Effects of acute exposure to aluminum on cognition in humans.

There is epidemiological evidence suggesting an association between aluminum in drinking water and Alzheimer's disease (AD), and between aluminum in dialysate and dialysis dementia. The exact role of aluminum in the pathogenesis of these and other dementias is not clear. This study examined the acute effects of aluminum on cognitive function in patients with AD and related dementias and in age-matched and younger volunteers with normal cognitive function. Whether individuals with AD and/or the APOE epsilon4 genotype had enhanced gastrointestinal absorption of aluminum was tested, and whether individuals with elevated blood aluminum concentrations exhibited acute cognitive effects was determined. Subjects were randomized to receive a single dose of aluminum orally (Amphojel plus citrate) for 3 d followed by a 3-wk washout, and then 3 d of matched placebo administration, or vice versa. Serum aluminum levels were measured and the daily dose of Amphojel was adjusted to a target aluminum level between 50 and 150 microg/L. Neuropsychological tests were administered at baseline and 90 min after the third dose of Amphojel or placebo. There was a large interindividual variation in aluminum serum levels in all study groups after the same initial dose of Amphojel. There were no significant differences in neuropsychological test scores after aluminum ingestion in normal volunteers or in patients with cognitive impairment. There was no association between APOE epsilon4 genotype and aluminum absorption. The results did not support the hypothesis that aluminum ingested at these doses produces acute effects on cognition or adverse effects, nor did they reveal that AD patients are more vulnerable to such outcomes. Further inquiry is required to explore any possible association between aluminum and cognition, but controlled trials may be limited by safety concerns.

Pre-school children's attitudes to fat and normal male and female stimulus figures.

OBJECTIVE: To investigate gender differences in attitudes to obesity in pre-school children. DESIGN: Evaluation of gender differences in judgements of stimulus figures varying in body shape and gender. SUBJECTS: Twenty-five children aged 2-5 y, 12 boys and 13 girls. MEASURES: Forced-choice ascriptions of personal, social and behavioural traits to normal and obese male and female dolls. RESULTS: Children ascribed more negative characteristics than positive ones to fat figures than to normal figures, and more to fat female than to fat male figures. CONCLUSION: Children can demonstrate prejudiced behaviour towards obesity at earlier ages than previously thought.

Toxicity, uptake, and mutagenicity of particulate and soluble nickel compounds.

Toxicity testing in AS52 cells (24-hr exposures) gave LC50 values of 2 to 130 micrograms Ni/ml for particulate nickel compounds and 45 to 60 micrograms Ni/ml for water-soluble salts (NiCl2, NiSO4, Ni(CH3COO)2). The Ni(OH)2, NiCO3, and sulfides (Ni3S2, Ni7S6, "amorphous NiS") exhibited similar toxicities (LC50's of 2 to 8 micrograms Ni/ml), while three nickel oxides were more variable and less toxic (LC50's of 18 to 130 micrograms Ni/ml). Most compounds displayed nuclear to cytoplasmic nickel ratios of approximately 1:1.5 to 1:5 (except approximately 1:20 for nickel salts). At the LC50's, a 75-fold range in exposure levels occurred compared to a 10-fold range in cytoplasmic and nuclear nickel concentrations, [Ni]. Cellular nickel distribution indicated three groupings: inert compounds (green NiO, lithium nickel oxide, relatively low nuclear and cytosolic [Ni]); water-soluble salts (very low nuclear [Ni]; high cytosolic [Ni]), and slightly soluble compounds (relatively high cytosolic and nuclear [Ni]). Nickel compounds are considered to be only weak or equivocal mutagens. In this study, a low but significant increase in mutation rate at the gpt locus was shown. Although the results would not be sufficient to deem nickel compounds mutagenic by traditional criteria, characterization by PCR analysis indicated that the spontaneous and nickel-induced mutants exhibited different and compound-specific mutational spectra (thus confirming nickel compound involvement). The results reported illustrate some of the methodologic problems involved in testing "weak" mutagens and indicate that alternative approaches may be necessary in classifying the mutagenicity of nickel and other compounds.

Characterization of nickel-induced mutations.

