ATTENTION DEFICIT HYPERACTIVITY DISORDER AND HAIR HEAVY METAL AND ESSENTIAL TRACE ELEMENT CONCENTRATIONS. IS THERE A LINK?

The aim of our study was to assess hair micro-elemental status in children with attention deficit hyperactivity disorder, determine micro-elemental misbalances and heavy metal concentrations and evaluate its impact on child behavior. Case-control study was conducted at Child Development Center of M. Iashvili Children's Central Hospital in 2015-2017years (Tbilisi, Georgia). We studied 70 children, mean age from 6 to 8 year. Target group involved 35 children with Attention Deficit Hyperactivity Disorder . Control group include 35 children of same age with normal behavior. Groups were homogenous based on different characteristics. To diagnose behavioral problems multi-profile group (pediatrician, neurologist, psychologist) assessment was used and final diagnostic was based on DSM V (Diagnostic and Statistical Manual of Mental Disorders from the American Psychiatric Association) and ICD-10 (International Clasiffication of Desease-10) criteria. Micro-elemental status was detected in the hair, with roentgen-fluorescence spectrometer method (Method MBИ 081/12-4502-000, Apparatus ELVAX-CIP, USA-UKRAIN). We study the content of 27 microelements (Zn, Fe, Cu, Mn, Co, Se, K, Cr, S , Cl, ,Ag ,V, Ni, Rb, Sr, Mo, Sr,, Pb, Hg, Br, Ti, Ba, As, Zr, Sb, Sn, Cd) in the hair in target and control groups. Computer program SPSS - 21 (Statistical Package for the Social Science - 21; Independent Samples T-Test,) was used for statistical analysis. The results of our study revealed deficiency of major elements (Fe, Mn, Co, Se), in target group and deficiency of zinc and cooper in both (control and target) groups,but the mean concentrations of manganese (sig 0,200; p>0,05), cooper(sig 0,813; p>0,05) and selenium(sig 0,320;p>0,05) does not show significant difference between control and target groups. Only in case of zinc (sig 0,000; p<0,05), iron (sig0,000;p<0,05) and cobalt (sig 0,000; p<0,05) deficiency we got significant values and meaningful associations between microelement's deficiency and ADHD.Our research didn't reveal any changes in other 17 elements (K, Cr, S, Cl, Ag, V, Ni, Rb, Sr, Mo, Sr, Ba, As, Zr, Sb, Sn, Cd) levels. We detected contamination with Pb (lead), Hg(mercury) and Ti (titanium) in both groups , but there were significant difference in Pb (sig 0,000; p<0,05) and Hg (sig 0,000; p<0,05) values between control and study groups, while difference of Ti (sig 0,177; p>0,05) level was not significant. Our study suggests that zinc, iron and cobalt deficiency as well as contamination with high lead and mercury are associated with attention deficit hyperactivity disorder.

High-level production of ethylmalonyl-CoA pathway-derived dicarboxylic acids by Methylobacterium extorquens under cobalt-deficient conditions and by polyhydroxybutyrate negative strains.

Bio-based production of dicarboxylic acids is an emerging research field with remarkable progress during the last decades. The recently established synthesis of the ethylmalonyl-CoA pathway (EMCP)-derived dicarboxylic acids, mesaconic acid and (2S)-methylsuccinic acid, from the alternative carbon source methanol (Sonntag et al., Appl Microbiol Biotechnol 98:4533-4544, 2014) gave a proof of concept for the sustainable production of hitherto biotechnologically inaccessible monomers. In this study, substantial optimizations of the process by different approaches are presented. Abolishment of mesaconic and (2S)-methylsuccinic acid reuptake from culture supernatant and a productivity increase were achieved by 30-fold decreased sodium ion availability in culture medium. Undesired flux from EMCP into polyhydroxybutyrate (PHB) cycle was hindered by the knockout of polyhydroxyalkanoate synthase phaC which was concomitant with 5-fold increased product concentrations. However, frequently occurring suppressors of strain ΔphaC lost their beneficial properties probably due to redirected channeling of acetyl-CoA. Pool sizes of the product precursors were increased by exploiting the presence of two cobalt-dependent mutases in the EMCP: Fine-tuned growth-limiting cobalt concentrations led to 16-fold accumulation of mesaconyl- and (2S)-methylsuccinyl-CoA which in turn resulted in 6-fold increased concentrations of mesaconic and (2S)-methylsuccinic acids, with a combined titer of 0.65 g/l, representing a yield of 0.17 g/g methanol. This work represents an important step toward an industrially relevant production of ethylmalonyl-CoA pathway-derived dicarboxylic acids and the generation of a stable PHB synthesis negative Methylobacterium extorquens strain.

