Changes in blood and urinary cadmium levels and bone mineral density according to osteoporosis medication in individuals with an increased cadmium body burden.

The aim of this study was to assess changes in bone mineral density (BMD) and cadmium (Cd) levels in blood and urine in individuals living in a Cd-contaminated area according to the type of osteoporosis medication over a three-year period. This follow-up study included 204 residents living in the vicinity of a closed copper refinery, who had been found to have elevated urinary or blood Cd levels. Cd levels in the blood and urine, as well as BMD, were measured every 6 months. After the first BMD measurement, individuals were prescribed antiresorptives such as alendronate or vitamin D and calcium, according to their BMD. Subjects were classified according to the type of medicine provided over the previous 6 months. General linear models controlling for other factors were used to evaluate the effects of each type of medication on the participants' Cd levels and BMD. Spinal BMD showed a significant increase in the antiresorptive group compared to the nontreatment group. Significant decreases in blood Cd levels were found in the vitamin D and calcium group, in comparison to the nontreatment group, as well as a marginally significant decrease in the antiresorptive group. The vitamin D and calcium group showed a significantly greater decrease in urinary Cd levels than the nontreatment group. In contrast, antiresorptive medication was found to have a negative effect on urinary Cd excretion. These results suggest that vitamin D and calcium treatment for osteoporosis lowers blood Cd levels more effectively and improves urinary Cd excretion.

Arsenic exposure and seafood intake in Korean adults.

Arsenic (As) is widely distributed in the environment, and humans can be exposed to As from various sources such as air, water, soil, and food. This study was performed to evaluate the As exposure levels in Korean adults by measuring total As in urine and its relation with the consumption of seafood, a favorite food in Korea. A total of 2077 adults were the study subjects; they ranged in age from 19 to 83, and they were recruited by probability sampling stratified by area, sex, and age. None of the subjects had been exposed to As occupationally. We collected information about the demographic characteristics, lifestyles, and food consumption of study subjects using a questionnaire and followed urine sampling. Diet was assessed in individual interviews using the 24-h recall method. Total As in urine was analyzed using inductively coupled plasma mass spectrometry (PerkinElmer NEXION 300S; Concord, Ontario, Canada). The geometric mean concentration of total As in urine was observed to be 97.6 µg/L and was higher in males (103.9 µg/L) than in females (93.0 µg/L). Total As levels in urine were affected by sex, age, seafood intake, and geographic location. In this study, total As in urine was positively correlated with fish and shellfish consumption, and was mainly determined by As intake through fish and shellfish/grains/flavors. These findings suggest that seafood consumption might be a major contributor to urinary As levels in Korean adults.

Half-dose ganciclovir preemptive treatment of cytomegalovirus infection after pediatric allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Ganciclovir (GCV) has been widely used as preemptive therapy after hematopoietic stem cell transplantation (HSCT), although bone marrow suppression is a known accompaniment, with secondary infection or bleeding as potential complications. Our aim was to evaluate clinical outcomes in pediatric patients with low cytomegalovirus (CMV) antigenemia levels using half the dosage of GCV generally given preemptively. METHODS: Patients received half doses of intravenous GCV (5 mg/kg once daily, 6 days/week) at CMV antigenemia levels <10/200,000 cells. At higher levels of CMV antigenemia, conventional doses of GCV (5 mg/kg every 12 h) were administered. RESULTS: A total of 130 patients were evaluated, detecting CMV antigenemia in 87 (66.9%). Of these patients, 74 (85.1%) were treated preemptively with half-dose GCV, which proved effective as sole therapy in 51 (68.9%). CMV retinitis developed in 4 patients, 2 of whom initially were given half-dose GCV. All infections resolved successfully, with no CMV-related deaths. CMV seropositivity in recipients was the only significant risk factor for positive CMV antigenemia (hazard ratio [HR] = 10.05, P = 0.046). Compared with half-dose GCV administration, conventional GCV dosing resulted in a higher rate of severe neutropenia, defined as absolute neutrophil count <0.5 × 10(9) /L (HR = 4.30, P = 0.015). CONCLUSION: Half-dose GCV therapy at CMV antigenemia levels <10/200,000 cells is an effective and safe means of preemptively treating pediatric CMV infection after HSCT.