A Chinese hamster ovary cell line (designated AS52) has been used to test the mutagenicity of nickel compounds. This line lacks the endogenous gene for hypoxanthine phosphoribosyl transferase (HPRT) but contains an inserted bacterial gene coding for the enzyme guanine-hypoxanthine phosphoribosyl transferase (gpt) which is the targeted locus for selection. Isolated mutants were clonally expanded and analysed utilizing the polymerase chain reaction (PCR) following exposure to ethyl methanesulfonate (EMS), Ni3S2, Ni(OH)2, NiSO4, and control conditions. Amplification of the gpt locus in normal AS52 cells results in the generation of two distinct bands, both of which have been characterized by restriction enzyme analysis and nucleotide sequencing. The smaller band represents the gpt gene. The larger band contains a large insert of bacterial origin and is non-functional. Analysis of mutants revealed three distinct patterns: (1) both PCR bands remain intact; (2) the smaller DNA band is deleted; (3) both bands are deleted. Mutant analysis was performed with two unique sets of DNA amplification primers with identical results. When compared to spontaneous or EMS induced mutants, those generated by exposure to nickel compounds exhibited an increase in gene deletions relative to point mutations; the extent of which was compound specific: NiSO4 > Ni(OH)2 > Ni3S2. These results clearly suggest that a variety of genotoxicological mechanisms are involved in the mutagenic activity of nickel compounds.

Motor skill learning in cerebral palsy: movement, action and computer-enhanced therapy.

This chapter discusses the extent to which previous research into movement control can provide key principles on which to model therapy for individuals with severe cerebral palsy. It is suggested that the movement perspective has traditionally stressed the role of implicit knowledge of the dynamic characteristics of the body and that this provides support for the principles of biofeedback training. From a more ecological 'action' perspective, however, it is concluded that previous approaches to biofeedback have been too constrained and do not translate well to functional tasks. A variation of biofeedback training is proposed that provides real-time feedback to shape the subject's action, thereby guiding them through learning contexts that are moulded to fit the individual's capabilities. A pilot study of the efficacy of such an approach in adolescents with cerebral palsy is then presented. The potential of extending computer-enhanced therapy into speculative areas such as virtual reality is also discussed.

Early intervention for children with or at risk of cerebral palsy.

Quantitative and qualitative analyses of well-conducted scientific studies of therapeutic early intervention for infants and young children with or at risk of a motor handicap failed to find convincing evidence for the efficacy of physical therapy. The shortcomings of present assessment tools are discussed and possible lines of enquiry identified.

Molecular biology approaches to biological monitoring of genotoxic substances.

Genetic testing is subdivided into genetic monitoring (evaluation over time of induced genetic changes) and genetic screening (detection of inherited traits). Genetic factors in relation to susceptibility to environmental agents are briefly examined, as well as mutation assays suitable for use in genetic monitoring, techniques for identifying specific DNA lesions, and oncogene products as biomarkers. In vitro studies with AS52 Chinese hamster ovary cells indicate that the distribution of lesions (e.g., point mutations or segment deletions) at the xanthine-guanine phosphoribosyl transferase (gpt) gene in mutants generated by exposure to nickel compounds show some substance specificity. This ability is viewed as a promising development for the molecular epidemiology of occupational and environmental cancers. It is concluded that technical limitations pertaining to specificity and sensitivity, as well as ethical and legal implications, need to be resolved before routine application of genetic monitoring and screening is feasible.

Physical and psychological characteristics of five male bulimics.

The case histories of five men who met DSM-III criteria for bulimia and details of their physical characteristics are given. Various eating disorder questionnaires were administered and the results indicated that most of these instruments would not have identified the men as suffering from an eating disorder. The necessity of caution in asserting the prevalence of bulimia using these measures is emphasised.

Oxidation of 1-14C-ascorbic acid in the guinea pig: effect of the route of administration.