Effect of cobalt on parameters of the cardiovascular system in elementary school children.

High incidence of cobalt deficiency (89%) was found in 7-8-year-old girls residents of the Republic of Tatarstan. Significant correlations were revealed between parameters of physical development and cardiovascular system and hair cobalt content. These data suggest that positive balance of cobalt is essential for normal growth and development of child's body and function of the cardiovascular system.

Effects of cobalt/vitamin B12 status in ewes on ovum development and lamb viability at birth.

Scottish Blackface ewes from cobalt-deficient farmland were fed a diet containing 0.06 mg cobalt per kg dry matter from approximately 30 days before embryo recovery/transfer until lambing. Ewes remained untreated (-Co; n = 82) or were given an intraruminal cobalt-containing bolus to compensate for the dietary deficit (+Co; n = 82). Ewes used as embryo donors (-Co, n = 17; +Co, n = 16) were artificially inseminated with semen from a single Suffolk sire. Day 6 embryos obtained from -Co and +Co donors were transferred in singleton to -Co and +Co recipients in a 2 x 2 factorial-designed experiment to determine the effects of cobalt/vitamin B12 status during the periconception period (factor 1) and pregnancy (factor 2) on lamb viability at birth. Mean (+/- s.e.m.) circulating concentrations of vitamin B12 in -Co and +Co donors at ovum recovery were 182 +/- 10 and 1288 +/- 64 pmol L(-1), respectively (P < 0.001), and the number of corpora lutea per ewe ovulating was 9.9 +/- 1.6 and 14.4 +/- 1.3, respectively (P < 0.05). Treatment did not affect the proportion of recovered ova that contained >32 cells (viable) or the median stage of development (late morula), but viable ova recovered from -Co v. +Co ewes had a better morphological grade (2.0 +/- 0.1 v. 2.20 +/- 0.04, respectively; P < 0.01). There was no effect of treatment on the proportion of recipient ewes that became pregnant. Circulating concentrations of vitamin B12 were lower in -Co than +Co ewes during pregnancy (P < 0.001) and at birth in lambs born to -Co ewes compared with those born to +Co ewes (P < 0.001). There was no effect of donor or recipient cobalt/vitamin B12 status on lamb birthweight, neonatal vigour or neonatal rectal temperatures, but lambs derived from +Co v. -Co embryo donors were more active in the first 3 days after birth (P < 0.05). Results show that sub-clinical cobalt/vitamin B12 deficiency reduces ovulatory response in superovulated ewes and that periconception nutrition can affect neonatal lamb behaviour.

The effect of alcohol consumption on maternal and cord blood electrolyte and trace element levels.

BACKGROUND: Earlier studies demonstrated that alcoholism significantly alters electrolyte and trace element homeostasis. However, the existing data on the interplay between maternal alcohol consumption and fetal trace element status are contradictory. Therefore, the primary objective of the present study was to assess the influence of alcohol consumption on maternal and cord blood trace elements. METHODS: A total of 30 pregnant women (15 women consuming alcohol and 15 controls) were examined. Assessment of electrolyte and trace elements concentration in maternal (1 and 3 trimesters) and umbilical cord blood was performed using inductively-coupled plasma mass spectrometry. RESULTS: In the first trimester of pregnancy alcohol consumption is associated with increased whole blood Ca and Na levels. In the third trimester of pregnancy, women consuming alcohol are characterized by significantly increased Co levels. Conversely, the level of Co and Mn in the cord blood of offspring maternally exposed to ethanol is decreased. A significant correlation between first trimester blood and cord blood concentrations of K was revealed both in control women and those consuming alcohol. In the third trimester of pregnancy in the control women, a significant correlation with cord blood was detected for Fe, Mg, P, and Pb. Oppositely, in the third trimester in women consuming alcohol we detected a close association between maternal whole blood and cord blood levels for Ca, Cd, and Pb. CONCLUSIONS: The data obtained demonstrate that maternal alcohol consumption results in fetal Co and Mn deficiency.