Estimated long-term dietary exposure to lead, cadmium, and mercury in young Korean children.

BACKGROUND: Controlling for day-to-day variation is a key issue in estimating long-term dietary exposure to heavy metals using 24-hour recall (24HR) data from a relatively small number of days. OBJECTIVES: This study was conducted to estimate long-term dietary exposure to lead, cadmium and mercury among Korean children using the Iowa State University (ISU) method and to assess the contributions of different food groups to heavy metal intake. METHODS: We analyzed 2 days of 24HR data from 457 children between 0 and 6 years of age in 2010. Using bootstrapped concentration data for 118 representative foods, 93.5% of total intake was included in the exposure estimates in this study. Using the 2-day exposure data, we estimated long-term exposure by controlling for within-individual variation using the ISU method. RESULTS: The long-term dietary exposure estimates (mean±standard deviation) for lead, cadmium, and mercury were 0.47±0.14, 0.38±0.20, and 0.22±0.08 µg/kg bw/day, respectively. For lead and cadmium, the percentages of children whose exposure was greater than the reference value were 35 and 42%, respectively. Fruits were an important source of lead exposure, and cereal and fish and shellfish made the greatest contributions to the total cadmium and mercury exposure. CONCLUSIONS: Our findings also suggest that the long-term exposure to lead and cadmium was somewhat greater than the reference values, whereas mercury exposure was well below than the reference value in this population. Further studies may be necessary to evaluate the food items contributing to heavy metal exposure, and continuous monitoring is needed to ensure the safety of food intake and dietary patterns among vulnerable groups in Korea.

Effect of lifestyles on the blood mercury level in Korean adults.

Mercury (Hg) is widely distributed in the environment and oral exposure is a main route in the general population. In this study, we estimated the dietary intake of Hg and its relationship with blood Hg levels in Korean adults. The study subjects were recruited from three different districts (rural: 189, coastal: 208 and urban: 184). We used a general questionnaire to collect information about demographic factors, lifestyles and diet. Dietary habits were studied using the 24-h recall method. The estimation of Hg intake was performed using the database of Hg contents in 128 Korean foods based on the previous studies. Blood Hg was analyzed using Direct Mercury Analyzer with the gold-amalgam method. Daily intake of Hg by diet was estimated at 13.57 µg (0.22 µg/kg body weight). The geometric mean Hg concentration in whole blood was 3.92 µg/L. Blood Hg level and Hg intake by diet was higher in coastal areas than in urban or rural areas, respectively. Blood Hg level correlated with the intake of Hg consumed from diet. Seafood was highly responsible and account for 75.6% of total dietary Hg intake. In this study, blood Hg concentrations were found to be significantly affected by sex, age, individual lifestyles and especially the amount of seafood intake, which might play an important role in determining blood Hg levels in Korean adults.

Effects of low-level arsenic exposure on urinary N-acetyl-ß-D-glucosaminidase activity.

This study was aimed to evaluate whether renal tubular function is impaired by exposure to relatively low concentrations of arsenic. Mean urinary arsenic concentrations and N-acetyl-ß-D-glucosaminidase (NAG) activities were compared among 365 and 502 Korean men and women, respectively, in relation to gender, smoking, alcohol consumption, and recent seafood consumption. The study subjects were divided into 4 groups according to urinary NAG activity and seafood consumption prior to urine sampling, and the correlation between arsenic concentration and urinary NAG activity was tested for each group. The mean urinary arsenic level was higher in women, non-smokers, and non-drinkers in comparison to men, smokers, and drinkers, respectively. Individuals who consumed seafood within 3 days prior to urine sampling showed a higher mean urinary arsenic level than those who did not. The correlation between urinary arsenic concentration and NAG activity in urine was significant only in subjects who did not consume seafood within 3 days prior to urine sampling and whose urinary NAG activity was 7.44 U/g creatinine (75th percentile) or higher. The urinary arsenic concentration was a significant determinant of urinary NAG activity in subjects with NAG activity higher than 7.44 U/g creatinine and especially in those who had not consumed seafood recently. These facts suggest that a relatively low-level exposure to inorganic arsenic produces renal tubular damage in humans.

