manganese-treated mice compared to controls. Increased motor activity was associated with significant elevation in the levels of dopamine and norepinephrine in the corpus striatum of treated mice. The levels of striatal tyrosine, homovanillic acid and manganese were also significantly increased in mice after manganese exposure. Thus an animal model of early manganese poisoning has been developed with a possible role of striatal amines in the production of behavioral dysfunction in the treated mice. Implications of these findings are discussed in relation to the manifestations of the psychiatric phase of early manganese poisoning in man.     

Metallic elements in exhaled breath condensate and serum of patients with exacerbation of chronic obstructive pulmonary disease

Biomarkers in exacerbated chronic obstructive pulmonary disease may be useful in aiding diagnosis, defining specific phenotypes of disease, monitoring the disease and evaluating the effects of drugs. The aim of this study was the characterization of metallic elements in exhaled breath condensate and serum as novel biomarkers of exposure and susceptibility in exacerbated chronic obstructive pulmonary disease using reference analytical techniques. C-Reactive protein and procalcitonin were assessed as previously validated diagnostic and prognostic biomarkers which have been associated with disease exacerbation, thus useful as a basis of comparison with metal levels. Exhaled breath condensate and serum were obtained in 28 patients at the beginning of an episode of disease exacerbation and when they recovered. Trace elements and toxic metals were measured by inductively coupled plasma-mass spectrometry. Serum biomarkers were measured by immunoassay. Exhaled manganese and magnesium levels were influenced by exacerbation of chronic obstructive pulmonary disease, an increase in their concentrations--respectively by 20 and 50%--being observed at exacerbation in comparison with values obtained at recovery; serum elemental composition was not modified by exacerbation; serum levels of C-reactive protein and procalcitonin at exacerbation were higher than values at recovery. In outpatients who experienced a mild-moderate chronic obstructive pulmonary disease exacerbation, manganese and magnesium levels in exhaled breath condensate are elevated at admission in comparison with values at recovery, whereas no other changes were observed in metallic elements at both the pulmonary and systemic level.     

Electrocardiographic Changes in Amitriptyline Poisoning

In imipramine and amitriptyline poisoning the electrocardiographic abnormalities comprise arrhythmias, widening of the QRS complex, and marked changes in die S–T segment. These features were found to be of value in the differential diagnosis of unknown poisoning. The unusual configuration of qR with raised S–T segment in V1, simulating myocardial infarction, was seen in one of our patients and has been noted in four cases reported by other workers.     

Regional cerebral metabolism in mouse under chronic manganese exposure: implications for manganism

Chronic manganese (Mn) exposure in rodents, non-human primates and humans has been linked to Parkinson's disease like condition known as Manganism. Mn being a cofactor for many enzymes in brain has been known to be accumulated in various regions differentially and thus exert toxic effect upon chronic overexposure. In present study, neuropathology of Manganism was investigated by evaluating regional neuronal and astroglial metabolism in mice under chronic Mn exposure. Male C57BL6 mice were treated with MnCl(2) (25 mg/kg, i.p.) for 21 days. Cerebral metabolism was studied by co-infusing [U-(13)C(6)]glucose and [2-(13)C]acetate, and monitoring (13)C labeling of amino acids in brain tissue extract using (1)H-[(13)C] and (13)C-[(1)H]-NMR spectroscopy. Glutamate, choline, N-acetyl aspartate and myo-inositol were found to be reduced in thalamus and hypothalamus indicating a loss in neuronal and astroglial cells due to Mn neurotoxicity. Reduced labeling of Glu(C4) from [U-(13)C(6)]glucose and [2-(13)C]acetate indicates an impairment of glucose oxidation by glutamatergic neurons and glutamate-glutamine neurotransmitter cycle in cortex, striatum, thalamus-hypothalamus and olfactory bulb with chronic Mn exposure. Additionally, reduced labeling of Gln(C4) from [2-(13)C]acetate indicates a decrease in acetate oxidation by astroglia in the same regions. However, GABAergic function was alleviated only in thalamus-hypothalamus. Our findings indicate that chronic Mn impairs excitatory (glutamatergic) function in the majority of regions of brain while inhibitory (GABAergic) activity is perturbed only in basal ganglia.     