Cobalt deficiency in cattle and its impact on production / Deficiência de cobalto em bovinos e seu impacto na produção

Two outbreaks of cobalt deficiency in beef cattle were diagnosed in Midwestern Brazil. We discuss the clinical, epidemiological, pathological features, therapeutic measures, and impact aspects of the production system associated with these outbreaks occurring outbreaks in two farms of extensive cattle raising-system in the state of Mato Grosso do Sul. Seven affected cattle were euthanized and necropsied. Tissues for histopathology and microelements dosage were secured. At Farm A, 3100 cattle of all ages got sick, and 396 died; at Farm B, 148 were affected, and 110 died. In both farms, cattle were fed the same mineral supplement. The main clinical signs were weight loss and weakness, even though a good supply of forage was available in the paddocks. Many cattle stop grazing and chew at tree barks, wood chips from fence posts, and bones. In addition to the deaths, there was a compromised growth, and the reproductive rates fell sharply. The necropsied cattle were thin, with rough hair coat and pale mucous membranes. The liver was diffusely orange and showed a lobular pattern. The bone marrow was gelatinous and diffusely yellow. Histological changes included hemosiderosis in the liver and spleen, hepatocellular vacuolar degeneration, and myeloid and erythroid hypoplasia of the bone marrow. In the white matter of four cattle's brains, the myelin sheath was markedly distended (spongy degeneration). Proliferative parasitic abomasitis was observed in three cattle. The presumptive diagnosis was based on the association of the clinical picture, the necropsy findings, and the ruling out of other possible causes. The diagnosis was confirmed by the favorable response to treatment with cobalt and vitamin B12 orally and by mineral supplementation.(AU)

Dois surtos de deficiência de cobalto em bovinos de corte foram diagnosticados. Os aspectos clínicos, epidemiológicos, anatomopatológicos, terapêuticos e impactos no sistema de produção são descritos e discutidos. Os surtos ocorreram em duas fazendas de criação extensiva estado de Mato Grosso do Sul, Centro-Oeste brasileiro. Sete bovinos afetados foram eutanasiados e necropsiados. Na necropsia foram colhidas amostras para exames histopatológicos e dosagem de microelementos. Na Fazenda A, 3100 bovinos de todas as idades adoeceram e 396 morreram e na Fazenda B, 148 bovinos adoeceram e 110 morreram. Ambas as fazendas utilizavam o mesmo suplemento mineral. Os principais sinais clínicos observados foram emagrecimento e fraqueza, apesar da boa oferta de forragem nos piquetes, muitos bovinos deixaram de pastejar e comiam cascas de árvores, madeira das porteiras e ossos. Além das mortes, tiveram crescimento comprometido e os índices reprodutivos tiveram queda acentuada. Os bovinos necropsiados estavam magros, com os pelos arrepiados e mucosas pálidas. O fígado estava difusamente alaranjado e com evidenciação do padrão lobular. A medula óssea estava de consistência gelatinosa e difusamente amarelada. Alterações histológicas incluíam degeneração vacuolar hemossiderose que era moderada no fígado e marcada no baço. Hipoplasia mieloide e eritoide era vista na medula óssea. Na substância branca do encéfalo de quatro bovinos, a bainha de mielina estava marcadamente distendida (degeneração esponjosa). Abomasite parasitária proliferativa foi observada em três bovinos. O diagnóstico presuntivo baseou-se na associação do quadro clínico, nos achados de necropsia e na eliminação de outras possíveis causas. O diagnóstico foi confirmado pela resposta favorável ao tratamento com cobalto e vitamina B12 por via oral, e a suplementação mineral.(AU)

A brief history of the influence of trace elements on brain function.

From this brief review of history it is evident that lead, mercury, iodine, cobalt, iron, copper, manganese, and zinc have important influences on brain development and function. Identity of thresholds at which effects occur is needed for determination of safe and/or essential levels of these elements in diets. Such knowledge will help define human needs for essential elements, and the hazards of toxic elements.