Biochemical and conformational changes of myosin purified from Pacific sardine at various pHs.

Biochemical and conformational changes of purified sardine myosin were investigated at various pHs. The purity of myosin, as determined by SDS-PAGE, was approximately 94.6%. One major band at 205 kDa, corresponding to myosin heavy chain, and 3 light chains at 31, 24, and 23 kDa were observed on the SDS-PAGE gel. The greatest myosin protein solubility was observed at pH 7 and remained constant up to pH 11. Sardine myosin showed no solubility at pHs 2.5 to 5.0. Three endothermic peaks were obtained for samples prepared at pHs 7 and 10, while no peaks were shown for pH 2 samples, indicating chemical denaturation of myosin occurred before thermal treatment. The greatest Ca(2+)-ATPase activity was observed at pH 7, while no activity was observed between pHs 2 and 5 and at pH 11. Total sulfhydryl content was not measured at pHs 2.5 to 4 while the greatest measure was obtained for samples at pH 5.5. Surface hydrophobicity was not detected from pHs 2.5 to 5.0; thereafter the content remained consistent through pH 11. Storage modulus, indicating the elastic element of myosin gels, was minimally affected at pH 2, indicating myosin was chemically denatured before the temperature sweep treatment. However, at pH 10, the thermal exposure of myosin, as evidenced by dynamic thermograms with deeper valleys at 40 to 60 degrees C, was noted, indicating myosin was not damaged by adjustment to pH 10 and therefore was still able to undergo thermal gelation.

Strain differences in the toxicity of cadmium to trigeminal ganglia in mice.

Cadmium (Cd) is toxic to sensory ganglia in many animal species. Cadmium uptake is low in the central nervous system, but it distributes preferentially to peripheral sensory and autonomic ganglia. Strain differences have been demonstrated in the sensitivity of mice to Cd-induced hepatotoxicity, testicular toxicity, and teratogenicity. To study the sensitivity of different mouse strains to Cd toxicity in sensory ganglia, eight strains of mice (four sensitive to testicular toxicity: 129/SVIM, AKR/J, DBA/1J, and C57BR/J; and four resistant: Balb/C, C3H/HeJ, A/J, and C57BL/6J) were given 15 micromol CdCl(2)/kg iv. Trigeminal ganglia (TG) were harvested 24 h later and examined by light microscopy for pathologic lesions. Cadmium induced degeneration of ganglion cells in five strains, namely 129/SVIM, AKR/J, DBA/1J, C57BR/J, and C3H/HeJ mice. These are the same strains that show sensitivity to testicular toxicity, except for C3H/HeJ, which is resistant to testicular toxicity. Cd also induced focal hemorrhages around the ganglion cells and nerve fibers in two of these strains (129/SVIM and AKR/J) and scattered foci of necrosis in C3H/HeJ and 129/SVIM strains. There was no morphologic abnormality in three strains, namely Balb/C, A/J, and C57BL/6J. To examine the mechanism of these strain differences in toxicity, all eight strains of mice were given a nontoxic dose of Cd (0.4 micromol CdCl(2)/kg, 20 microCi (109)Cd/kg iv). Cadmium distribution to the brain and trigeminal ganglia was determined 30 min later by gamma scintillation spectrometry. Cadmium content in the brain was very low and did not differ among the eight strains. In contrast, Cd content was higher in trigeminal ganglia of four of the five strains showing trigeminal ganglia sensitivity than in the three strains showing resistance. In conclusion, the toxicity of Cd to trigeminal ganglia is different among various strains of mice. This strain difference in toxicity appears to be due, at least in part, to differences in the distribution of Cd to the ganglia, but it is clearly not the only factor.

Protective effect of metallothionein against the toxicity of cadmium and other metals(1).