Unusual Non-Occupational Exposure to Metals

Exposure to metals at workplaces is well known and in many cases occupational studies led to an adoption of limit values. For airborne concentrations of substances as metals refer to the “Maximaleo Arbeitsplatz-Konzentration” (MAK) in Germany or the “Threshold Limit Value” (TLV) in USA. Biological monitoring consists of an assessment of overall exposure to chemicals at the workplace and in the environment. The “Biologischer Arbeitsstoff Toleranzwert” (BAT) in Germany and the “Biological Exposure Index” in the USA serve as reference values. Besides these occupational limit values, reference values exist in Germany for the background exposure of the non occupationally exposed general population. In some cases the reference values are exceeded without any occupational exposure. Several cases of unusual environmental exposure to cobalt, mercury and manganese are reported. In such cases, it is often difficult to evaluate the measured concentration. In Germany, therefore, the “Human-Biomonitoring-Werte” (HBMValues) have been adopted in order to evaluate such high background exposures. The HBM-concept is presented. Environmental exposure to metals is usual within some limits. Reference values are helpful for an assessment. Unusual exposure occurs and the physician should be alert to symptoms of poisoning.     

Differentiation of Nijmegen breakage syndrome from Fanconi anemia

Nijmegen breakage syndrome (NBS) is a rare auto-somal recessive condition with chromosomal instability. Clinical and biological overlap between Fanconi anemia and ataxia telangiectasia has been reported. We report two cases of NBS born to consanguineous parents. Case one had NBS and Falconi anemia clinical features but relatively little chromosome breakage. The second case had mild NBS features, while cytogenetic evaluation with mitomycin C induction showed chromosome damage. Chromosomal analysis of bone marrow cells revealed tetraploidy, which indicates progression towards leukemia. On the basis of clinical and cytogenetic evaluation, these two cases were confirmed as NBS. However, detailed molecular studies are essential for accurate diagnosis and management of this disease.     

Lead Poisoning in Rural Scotland

Nine people from four families living in rural parts of Scotland have been found to suffer from clinical or biochemical effects of lead poisoning. Five had symptoms and four had unequivocal evidence of excessive lead exposure. The source of lead has been traced to the domestic water supply which in all cases was grossly contaminated with lead acquired from lead plumbing systems, including lead storage tanks. Clinical improvement followed the replacement of lead piping in two families studied. Lead poisoning is a possible cause of chronic ill health in areas of plumbosolvent water.     

An Unusual Cause of Renal Amyloidosis Secondary to Gout—the First Description of Familial Occurrence

Background: AA amyloidosis caused by the chronic inflammation accompanying gouty arthritis is extremely rare and familial occurrence has not been described so far. Case report: We present the case of two brothers (47 and 44 years old) with 7- and 10-year history of hyperuricaemia and chronic tophaceous gout with polyarticular involvement. The enzymatic assay performed in their erythrocytes proved the partial hypoxanthine-guanine phosphoribosyl transferase deficiency (Kelley-Seegmiller syndrome), the genetic defect of purine metabolism. Later on they developed proteinuria and chronic renal insufficiency /CRI/. Renal biopsy disclosed the combination of AA amyloidosis and gouty nephropathy in both the cases. Despite the standard treatment the older brother progressed to chronic renal failure. On the contrary, the younger one being longterm treated with oral colchicin have stabilized CRI. Conclusions: Only several cases of AA renal amyloidosis until recently, secondary to gout have been reported. Our case represents the first report of familial occurrence of this extremely rare disease.     