Nova Scotia moose mystery--a moose sickness related to cobalt- and vitamin B12 deficiency.

A wasting, debilitating disease with uncertain aetiology affecting moose (Alces alces americana) in Eastern North America has been reported repeatedly ever since the 1910s. Despite the intensive studies during 1930-1960s the cause of the sickness could not be established. In the 1960s a parasitic nematode (Parelaphostrongylus tenuis) was reported as constituting a probable explanation for the sickness, although several clinical and pathological signs remained unexplained. In Sweden, a moose disease with similar signs, has been shown to be caused by molybdenosis resulting from a nutritional imbalance. The findings of this investigation were applied in Nova Scotia to determine trace element concentrations in tissues from indigenous moose. Co deficiency was found in about half of the cases and the investigation was complemented by determining the vitamin B12 level, which proved nutritional Co/vitamin B12 deficiency, further verified by an increased MMA (methylmalonic acid) level in plasma. Deficiencies were found mainly in the Tobeatic and Cape Breton Highland regions. No indications of molybdenosis or other trace element disturbances were found in Nova Scotia. Otherwise, extremely high Cd levels (148 mg Cd/kg kidney wet wt., maximum) were found, though probably not contributing to the moose sickness. The Cd burden of moose on mainland Nova Scotia was more than 50% higher than that of moose in Huntville and Alonquin (Ontario, Canada) and five- to six-fold is higher than the highest Cd levels found in Sweden. To counteract the bio-geochemical effects of Co deficiency in the moose environment, provision of Co-containing salt licks is suggested.

Contribution of cobalamin analogues to plasma vitamin B12 concentrations in cattle.

Plasma vitamin B12 concentrations in cattle were analysed by a radioisotope dilution assay using pig intrinsic factor and a microbiological assay using Euglena gracilis. Both assays provided similar results for samples of cattle plasma containing vitamin B12 concentrations ranging from 0.07 to 3.60 micrograms litre-1 (r = 0.95, P less than 0.001). The addition of excess cobinamide in the radioisotope dilution assay to block non-specific binding in the intrinsic factor preparation due to the presence of R-type binders, was used to determine the presence of cobalamin analogues. Cobalamin analogues accounted for up to 50 per cent of the total vitamin B12 concentration in samples of plasma from cows but were virtually undetectable in plasma from sheep.

Effect of cobalt deficiency in the pregnant ewe on reproductive performance and lamb viability.

Reproductive performance and lamb viability in cobalt sufficient and subclinically deficient ewes, and from ewes experiencing repletion from and depletion into cobalt deficiency, were investigated in two experiments. The sheep were fed a cobalt deficient ration and supplementation was by oral dose according to treatment. The treatments had a significant effect (P less than 0.001) on ewe serum vitamin B12 and methylmalonic acid concentrations. There were no significant effects on ewe liveweight, condition score or conception rate. Cobalt deficient ewes produced fewer lambs and had more stillbirths and neonatal mortalities than cobalt sufficient controls. Lambs from deficient ewes were slower to start suckling (P less than 0.05), had reduced concentrations of serum immunoglobulin G and zinc sulphate turbidity levels (P less than 0.05), and had lower serum vitamin B12 and higher methylmalonic acid concentrations (P less than 0.05), than lambs from cobalt sufficient dams. Cobalt supplementation in either the first or second half of pregnancy only did not fully alleviate these adverse effects.

Caprine hepatic lipidosis induced through the intake of low levels of dietary cobalt.

