Behavioral and psychological symptoms assessed with the BEHAVE-AD-FW are differentially associated with cognitive dysfunction in Alzheimer's disease.

To assess the possible neurological basis of behavioral and psychological symptoms of dementia (BPSD), the relationships between BPSD and cognitive function were evaluated in 40 patients with Alzheimer's disease (AD). BPSD was assessed using the Behavioral Pathology in Alzheimer's Disease Frequency Weighted Severity Scale (BEHAVE-AD-FW) for behavioral symptoms and psychological symptoms separately, and cognitive function was also assessed using the Cognitive Abilities Screening Instrument (CASI). We found that only behavioral symptoms were associated with cognitive function based on the CASI total score and the score for the CASI attention domain. Administration of risperidone, an atypical anti-psychotic drug, for one month, improved the behavioral symptoms and the scores for the CASI attention and orientation domains. Our data suggest that BPSD in AD may reflect two largely independent pathophysiological processes: one associated with behavioral symptoms partly overlapping with attention, and the other associated with psychological symptoms predominantly unrelated to cognitive function.

Hepatic regeneration in the absence of portal viscera.

In an effort to investigate the influence of portal factors on hepatic regeneration in the rat and to clarify glucagon's apparent regulatory role, a rat preparation was developed which was totally devoid of portal viscera and thus deficient in all possible hepatotrophic substances of portal origin. It was found that, following partial hepatectomy, such an eviscerate rat was able to undergo hepatic deoxyribonucleic acid (DNA) synthesis, but the peak DNA synthetic response was significantly delayed by such portal deprivation. As demonstrated by a group of rats with intact portal viscera, but with a portacaval shunt, reduction of blood supply to the hepatic remnant by diversion of portal flow accounted for only a portion of the delay. The remainder of the delay encountered in the eviscerate group was attributed to the deprivation of specific portal substances. Since glucagon supplementation administered to the deficient eviscerate animal restored peak DNA synthesis to the time of its appropriate shunted control, this hepatotrophic substance is a major portal factor modifying the response to partial hepatectomy. Evidence is cited which suggests that glucagon's influence on DNA synthesis is mediated through the formation of cyclic adenosine monophosphate (AMP) and subsequent histone phosphorylation.

The actions of ivermectin on cultured chick spinal cord neurons.

The effects of ivermectin (IVM) on cultured chick spinal neurons sensitive to GABA agonists were investigated. IVM caused a change of membrane potential which was associated with an increase in membrane conductance, apparently reversed at about -40 mV and weakened by repetitive application. Furthermore, this agent did not have any effects on either the actions of GABA agonists on neurons or [3H]GABA efflux from those cells. These results suggest that IVM increases membrane conductance through sites which are different from GABA recognition sites.

Toxicity of butylbenzyl phthalate (BBP) and other phthalate esters to nervous tissue in culture.

Butylbenzyl phthalate (BBP) and n-butyl lauryl phthalate (BLP) markedly inhibited the outgrowth of nerve fibers and glial cells from cerebellar explants of newborn rat in primary culture at concentrations of 7.0 and 12.5 x 10(-4) M, respectively. The toxicity of butyl phthalyl butyl glycolate (BPBG) was not significant. From these results the order of toxicity of these three phthalate esters was determined as BBP > BLP > BPBG.

The effect of methylcobalamin on the toxicity of methylmercury and mercuric chloride on nervous tissue in culture.

Methylcobalamin (methyl-B12, vitamin B12 analog) at a concentration of 0.2 x 10(-5) M tended to inhibit the toxic effect of 1 and 1.5 x 10(-5) M methylmercuric chloride (MMC) on the development of nerve fibers, glial cells and fibroblasts from newborn rat cerebellum explants. Methyl-B12 at greater than 1 x 10(-5) M significantly inhibited the toxic effect of 1 and 1.5 x 10(-5) M MMC. However, the protective effect of methyl-B12 against the toxicity of mercuric chloride (MC) was not significant. These results are in accord with an interaction of alkyl mercurials with membranes of nervous tissue, producing the degenerative changes in the cells, since vitamin B12 increases the lipid synthesis in nervous tissue. The results also indicate that the mechanism of toxic action of organic mercury is different from that of inorganic mercury.

Preliminary study on serum levels of 1,25-dihydroxyvitamin D and 25-hydroxyvitamin D in cadmium-induced renal tubular dysfunction.