Metallothionein (MT) is a small-molecular weight, cysteine-rich protein that binds metals. The protective role of MT in Cd toxicity is well established but its ability to protect against toxicity of other metals remains unclear. In this study, wild-type and MT-I and -II null mice (MT-null mice) were used to determine whether MT is protective against the lethality of not only Cd but also Zn, Cu, Fe, Pb, Hg and As. Following daily subcutaneous administration of an increasing dose of each metal, starting with a low, non-toxic dose, we compared the cumulative median lethal dose (LD(50)) of each metal between wild-type and MT-null mice. The LD(50) of Cd for wild-type mice was 6.9-fold higher than for MT-null mice. The LD(50) of Zn was 2.4-fold higher for wild-type mice than for MT-null mice, and 1.4-fold higher for Cu and As. The LD(50) of Hg was 1.3-fold higher for wild-type mice than for MT-null mice, but this was not statistically significant. No difference in LD(50) values was observed between wild-type and MT-null mice following Pb and Fe administration. These results suggest that MT is an important protein in the cellular defense against Cd toxicity and lethality, but it provides much less protection against the lethality of the other metals.

Nitric oxide is involved in the immunomodulating activities of acidic polysaccharide from Panax ginseng.

The effects of an acidic polysaccharide isolated from the ethanol-insoluble and water-soluble fraction of Panax ginseng C. A. Meyer on immunomodulating activities were investigated. A high output nitric oxide synthase (iNOS) was shown in female BALB/c mice administered intraperitoneally with the acidic polysaccharide from ginseng. Newly synthesized iNOS protein was also observed in peritoneal macrophages cultured with interferon-gamma and the acidic polysaccharide. Spleen cells from acidic polysaccharide-treated mice did not proliferate in response to concanavalin A, but restored the responsiveness by the cotreatment of NG-monomethyl-L-arginine (NMMA) with concanavalin A. The treatment of mice with aminoguanidine, a specific iNOS inhibitor, alleviated the acidic polysaccharide-induced suppression of antibody response to sheep red blood cells. Present results suggest that the immunomodulating activities of the acidic polysaccharide were mediated by the production of nitric oxide.

A new inhibitor design strategy for carboxypeptidase A as exemplified by N-(2-chloroethyl)-N-methylphenylalanine.

N-(2-Chloroethyl)-N-methylphenylalanine was designed and synthesized in an optically active form as a novel class of mechanism-based inactivator for carboxypeptidase A (CPA). It was anticipated that the chloroethylamino moiety of the CPA bound inhibitor undergoes an intramolecular SN2 reaction to generate a chemically reactive species (an aziridinium ion) which is expectedly subjected to a nucleophilic attack by the carboxylate of Glu-270, leading to covalent modification of the carboxylate. The irreversible nature of the inhibition of CPA by the inhibitor was supported by the kinetic data: the enzyme lost its enzymic activity in a time-dependent manner in the presence of the inhibitor and the inactivated CPA failed to regain the activity upon dialysis. Interestingly, the (R)-isomer that belongs to the D-series was more potent than its enantiomer.

Differential expression of protein kinase C subtypes during ginsenoside Rh2-lnduced apoptosis in SK-N-BE(2) and C6Bu-1 cells.

We examined the modulation of protein kinase C (PKC) subtypes during apoptosis induced by ginsenoside Rh2 (G-Rh2) in human neuroblastoma SK-N-BE(2) and rat glioma C6Bu-1 cells. Apoptosis induced by G-Rh2 in both cell lines was confirmed, as indicated by DNA fragmentation and in situ strand breaks, and characteristic morphological changes. During apoptosis induced by G-Rh2 in SK-N-BE(2) cells, PKC subtypes alpha, beta and gamma were progressively increased with prolonged treatment, whereas PKC delta increased transiently at 3 and 6 h and PKC epsilon was gradually down-regulated after 6 h following the treatment. On the other hand, PKC subtype zeta markedly increased at 24 h when maximal apoptosis was achieved. In C6Bu-1 cells, no significant changes in PKC subtypes alpha, gamma, delta, epsilon and zeta were observed during apoptosis induced by G-Rh2. These results suggest the evidence for a possible role of PKC subtype in apoptosis induced by G-Rh2 in SK-N-BE(2) cells but not in C6Bu-1 cells, and raise the possibility that G-Rh2 may induce apoptosis via different pathways interacting with or without PKC in different cell types.

