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.

Development of the fluorometric ELISA method for determination of alpha1-microglobulinuria in a cadmium-polluted area in Japan.

OBJECTIVES: To evaluate the usefulness of a newly developed fluorometric enzyme-linked immunosorbent assay (fluorometric ELISA) method for quantification of alpha1 -microglobulin (alpha1-m, protein HC) in an epidemiological study. METHODS: Urinary alpha1-m in 37 female inhabitants in a cadmium-polluted area, including seven cases with Itai-itai disease, and ten inhabitants in a non-polluted area in Japan were examined. The alpha1-m was measured by both the fluorometric ELISA and a commercially available enzyme immunoassay (EIA) method to evaluate correlation of the two measurements. Concentration of beta2-microglobulin (beta2-m) was also determined in the same samples. RESULTS: The detection limit of this method was 3 ng/ml or less of alpha1-m. A significant, high positive correlation was obtained between the alpha1-m concentrations measured with the fluorometric ELISA and that of EIA (r = 0.95, P < 0.0001). A significant association was also shown between the alpha1-m and beta2-m concentrations in the urine samples. The concentrations of urinary alphal-m of the inhabitants in the cadmium-polluted area (mean: 6.21 mg/l, 95% confidence interval (95% CI): 4.06-9.50 mg/l) were significantly higher than those of the reference area (mean: 2.19 mg/l, 95% CI: 1.90-2.67 mg/l). The urinary alpha1-m level of the Itai-itai patients was shown to be highest at 39.63 mg/l (95% CI: 28.27 55.55 mg/l). When the cut-off value of 10 mg/l was employed, alpha1-m had a sensitivity of 100% and specificity of 100% for Itai-itai disease. CONCLUSION: These results suggest that this fluorometric ELISA is a useful tool to determine urinary alpha1-m in the epidemiological survey of renal tubular dysfunction, especially in the cadmium-polluted area of Japan.

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.

Renal tubular dysfunction in male inhabitants of a cadmium-polluted area in Toyama, Japan--an eleven-year follow-up study.

An eleven-year follow-up study was carried out to elucidate the changes in the level of environmental exposure to cadmium (Cd) from rice after soil replacement of polluted paddy fields and these effects on urinary excretion of Cd in male inhabitants of a Cd-polluted area in Toyama, Japan. In addition, the prevalence of renal tubular dysfunction (RTD) was examined to clarify the progress of Cd-induced RTD. One hundred and twenty-seven male inhabitants born between 1914 and 1929 in 11 districts of the Cd-polluted Jinzu River basin and 31 reference subjects in 2 adjacent districts were examined twice in 1985-86 and 1996-97. The geometric means of Cd concentrations in polished rice (Cd-R) in the Cd-polluted areas were 0.18 ppm in 1985 and 0.21 ppm in 1986; these values were significantly higher than those of the reference areas (0.13 ppm in 1985 and 0.12 ppm in 1986). After 11 years, the Cd-R levels were significantly decreased to approximately half (0.08 ppm in 1996, 0.12 ppm in 1997) due to soil replacement of polluted paddy fields, which has been carried out since 1980. The mean Cd levels in urine (Cd-U) were significantly reduced from 7.9 and 9.5 microg/g creatinine in the initial study to 6.9 and 6.8 microg/g creatinine in the follow-up study. However, the prevalence of RTD, which was determined by urinary beta2-microglobulin exceeding 1 mg/g creatinine and urinary glucose exceeding 150 mg/g creatinine, increased from 18 and 23% in the 1985-86 study to 25 and 32% in the 1996-97 study, and a total of 12 new cases (12%) of RTD were found. Whereas, only one subject (4%) in the reference control areas was identified as RTD. Cd-induced RTD was prevalent, progressive and irreversible for male inhabitants of the Cd-polluted Jinzu River basin, although the environmental exposure to Cd through rice was significantly reduced by soil replacement of polluted paddy fields.

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.

Apoptosis induced by cadmium in human lymphoma U937 cells through Ca2+-calpain and caspase-mitochondria- dependent pathways.