Serum 1,25-dihydroxyvitamin D [1,25(OH)2D] and 25-hydroxyvitamin D [25(OH)D] were measured in 7 women living in a cadmium-polluted area in Toyama, Japan. Despite the fact that these subjects had severe proximal renal tubular dysfunction showing increased fractional excretion of beta 2-microglobulin (FE beta 2-m) ranging from 9.7-49.1% with a mean of 30.7%, the levels of serum 1,25(OH)2D, which is produced in the proximal tubules, were within the normal range in 6 subjects. Significant correlations were found between 1,25(OH)2D and creatinine clearance (r = 0.802, P less than 0.05), and FE beta 2-m (r = -0.829, P less than 0.05), respectively. These results suggest that renal production of 1,25(OH)2D decreases with progression of cadmium-induced renal tubular dysfunction.

Interactions between mercuric chloride and sodium selenite on cultured rat cerebrum.

Explants of rat cerebrum in culture were treated with toxic concentration of HgCl2 of 1 x 10(-4) M and with varying concentrations of sodium selenite. Treatment with sodium selenite resulted in a reduced neurotoxicity of HgCl2, a maximal effect being attained at a selenite concentration of 1 x 10(-5) M. However, 1 x 10(-5) M sodium selenite was itself toxic. In in vitro cell systems, the toxicity of either mercury or selenium is decreased in the presence of the other element.

The effects of phthalate esters on fibroblasts in primary culture.

The toxicity of butylbenzyl phthalate(BLP), di-n-heptyl phthalate (DNHP) and n-butyl lauryl phthalate (BLP) to fibroblasts from newborn rat cerebellum in primary culture was significant at concentrations of 7.0, 2.7, and 5.0 x 10(-4) M, respectively. The toxicity of di-methoxyethyl phthalate(DMEP), butyl phthalyl butyl glycolate(BPBG), di-n-octyl phthalate(DNOP), and di-(2-ethylhexyl) phthalate(DEHP) was not significant. Phthalic acid and potassium hydrogen phthalate (K-phthalate) were the least toxic to fibroblasts. Comparison of the toxicity to fibroblasts of five phthalate esters of normal series showed that dimethyl phthalate(DMP) < diethyl phthalate(DEP) < di-n-butyl phthalate(DNBP) > DNHP > DNOP.

Effect of cadmium chloride and Cd-metallothionein on the nervous tissue culture.

Influence of metallothionein (MT) isolated from rat liver on rat cerebellum in culture was investigated by comparison with that of CdCl2. Cd-MT at 0.2 X 10(-5) M as Cd significantly depressed the outgrowth of nerve fibers, fibroblasts and glial cells as compared to the control culture. In the range from 0.2 X 10(-5) M to 2.7 X 10(-5) M Cd, the toxicity of Cd-MT was the same as that of CdCl2. Above 5 X 10(-5) M Cd, however, the toxicity of Cd-MT was less than that of CdCl2. Cadmium added as CdCl2 was perfectly recovered at a region of higher Mr than MT on the Sephadex G-75 column. Cadmium added as Cd-MT was detected in part at the higher Mr region and in part at the MT region, depending on incubation time and Cd concentration in the medium. The toxic action of Cd-MT was proportional to the recovery level of Cd at the higher Mr region.

Urinary trehalase activity and renal brush-border damage in inhabitants of a cadmium-polluted area (Jinzu River basin).

Elevated urinary trehalase activity was observed in the inhabitants of the Jinzu River basin. Urinary trehalase activity was correlated with other urinalysis components, such as beta 2-microglobulin, glucose, amino nitrogen, and cadmium, of which a high level was observed in cadmium-polluted areas as compared with the reference area. Renal trehalase is specifically localized in tubular brush borders [M. Nakano, J. Histochem. Cytochem., 30 (1982) 1243-1248]. From these results it is inferred that tubular brush-border damage occurs in inhabitants of the Jinzu River basin.

Demonstration of vitamin D-binding protein (Gc-globulin) in the urine of Itai-itai disease patients.

Vitamin D-binding protein (VDBP, known as Gc-globulin) was discovered by an immunochemical method in the urine of patients with Itai-itai disease. The urine and sera of Itai-itai disease patients produced specific precipitin lines with anti-human VDBP antisera. The electrophoretic mobility of the protein in the urine is the same as that in the serum. A significant correlation was found between VDBP and beta 2-microglobulin in the urine. Based on this result, it was concluded that Itai-itai disease is associated with disturbances of vitamin D transport and/or metabolism.

Serum bone-type alkaline phosphatase activity in women living in a cadmium-polluted area.

To clarify the significance of elevated serum total alkaline phosphatase activity (t-ALP) in persons exposed to environmental cadmium (Cd), the fraction of ALP originating from bone (b-ALP) was assayed using a wheat-germ agglutinin method in 23 men and 20 women in a Cd-polluted area who showed excessive urinary beta 2-microglobulin excretion, and in 21 men and 44 women in a non-polluted area, in addition to 7 patients with itai-itai disease. The fraction of b-ALP increased linearly with the increase in t-ALP in the women, irrespective of Cd-exposure. Elevations of both t-ALP and b-ALP in the Cd-exposed women, including inhabitants of the Cd-polluted area and patients with itai-itai disease, were found with decreases in serum calcium and bone density. It is concluded that elevated serum ALP levels found in Cd-exposed persons reflect the development of Cd-induced bone damage.