Metals accelerate production of the aberrant splicing isoform of the presenilin-2

Oxidative stress is a major risk factor for Alzheimer's disease (AD) and other neurodegenerative disorders. Metals are known to be one of the factors that contribute to oxidative stress. Recently, we reported that the aberrant splicing isoform (PS2V) generated by skipping exon5 of the presenilin-2 (PS2) gene is a diagnostic feature of sporadic AD (SAD). PS2V is inducible by exposure of human neuroblastoma to hypoxia. We examined whether this aberrant splicing was caused by metal-induced oxidative stress, such as exposure to aluminum. As a result, we demonstrated that exposure to aluminum accelerated PS2V production induced by hypoxia. This acceleration of the production of PS2V to hypoxia was caused by chronic aluminum exposure, but was not related to the intracellular content of aluminum. HMGA1a is a mediator of PS2V production, and it was induced by aluminum as well as by hypoxia. Induction of HMGA1a was increased by chronic exposure to aluminum, and a nuclear extract containing HMGA1a bound to a specific sequence on exon5 of PS2 pre-mRNA, as reported previously. Finally, the acceleration of PS2V production induced by aluminum under hypoxic conditions reflected, but has not yet been directly shown to cause, vulnerability to endoplasmic reticulum stress. These results suggest that exposure to some metals can accelerate and enhance PS2V generation, and that hypoxia plus chronic exposure to metals may promote the development of AD.     

Lymphoepithelial cyst with crystalloid formation. Cytologic features of two cases

BACKGROUND: The presence of amylase crystalloids (AC) in cystic lesions of the parotid gland is a rare occurrence and has been diagnosed to date as sialadenitis. We report the first two cases of parotid lymphoepithelial cyst (LC) containing this type of crystalloid. CASES: Case 1, a 56-year-old male, presented with a 3-cm parotid cyst. Fine needle aspiration (FNA) was performed on the mass. Smears showed numerous crystalloids identical to those described as crystallized amylase. Case 2, a 36-year-old female, had a 2-cm parotid mass. FNA smears exhibited the same features as did case 1. The two patients were treated with superficial parotidectomy, and an LC containing AC was diagnosed in both cases. CONCLUSION: When the above findings are present on FNA of parotid gland, the diagnosis of LC must be considered.     

Distribution of trace elements in human hair

Scalp hair has been successfully used in forensic medicine, screening populations for heavy metal poisoning, and for monitoring environmental pollutants. However, its use for the diagnosis of the individual for disease or nutritional status has been questionable. This is primarily due to the large individual differences associated with age, sex, race, hair color, hair treatment, and environmental exposure.     

Radiation-induced glioblastoma multiforme in two adult baboons (Papio cynocephalus anubis)

A diagnosis of glioblastoma multiforme (GBM) was made for cerebral masses found at necropsy in two baboons (Papio cynocephalus anubis). Case 1 was an adult (6.18 years old) male baboon that suddenly died during a physical examination as part of a clinical evaluation for a leg lameness. Case 2 was an adult (5.95 years old) female baboon that stopped breathing during anesthesia for an magnetic resonance imaging to evaluate lethargy, weight loss, inappetence, and dilated pupils. Both animals had undergone total body irradiation with cobalt during a research protocol. The incidence of spontaneous brain tumors in nonhuman primates is low, but radiation-induced GBM lesions in rhesus macaques (Macaca mulatta) have been reported. A definitive diagnosis was made in these cases, using histopathologic criteria of cellular pleomorphism, high mitotic rate, regions of coagulation necrosis, and endothelial proliferation.     

A pilot study of the cognitive and psychological correlates of chronic ciguatera poisoning

Ciguatera fish poisoning is the most frequently reported seafood-toxin illness in the world, caused by the consumption of coral reef fishes contaminated with a group of natural toxins produced by minute phytoplankton (dinoflagellates). These toxins are potent and cause both acute and chronic neurologic disease in humans.Although ciguatera fish poisoning is associated with established neurotoxins in animal models, and with known peripheral nervous system effects in humans, this pilot study was the first to explore possible central nervous system effects associated with chronic ciguatera poisoning in humans. In a matched cohort design, 12 cases and 12 their age and gender matched friend controls underwent a battery of neuropsychological tests. The results indicated that although their scores on objective neuropsychological tests did not differ significantly from matched controls, persons with ciguatera reported a higher degree of toxicity-related symptomatology and endorsed significantly more depressive symptomatology than controls. Future research should explore larger numbers of persons with both acute and chronic ciguatera, with and without mannitol treatment.