Forty-one, 10-week-old newly weaned goats were randomly allocated into two groups, namely control (n=22) and treated (n=19). Kids in both groups were fed Rhodegrass hay ad libitum that contained < 0.1 mg/kg DM cobalt and 150 g/day of a commercially prepared ruminant concentrate that contained approximately 0.12 mg/kg DM cobalt. This diet provided the minimum daily requirement of cobalt as specified for sheep. The treated goats were supplemented with bi-monthly subcutaneous injections of 2000 microg of hydroxycobalamin. All goats were weighed and blood samples collected monthly for haematological, clinical biochemical and serum vitamin B12 analysis. After a 10-month experimental period the goats were slaughtered. The control animals exhibited significantly (P<0.05) lower weight gains, and had dry scruffy hair coats. In addition, there was a decline in erythrocyte counts, mean haemoglobin, packed cell volume, mean corpuscular volume, mean corpuscular haemoglobin and mean corpuscular haemoglobin concentration. Controls also exhibited significantly (P<0.05) lower levels of total serum proteins and elevated levels of serum alkaline phosphatase compared to treated goats. Fourteen (63.6%) of the control goats developed pathology consistent with reported field cases of hepatic lipidosis associated with low liver levels of cobalt. Only one (5.3%) of the treated goats developed hepatic lipidosis. Contrary to previous reports that suggested that goats are less sensitive to low levels of dietary cobalt than sheep, it is apparent that this is not the case with Omani goats. This is the first report of the induction of hepatic lipidosis in goats due to feeding low levels of cobalt in their diet.

Biochemical and physiological indicators of mineral status in animals: copper, cobalt and zinc.

The value of estimates of trace element requirements or of data on tissue trace element content for identifying and controlling trace element-related disorders is often limited by inadequate data on the relationships of such criteria to physiological performance. Investigations of metabolic events initiating early pathological responses to deficiency are beginning to suggest more effective indicators of physiologically relevant abnormalities in trace element intake or status. Progress in studies of metabolic responses to deficiencies of copper, cobalt and zinc is reviewed.

Sequential changes in propionate metabolism during the development of cobalt/vitamin B12 deficiency in sheep.

The changes in propionate metabolism that accompany cobalt deficiency in sheep are described. Two groups of sheep, fed either a cobalt sufficient or deficient diet, were given an iv propionate load at intervals during a 14 w experiment. There was a tendency towards increased propionate half-life as the animals became cobalt deficient. However, significant changes in the area under the plasma methylmalonic acid-time curve occurred very early, indicating significant impairment of propionate metabolism. Despite this, the area under the plasma glucose-time curve was unaffected by cobalt deficiency, suggesting that the impairment of propionate metabolism, although significant, is not extensive.

Development and application of an alpha-face-specific radioimmunoassay for vitamin B12.

The first development of an alpha-face-specific radioimmunoassay for vitamin B12 is described. Sheep, fed a cobalt-deficient diet, and immunized with a conjugate between Co-beta carboxypropyl cobalamin and keyhole limpet hemocyanin, were used to produce antisera. The antisera crossreacted with Co-beta derivatives of vitamin B12, but did not crossreact with the alpha-face vitamin B12 analog cobinamide. The antisera were used to develop a sensitive and reproducible radioimmunoassay that was free from contamination with the nonspecific vitamin B12 binding protein, R-protein. Both the radioimmunoassay and measurements of plasma concentrations of methylmalonic acid were applied to the diagnosis of cobalt/vitamin B12 deficiency in sheep. The assay correlated well with a commercially available radioassay and did not falsely detect normal vitamin B12 concentration in plasma samples containing elevated concentrations of methylmalonic acid.

Sequential changes in plasma methylmalonic acid and vitamin B12 in sheep eating cobalt-deficient grass.

Methylmalonic acid (MMA) concentrations are elevated in plasma as a result of vitamin B12 deficiency. This study reports the sequential changes in plasma MMA in lambs maintained on a cobalt-deficient pasture compared with supplemented controls. The results indicate that MMA is elevated in the early stages of deficiency, preceding the onset of loss of production and clinical signs of disease. It remains elevated as long as the lambs are unsupplemented with cobalt (Co). The most striking clinical sign was a loss of body condition as opposed to weight. The defect in the methylmalonyl CoA mutase is obviously an early defect in cobalt deficiency.

Formation of cobalt-free corrinoids in Rhodopseudomonas spheroides.

Co-free corrinoids (CFCs) were found in the cells of Rhodopseudomonas spheroides grown without cobalt salt. A predominant fraction of three CFCs on paper-electrophoregram was further purified, and investigated physico-chemically as well as microbiologically in comparison with that isolated by Toohey from Chromatium. The electrophoretic as well as spectrophotometric patterns of CFC from Rh. spheroides were partly different from those of Chromatium CFC. The former CFC was a competitive inhibitor of cyanocobalamin in Ochromonas malhamensis. The findings obtained indicate that the CFC from Rh. spheroides resembles that from Chromatium in chemical structure with some difference, and that the compound has an anti-vitamin B12 activity in O. malhamensis.