Azido glycoside primer: a versatile building block for the biocombinatorial synthesis of glycosphingolipid analogues.

A lactoside primer, 12-azidododecyl beta-lactoside, was synthesized via the Koenigs-Knorr method by glycosylation of 1,12-dodecyldiol with perbenzoylated lactosyl bromide. The presence of the 2-O-acyl substituent in the donor gave the beta-lactoside, and an excess of acceptor ensured monoglycosylation of the diol. Mesylation of the omega-hydroxyl group in the aglycon, followed by displacement of the mesylate with azide and subsequent O-debenzoylation gave the desired omega-azidododecyl beta-lactoside. The azido glycoside primer was examined in mouse B16 melanoma cells for its feasibility as a building block for oligosaccharide biosynthesis. Uptake of the azido glycoside primer by B16 cells resulted in the sialylation of the galactose residue of the primer to give a glycosylated product having the same glycan as in ganglioside GM3. After 24 h incubation of B16 cells with the primers, the amount of sialylated omega-azidododecyl beta-lactoside primer was 75% of the amount of sialylated n-dodecyl beta-lactoside. However, after 48 h incubation, both primers gave equal amounts of the sialylated products. Interestingly, the remaining azido glycoside primer after 48 h incubation was 5.6-fold greater than that of the alkyl primer, indicating degradation of the alkyl primer to a larger extent than the omega-azido glycoside primer. The facile chemical synthesis and the efficient uptake in cells make the azido glycoside primer a versatile building block for the biocombinatorial synthesis of glycolipid oligosaccharides.

Effects of 2-mercaptopropionylglycine on the development of X-ray-induced cataract in rats.

The effect of 2-mercaptopropionylglycine on the development of cataract induced by a single dose of X-ray (10 Gy) was investigated in rats. Intraperitoneal injection of 20 mg/kg, three times weekly starting 1 day after irradiation delayed the development of X-ray-induced cataracts significantly. The amounts of non-protein SH groups, malondialdehyde and the Na+/K+ ratio, in the lenses of rats post-treated with the drug were significantly maintained at normal levels even at 27 weeks after irradiation. On the other hand, a single administration of 250 mg/kg of the compound, 30 min prior to irradiation had no effect on cataract progression induced by X-ray.

Glutathione isopropyl ester (YM737) inhibits the progression of X-ray-induced cataract in rats.

The effect of glutathione (GSH) isopropyl ester on the progression of X-ray-induced cataract was investigated in rats. Intraperitoneal administration of 20 mg/kg GSH isopropyl ester, three times weekly, 1 day after a single irradiation dose delayed the progression of X-ray-induced cataracts significantly. The amount of non-protein SH groups and the Na+/K+ ratio in the lenses of drug-treated rats were maintained at the normal levels even 27 weeks after irradiation. Posttreatment with the drug resulted in a significantly lower level of malondialdehyde in the irradiated lenses than in the nontreated lenses. When 500 mg/kg GSH-isopropyl ester was administered by i.p. injection to normal rats, the GSH-ester was detected in plasma and aqueous humor after 15 min. In the lenses of the GSH-isopropyl ester-injected rats, the GSH level was 120% of that in the non-treated rats after 4 h, suggesting that GSH-isopropyl ester is transported from the aqueous humor to the lens and there converted to GSH after about 4 h. Our observations lead us to conclude that the delay of X-ray-induced lens opacity progression is due to maintenance of normal lenticular GSH levels achieved by post-irradiation administration of GSH-isopropyl ester. However, continuous administration of 100 mg/kg after irradiation had no effect on the progression of cataracts induced by X-rays.

Cross-sectional assessment of renal function in the inhabitants of a cadmium-polluted area.