Apoptosis induced by cadmium has been shown in many tissues in vivo and in cultured cells in vitro. However, its molecular mechanism is not fully understood. When the human histiocytic lymphoma cell line U937 was treated with cadmium for 12 h, evidence of apoptotic features, including change in nuclear morphology, DNA fragmentation, formation of DNA ladder in agarose gel electrophoresis, and phosphatidylserine externalization, were obtained. Moreover, loss of the mitochondrial membrane potential (Deltapsi(m)) was observed in the cadmium-treated cells and was inhibited by a broad caspase inhibitor (Z-VAD-FMK). Caspase inhibitors suppressed the DNA fragmentation in the order of Z-VAD-FMK > caspase-8 inhibitor > caspase-3 inhibitor. Expression of Bcl-x(L) and Bid decreased significantly in the cadmium-treated cells, although no apparent change in Bcl-2 and Bax expression was found. Tetrakis-(2-pyridylmethyl) ethylendiamine, a cell-permeable heavy metal chelator, partially reversed the increase of fluorescence of Fura-2 in the cadmium-treated cells. In addition, verapamil (70 microm), a voltage-dependent Ca(2+) channel blocker, inhibited the DNA fragmentation induced by cadmium less than 100 microm and decreased the fluorescence of Fura-2. Cadmium up-regulated the expression of type 1 inositol 1,4,5-trisphosphate receptor (IP(3)R) but not type 2 or type 3 IP(3)R. Calpain inhibitors I and II partially prevented DNA fragmentation. No effects of Z-VAD-FMK on the expression of type 1 IP(3)R or of calpain inhibitors on the loss of Deltapsi(m) were observed. These results suggest that cadmium possibly induced apoptosis in U937 cells through two independent pathways, the Ca(2+)-calpain-dependent pathway and the caspase-mitochondria-dependent pathway.

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.

[A follow-up study on renal tubular dysfunction in women living in the cadmium-polluted Jinzu River basin in Toyama, Japan. Part 1. Changes in the level of exposure to cadmium after soil replacement of polluted paddy fields and the related effects on the prognosis of renal tubular dysfunction].

A follow-up study on renal tubular dysfunction was carried out on 193 female inhabitants of the cadmium (Cd)-polluted Jinzu River basin and 40 reference subjects living in an adjacent area in 1994-95. They were 54 to 70 years old when the initial examination was conducted in 1983-84. In the Cd-polluted Jinzu River basin, extensive reclamation of polluted rice fields has been conducted since 1979; as a result, the average Cd concentrations in polished rice consumed by the subjects in the 1994-95 study (0.12 ppm in 1994, 0.14 ppm in 1995) were significantly lower than those in the 1983-84 study (0.26 ppm in 1983, 0.29 ppm in 1984). The average Cd levels in urine in the follow-up study (7.5 micrograms/g Cr. in 1994, 7.7 micrograms/g Cr. in 1995) were also significantly lower than those in the initial study (13.5 micrograms/g Cr. in 1983, 13.3 micrograms/g Cr. in 1984). However, the mean values for urinary excretion of beta 2-microglobulin (beta 2-m) (3.9 mg/g Cr. in 1994, 3.7 mg/g Cr. in 1995) and glucose (203 mg/g Cr. in 1994, 251 mg/g Cr. in 1995) in the follow-up study were significantly higher than those obtained at the initial examination (2.0 mg/g Cr. and 125 mg/g Cr. in 1983 and 1.1 mg/g Cr. and 78 mg/g Cr. in 1984 for beta 2-m and glucose excretion, respectively). The magnitude of increase in urinary excretion of beta 2-m and glucose in inhabitants of the Cd-polluted area was significantly higher than that of the inhabitants of the reference area. Moreover, an increase was observed in the prevalence of renal tubular dysfunction determined by urinary beta 2-m exceeding 10 mg/g creatinine and urinary glucose exceeding 150 mg/g creatinine only among inhabitants of the Cd-polluted area; it is noteworthy that 31 new cases of renal tubular dysfunction were observed in the follow-up study. These results indicate that renal tubular dysfunction among inhabitants of the Cd-polluted Jinzu River basin is irreversible and progressive, and many new cases of renal tubular dysfunction were also noted over a period of 11 years, despite the fact that Cd exposure had decreased over the past 11 years.

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.

[Relationships between atmospheric Sugi (Japanese cedar)-pollen counts and indices of climatic conditions].

Atmospheric pollen surveys have been conducted using Durham's standard sampler for 12 years in Toyama Prefecture. The relationships between Sugi (Japanese cedar, Cryptomeria japonica D. Don) pollen and some indices of climatic conditions were analyzed. The results were as follows: 1. Total pollen counts showed a tendency to increase for 12 years, although the variation of the count was relatively large. 2. Significant correlations were found between pollen counts and some indices of the climatic conditions in July of the previous year, such as duration of sunshine, mean daily temperature and daily maximum, as well as minimum temperature. 3. Significant correlation was found between pollen count and duration of sunshine in January and March, and the amount of snowfall in March of the observed year using multiple regression analysis. Pollen counts were shown to be relatively high in years with short sunshine in January and long sunshine and heavy snow in March.

Occupational allergy to adult chironomid midges among environmental researchers.