Insecticidal and fumigant activities of Cinnamomum cassia bark-derived materials against Mechoris ursulus (Coleoptera: attelabidae).

The insecticidal and fumigant activities of Cinnamomum cassia (Blume) bark-derived materials against the oak nut weevil (Mechoris ursulus Roelofs) were examined using filter paper diffusion and fumigation methods and compared to those of the commercially available Cinnamomum bark-derived compounds (eugenol, salicylaldehyde, trans-cinnamic acid, and cinnamyl alcohol). The biologically active constituent of the Cinnamomum bark was characterized as trans-cinnamaldehyde by spectroscopic analysis. In a test with the filter paper diffusion method, trans-cinnamaldehyde showed 100 and 83.3% mortality at rates of 2.5 and 1.0 mg/filter paper, respectively. At 2.5 mg/paper, strong insecticidal activity was produced from eugenol (90.0% mortality) and salicylaldehyde (88. 9%), whereas trans-cinnamic acid revealed moderate activity (73.3%). At 5 mg/paper, weak insecticidal activity (50.0%) was produced from cinnamyl alcohol. In a fumigation test, the Cinnamomum bark-derived compounds were much more effective against M. ursulus larvae in closed cups than in open ones. These results indicate that the insecticidal activity of test compounds was attributable to fumigant action, although there is also significant contact toxicity. As a naturally occurring insect-control agent, the Cinnamomum bark-derived materials described could be useful as a new preventive agent against damage caused by M. ursulus.

Antifeeding activity of isoquinoline alkaloids identified in Coptis japonica roots against Hyphantria cunea (Lepidoptera: Arctiidae) and Agelastica coerulea (Coleoptera: Galerucinae).

The anti-feeding activity of 3 isoquinoline alkaloids identified from roots of Coptis japonica Makino toward 4th-instar larvae of Hyphantria cunea Drury and adults of Agelastica coerulea Baly was examined using the leaf-dipping bioassay. The biologically active constituents of the Coptis roots were characterized as the isoquinoline alkaloids berberine, palmatine and coptisine by spectroscopic analysis. In a test with H. cunea larvae, the anti-feeding activity was much more pronounced in an application of a mixture of palmatine iodide and berberine chloride (1:1, wt:wt) at 250 ppm (82.3%) and 500 ppm (100%), compared with palmatine iodide (76.0%) and berberine chloride (75.4%) alone at 500 ppm. These results indicate a synergistic effect. With A. courulea adults, berberine chloride showed 57.5 and 91.1% anti-feeding activity at 125 and 250 ppm, respectively; whereas, weak activity was obtained in application of 500 ppm of palmatine iodide (41.4%) and coptisine chloride (52.4%) alone. The Coptis root-derived compounds merit further study as potential insect-control agents.

Relationship between normal heart size and body indices in Korean.

We provided a curve-fit equation to predict the normal heart weight (g) in Koreans by examining 422 autopsies (215 males and 207 females, from newborn to age 77 yr) who were relatively in good general condition. Heart weight was well correlated with body surface area (m2), body weight (kg), and body height (cm) but poorly with age in both sex. Heart weight progressively increased from birth to the earlier 3rd and 4th decades in male and female, respectively, and then gradually decreased; mean heart weight of all age group was greater in male than in female and significantly different from birth to 4th decade. In both sex, heart weight exponentially increased in accordance with the increase of body height, body weight, and body surface (in male, heart weight=0.00312 x body height(2.239), r2=0.750, p<0.0001; in female, heart weight=0.00443 x body height(2170), r2=0.781, p<0.0001; in male, heart weight=9.22 x body weight(0.853), r2=0.770, p<0.0001; in female, heart weight=9.00 x body weight0.855, r2=0.820, p<0.0001; in male, heart weight=155.18 x body surface area1.290, r=0.808, p<0.0001; in female, heart weight=124.13 x body surface area1.242, r=0.834, p<0.0001). These results indicate that heart weight is better correlated with body surface area than with body weight; however, body weight should be a better determinant of a predicted heart weight, since body surface area is entirely dependent on body height and body weight.