To understand the development of cadmium (Cd)-induced renal tubular dysfunction, cross-sectional assessment of renal function in the inhabitants of the Cd-polluted Jinzu River basin in Toyama, Japan, was carried out. Sixty-seven men and 78 women, aged 56 to 71 years whose urinary beta 2-microglobulin (beta 2-m) exceeded 1,000 micrograms/g creatinine, were examined and divided into five groups according to their values of fractional excretion of beta 2-m (FE beta 2-m). Comparisons were made between six groups including the inhabitants of a non-polluted area as a reference group. Significantly increased values of fractional excretion of urate (FEUA), calcium (FECa), sodium (FENa), and chloride (FECl), serum creatinine and beta 2-m, and urinary protein were detected even in the subjects with FE beta 2-m level below 1 percent compared with the reference group. Fractional phosphate reabsorption (percent TRP) was significantly decreased in the subjects with FE beta 2-m level above 10 percent. Creatinine clearance (CCr) decreased with increase in FE beta 2-m, and the subjects with FE beta 2-m above 30 percent showed significantly decreased CCr values compared to those with FE beta 2-m below 30 percent. In summary, FEUA, FECa, FENa, and FECl, as well as low-molecular-weight proteins such as beta 2-m, are increased in the early stage of Cd-induced renal tubular dysfunction. Although percent TRP was maintained by the decreased CCr, there was a marked decrease in percent TRP in subjects with progressive stage showing FE beta 2-m level above 10 percent. No sex difference in renal tubular dysfunction was found in this cross-sectional study.

Psychological study of cleft palate children with or without cleft lip by kinetic family drawing.

To clarify how cleft palate children with or without cleft lip perceive their family, we applied the Kinetic Family Drawing (KFD) technique to 60 cleft palate children (with or without cleft lip). The children were aged 7-9 years (in the 1-3 grade of elementary school) and attended the Department of Oral Surgery, Nagoya University Hospital, between 1990 and 1997. Controls consisted of 100 normal elementary school children of the same age. Major findings were: (1) Compared with normal children, cleft lip and palate boys and cleft palate only girls drew their self-images significantly more often in region D (lower right) and in region A (upper left), respectively. (2) Cleft palate children with or without cleft lip felt anxiety and fear toward their family, rarely viewing their homes as a restful place; this suggested insecurity. Uniquely dynamic relations were also suggested in their homes. (3) Cleft palate children with or without cleft lip often perceived their father or mother as persons easily acceptable in society. Rather remote psychological distance between parents and cleft palate children with or without cleft lip was suggested.

Spatial image of school environment in children with cleft lip and/or palate.

To evaluate the adaptability of children with cleft lip and/or palate to school, their mental images of the school environment were investigated in a semantic differential method survey using 23 pairs of adjectives. The following eight places on and off the school grounds were chosen as environmental factors; classroom, gymnasium, school nurse's office, teachers' office, playground, hallway, road leading to school and road leading back home. 50 children with cleft lip and/or palate (ages 10-11 years) were enrolled in this study. These children had a feeling of liberation in the teachers' office and school nurse's office. However, they did not have an established feeling of relaxation or affinity in the classroom, gymnasium, playground, hallway, or on the road to and from school, the very locales that were the main areas of their school activity. This suggested that self-expression and adaptation were difficult for these children.

Elemental concentrations in hair of inhabitants of a cadmium-polluted area.

To investigate the present situation of inhabitants living in the cadmium-polluted area of Toyama Prefecture, 95 hair samples were analyzed instrumentally by the neutron activation method. The concentrations were compared with nonpolluted samples. The concentrations of Cd, Cu, Zn, and Cu/Zn in hair were compared with those in some reported organs. The values of Cu/Zn were significantly lower (p less than 0.001) in hair of both female groups, but only somewhat lower (p less than 0.05) in hair of the male group. Causes of these facts are discussed. Results obtained from principal component analysis are also mentioned.

[Evaluation of qualitative and quantitative tests for proteinuria and glucosuria as screening tests for cadmium-induced renal tubular dysfunction].

To evaluate the screening tests for cadmium-induced renal tubular dysfunction, qualitative and quantitative tests for urinary protein and glucose have been done in 146 urine samples obtained from subjects who had lived in the cadmium-polluted Jinzu River basin in Toyama Prefecture, Japan. The subjects consisted of 66 men and 80 women aged 55 to 71 years with beta 2-microglobulinuria exceeding 1,000 micrograms/g creatinine. The results obtained from this study were as follows; 1) The positive reaction (above 1+) for protein by the dipstick method was seen in 19.7% of men and 20.0% of women, and for glucose using Tes-tape in 48.5% of men and 33.8% of women. 2) The geometric means of protein and glucose concentrations in urine were 16.4 mg/dl and 12.7 mg/dl in men, and 14.2 mg/dl and 6.8 mg/dl in women, respectively. 3) The criteria of the primary screening in the health survey system for the residents in cadmium-contaminated areas conducted by the Japan Environment Agency were a proteinuria level exceeding 10 mg/dl and a glucosuria above (+/-) with Tes-tape. Nearly all subjects with urinary beta 2-microglobulin exceeding 30 mg/g creatinine were screened by these criteria in both sexes, whereas only 52.9% of men and 30.0% of women who had urinary beta 2-microglobulin between 10 to 30 mg/g creatinine could be screened in this manner. These results indicate that semiquantitative tests are insufficient as initial tests for screening cadmium-induced renal tubular dysfunction.