A case of occupational allergy to chironomid midges in research work is described. A researcher was exposed to adult chironomid midges during his research and developed allergic rhinitis after 10 years of such exposure. Using the midge extract of adult Chironomus plumosus (CP) (Linnaeus, 1758), both immediate skin test and the ophthalmic challenge test gave positive results. IgE antibody against adult CP was also demonstrated by the radioallergosorbent test. Four of the five serum samples of the environmental researcher examined showed a positive radioallergosorbent test to at least one of the adult midges breeding around eutrophic Japanese lakes. Enzyme-linked immunosorbent assay inhibition test and immunoblot experiments indicated that the remaining hemoglobin is one of the major allergens of adult CP. These results demonstrate that the exposure to adult chironomid midges is an important occupational hazard among environmental researchers.

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.

Hypoproduction of erythropoietin contributes to anemia in chronic cadmium intoxication: clinical study on Itai-itai disease in Japan.

Itai-itai disease is a condition caused by long-term exposure of the inhabitants of Toyama prefecture, Japan, to cadmium intoxication. The characteristic clinical features of this disease include renal tubular dysfunction, osteomalacia, and anemia. In order to clarify the pathogenesis of the anemia, the red blood cell count, hemoglobin concentration, hematocrit, serum iron level, total iron-binding capacity, serum ferritin level, serum erythropoietin level, creatinine clearance, fractional excretion of beta 2-microglobulin, and bone marrow morphology were determined in ten patients with Itai-itai disease. Low serum iron or ferritin levels were not observed, and bone marrow aspiration did not reveal any specific hematological disorders. A close relationship was observed between the decrease in the hemoglobin level and the progression of renal dysfunction. Low serum erythropoietin levels were detected despite the presence of severe anemia. These results suggest an important role of renal damage in the anemia which develops in Itai-itai disease.

Cadmium induces interleukin-8 production in human peripheral blood mononuclear cells with the concomitant generation of superoxide radicals.

Acute or chronic exposure to cadmium (Cd) causes severe organ damages with the infiltration of leukocytes, neutrophils in particular occurring in the acute phase. Interleukin-8 (IL-8), a novel neutrophil chemotactic and activating cytokine, is produced by various types of cells in response to a wide variety of inflammatory stimuli. The administration of an antibody against IL-8 has been shown to inhibit neutrophil infiltration in several animal models, indicating a causal relationship between IL-8 and neutrophil infiltration. Hence, in this study we investigated whether Cd induced IL-8 production in human peripheral blood mononuclear cells (PBMC). Cd, over a wide range of concentrations, did induce human PBMC to produce large amounts of bioactive IL-8, the maximal induction being observed at 10(-4) M. The production was inhibited specifically by a metal chelating agent, ethylenediaminetetraacetic acid (EDTA). Steady level of IL-8 mRNA increased within 30 min after the addition of Cd and reached a maximal level at 2 h, decreasing thereafter. A protein synthesis inhibitor, cycloheximide, failed to inhibit IL-8 mRNA accumulation, indicating that new protein synthesis was not required for IL-8 mRNA induction. Concomitantly with the induction of IL-8, within 10 min Cd generated reactive oxygen intermediates (ROI) in human PBMC. A radical scavenger, N-acetyl-L-cysteine (NAC), inhibited both IL-8 production and the generation of ROI, implying the possible involvement of ROI in IL-8 production. This notion was also supported by our findings that a superoxide generating agent, paraquat, induced IL-8 production in human PBMC and that NAC blocked this paraquat-induced IL-8 production.

[Abnormalities of calcium, phosphorous and vitamin D metabolism with proximal renal tubular dysfunction in subjects environmentally exposed to cadmium].

Calcium, phosphorus and vitamin D metabolism were examined in 21 male and 13 female subjects with renal tubular dysfunction in the cadmium-polluted Jinzu River basin in Toyama prefecture, Japan. Multiple proximal renal tubular dysfunction was detected in all subjects showing increased FE beta 2-m and FFua, generalized aminoaciduria and renal glucosuria. Reduced ability of tubular reabsorption of phosphate resulted in hypophosphatemia in 31% of the women. Despite decreased tubular reabsorption of calcium, the level of serum calcium remained normal in all subjects. Serum 1,25-dihydroxyvitamin-D [1,25(OH)2D], which is produced in the proximal tubules through 1 alpha-hydroxylation from 25-hydroxyvitamin-D [25OHD], was normal or increased to more than 60pg/ml. The serum level of 1,25(OH)2D was inversely related to creatinine clearance in both the men (p < 0.05) and women (p < 0.01). Serum iPTH was slightly increased to more than 0.9 mg/ml, whereas the levels of other hormones, including 25OHD, calcitonin, thyroxine (T4) and triiodothyronine (T3) were normal. The serum alkaline phosphatase activity and serum osteocalcin concentration were significantly increased compared to those of controls in both sexes. Bone loss detected by the measurement of bone density was prominent in female subjects. These results support the hypothesis that the serum phosphate concentration is more important than the serum concentration of 1,25(OH)2D for abnormalities of bone metabolism in cadmium-induced renal tubular dysfunction.

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.

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.