Changes in serum levels of vitamin B12, feed intake, liveweight and hematological parameters in cobalt deficient small east African goats.

Thirty short-horned East African goats were divided into two groups (treatments 1 and 2) consisting of fifteen goats each. All the goats were fed on a cobalt deficient diet containing 0.02 mg Co/kg of dry matter for a period of twenty three weeks. Goats in treatment 1 were supplemented with an oral cobalt chloride drench. Cobalt deficiency developed in goats in treatment 2 after ten weeks when their serum vitamin B12 concentration fell below 200-250 pg/ml. Between the third and the twenty-third weeks of the experiment, the mean serum concentration of vitamin B12 was significantly (P < 0.01) higher in cobalt supplemented (289.6 +/- 40.76 pg/ml) than deficient (142.8 +/- 28.27 pg/ml) goats. Total dry matter intake, intake per metabolic body weight and liveweight changes were not significantly (P > 0.05) different between goats in the two treatments. Although packed cell volume, hemoglobin concentration, and erythrocyte count were significantly (P < 0.05) higher in cobalt adequate than deficient goats, these blood parameters were within the normal range for goats. It is suggested that although serum vitamin B12 standard for sheep is applied for goats, the latter species is likely to be more resistant to low dietary cobalt intake than sheep.

Erythrocyte glutathione metabolism in cobalt-deficient goats.

Cobalt deficiency was produced in goats by feeding them rhode grass hay. The deficient animals excreted increased amounts of methyl malonic acid in their urine, indicating a lack of vitamin B12. Erythrocyte reduced glutathione levels increased with the onset of anemia. There was a concomitant increase in the levels of erythrocyte glutathione reductase (GSSG NADPH Reductase) and glutathione peroxidase (GSH:H2O2 peroxidase)during deficiency. These results are compared with similar observations reported for vitamin B12 deficiency in humans.

Plasma vitamin B12 and reproductive performance of cows on cobalt-deficient pastures in the Rift Valley of Kenya.

Plasma vitamin B12 and glucose in beef and dairy cattle were determined in a well-managed and poorly-managed farm in the cobalt-deficient pastures of the Naivasha area of the Rift Valley of Kenya. These values were compared to those obtained in a well-managed farm from cobalt-replete pastures outside the Rift Valley. Whilst plasma vitamin B12 from the well-managed farm in the Rift Valley (371 +/- 20 pg/ml) were comparable to those from the cobalt-replete pastures (288 +/- 19 pg/ml), those from the poorly-managed farm were significantly lower (156 +/- 13 pg/ml, P less than 0.001). It was noted, however, that even the well-managed farm in the Rift Valley had herd differences indicating how easy it is for the animals to slip into deficiency in the affected pastures. There was no difference in plasma glucose in any of the herds. Fertility, however, was very different. The conception rate at the poorly managed farm was only 30% (with high calf mortality) as compared to 67% in the well-managed farm in the same vicinity. It is suggested that apart from provision of cobalt salt licks, periodic monitoring of plasma vitamin B12 would be a useful safeguard against the onset of unintended, subclinical deficiency.

Cobalt-vitamin B12 deficiency and the activity of methylmalonyl CoA mutase and methionine synthase in cattle.

Cobalt deficiency was induced in cattle by feeding two groups of animals either a basal diet that was very low in Co (12.9-17.6 micrograms Co per kg), or the same diet supplemented with cobalt, for a total of 64 weeks. Vitamin B12 deficiency was induced, as judged by hepatic concentrations of vitamin B12 and plasma concentrations of MMA. However, the activity of holo-methylmalonyl CoA mutase was significantly reduced only in brain. This was reflected in very minor alterations in the tissue concentrations of branched chain- and odd numbered-fatty acids. The activity of holo-methionine synthase was significantly reduced in liver and brain, but there were no consequent alterations in the concentrations of phosphatidyl choline and phosphatidyl ethanolamine. This study confirms that cattle are less susceptible to the effects of cobalt deficiency than sheep, and concludes that prolonged cobalt deficiency had little significant effect on tissue metabolism.