Ginsenoside Rh2 induces apoptosis independently of Bcl-2, Bcl-xL, or Bax in C6Bu-1 cells.

In ginsenoside Rh2-treated rat glioma C6Bu-1 cells, apoptotic morphological changes, such as cell shrinkage, chromatin condensation and pyknosis were confirmed by means of electron microscopy. To evaluate whether induction of apoptosis by ginsenoside Rh2 is mediated by the members of Bcl-2 family, we first established C6Bu-1 cells overexpressing Bcl-2. It was demonstrated that the expression of Bcl-2, Bcl-xL and Bax was not altered in ginsenoside Rh2-treated C6Bu-1 cells. Bcl-2 overexpressing C6Bu-1 cells failed to prevent from ginsenoside Rh2-induced cell death. These results suggest the existence of other apoptotic pathway that requires induction of apoptosis by ginsenoside Rh2 rather than the pathway through Bcl-2, Bcl-xL or Bax in C6Bu-1 cells.

Co-administration of toluene and xylene antagonized the testicular toxicity but not the hematopoietic toxicity caused by ethylene glycol monoethyl ether in Sprague-Dawley rats.

Occupational painters are exposed to ethylene glycol monoethyl ether (EGEE), a widely used emulsifying solvent known to cause testicular degeneration and bone marrow depression, together with toluene (TOL) and xylene (XYL) as a mixture. In the previous study (Chung et al., Tox. Lett. 104:143, 1999), testicular atrophy caused by EGEE (200 mg/kg) was shown to be antagonized by co-administration of TOL (250 mg/kg) and XYL (500 mg/kg). This study was conducted to provide histological support for the previously observed antagonistic protective effect of TOL + XYL on EGEE inducible testicular toxicity and to determine whether a similar antagonistic effect can be demonstrated against the EGEE derived hematopoietic toxicity. Compared to the extent of seminiferous tubule degeneration caused by EGEE (150 mg/kg, six times per week for 4 weeks), testes of rats given co-administration of TOL (250 mg/kg) + XYL (500 mg/kg) showed dramatically reduced tubular degeneration. Hyperplasia of Leydig cells in the interstitium was observed in both EGEE and EGEE + TOL + XYL-treated rats. Although a minimal dose of EGEE causing testicular atrophy was used, WBC and platelet counts were decreased significantly. In the TOL + XYL-treated control group, the WBC and platelet counts were not decreased. However, the bone marrow depression caused by EGEE was not reversed by the combined administration of TOL + XYL. In all experimental groups (EGEE alone, TOL + XYL, EGEE + TOL + XYL), plasma levels of creatinine and alkaline phosphatase were significantly decreased. In addition to the marked testicular atrophy, EGEE also decreased the weights of adrenal glands and epididymis. In conclusion, while the testicular degeneration caused by EGEE was antagonized by TOL + XYL, the EGEE derived hematopoietic suppression was not reversed.

Acyl-CoA: cholesterol acyltransferase inhibitory activity of ginseng sapogenins, produced from the ginseng saponins.

Ginseng sapogenins were produced from ginseng saponins, isolated from Korean ginseng roots. Ginseng saponins very mildly inhibited acyl-CoA:cholesterol acyltransferase (ACAT) in vitro, however, the sapogenins showed strong inhibitory activity on microsomal ACAT. Therefore, the sapogenins will be one of key ingredients of ginseng affected a lowering of the serum total cholesterol level.

Platelet activating factor antagonist activity of ginsenosides.

Ginseng saponins and their degradation products have been screened for antagonist activity towards [3H]PAF (platelet activating factor) in washed rabbit platelet receptor binding studies. 20(S)- and delta20-ginsenosides Rg3, protopanaxadiol-type saponins, were found to be relatively potent PAF antagonists (IC50 = 4.9 x 10(-5) M and 9.2 x 10(-5) M, respectively).