Twenty-four hours after the administration of (1-14C)-ascorbic acid to guinea pigs by oral, intraperitoneal or intracardiac routes, 14CO2 expired levels were 22.6 plus or minus 1.8, 17.6 plus or minus 1.4 and 14.4 plus or minus 0.6 percent, respectively, of the administered radioactive doses. Whole blood concentrations of ascorbic acid were 80.2 plus or minus 2 micrograms per ml and, in general they were inversely related to expired 14CO2 production, which in turn reflects the degree of ascorbic acid catabolism in ascorbic acid adequate animals. Regardless of the route of (1-14C)-ascorbic acid administration, there was a biphasic pattern of 14CO2 evolution; the first peak occurs at two hours and the second peak at five hours after administration of the doses. Thin layer chromatography analysis of (1-14C)-ascorbic acid verified the reagent's purity. In vitro isolated stomach content and intestinal content experiments illustrated that at least 1-2% of the expired 14CO2 might also result from enterohepatic circulation of the label.

Depletion and repletion of ascorbic acid in the Rhesus monkey: relationship between ascorbic acid concentration in blood components with total body pool and liver concentration of ascorbic acid.

Eight female monkeys (Macaca mulatta) were fed an ascorbic acid-free diet for 7 weeks, followed by repletion with a supplementation of 10 mg ascorbic acid per kg of body weight for 3 weeks. Once each week the ascorbic acid contents of blood components and liver samples, obtained by closed needle biopsy, were determined as the 2,4-dinitrophenylhydrazine derivative. In selected animals the size of the total body pool ascorbic acid was determined by isotope dilution after administration (i.v.) of 14C-ascorbic acid. At no time were the monkeys frankly scorbutic. Values for r2 were less than 0.10 between plasma, whole blood, and erythrocyte ascorbic acid contents compared with the total body pool of ascorbic acid. Leukocyte ascorbic acid content was positively related to the total body pool of ascorbic acid (P less than 0.001, r2 = 0.923). Values for r2 were less than 0.15 when whole blood and (erythrocyte) ascorbic acid content were each compared with liver ascorbic acid levels; however, there was a tendency for plasma ascorbic acid levels to be directly related to liver ascorbic acid levels (P less than 0.05, r2 = 0.477), when plasma ascorbic acid was greater than 0.1 micrograms/ml. The relationship between liver ascorbic acid and leukocyte ascorbic acid levels was statistically significant (P less than 0.01, r2 = 0.683). The high correlation of leukocyte ascorbic acid levels with liver ascorbic levels and with the total body pool of ascorbic acid suggests that leukocyte ascorbic acid values best represent the vitamin C status of the female Rhesus monkeys.

Effects of ascorbic acid deficiency and of erythorbic acid on blood components in the Cynomolgus monkey.

Eight male Cynomolgus monkeys were fed an ascorbic acid-free total liquid diet until plasma levels decreased from a mean of 1.1 mg/dl to 0.04 mg/dl at 8 weeks. They showed no visible signs of scurvy. The animals were then given a daily oral dose of 10 mg ascorbic acid/kg body weight for 4 weeks, when the experiment was ended. Four of the animals were given, in addition, 200 mg erythorbic acid/kg body weight orally each day. In all animals repletion was accomplished in two to three weeks using return to initial plasma ascorbic acid levels as the criterion. During deficiency, blood cellular elements were found to be more resistant to depletion than plasma. For erythrocytes, this may be explained at least partially by the observation that in vitro uptake of ascorbic acid tended to be related inversely to blood ascorbic acid levels. However, no such relationship was seen in leucocytes or platelets. Other measurements made on blood did not vary in response to changing ascorbic acid levels. These include serum cholesterol; erythrocyte, leucocyte, or platelet counts; leucocyte differential; hemoglobin concentration; and hematocrit. Urinary hydroxyproline/creatinine ratios were also unchanged. Erythorbic acid, a stereoisomer of ascorbic acid and a common food additive, has been cited as a possible interferent in the determination of whole blood or plasma ascorbic acid, since in the guinea pig it is absorbed from the gut and no commonly used ascorbic acid analysis can distinguish between the isomers. Under conditions of the present experiment, however, no elevation of apparent whole blood or plasma ascorbic acid was produced by inclusion of high levels of erythorbic acid in the diet. Animals given erythorbic acid in addition to ascorbic acid during repletion did not differ from those given ascorbic acid alone in any aspect mentioned above.