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Chemicals/CAS: soybean oil, 8001-22-7; vinyl chloride, 75-01-4

Objective. To determine the prevalence of vitamin K deficiency bleeding in the Netherlands, in order to evaluate the efficacy of recommendations on vitamin K prophylaxis. Design. Descriptive. Setting. University Hospital Nijmegen, the Netherlands. Methods. Active surveillance of vitamin K deficiency bleeding (VKDB) by the Dutch Paediatric Surveillance Unit from October 1, 1992 to December 31, 1994. Results. Of the 19 reported cases 5 could be validated as late vitamin K deficiency bleeding: 2 idiopathic cases, and 3 secondary cases due to liver disorders. One case had intracranial bleeding and died. None of the cases had received exactly the recommended prophylaxis. The incidence of late VKDB was calculated to be 1.1/100,000 live births. Before vitamin K prophylaxis was recommended the incidence was estimated to be 7/100,000. Conclusion. The present Dutch recommendations for prevention of vitamin K deficiency bleeding - 1 mg vitamin K at birth and there after for breastfed infants daily 25 μg from 2 to 13 weeks - appear effective. Chemicals/CAS: Vitamin K, 12001-79-5

Chemicals/CAS: dapsone, 80-08-0

Chemicals/CAS: cysteine, 4371-52-2, 52-89-1, 52-90-4; mercaptamine, 156-57-0, 60-23-1; n (1 adamantylmethyl)thioglycolamidine, 60833-81-0

Chemicals/CAS: Folic Acid, 59-30-3

Contents of bile acids and lipids, as well as rates of triglyceride synthesis, were determined in isolated hepatocytes from control or cholestyramine-fed rats (denoted below as "control" or "treated" hepatocytes, respectively). During a 3-hr incubation period, total bile acid production was markedly higher in "treated" cells than in "conrol" cells. With both kinds of cells a marked fall in production rate occurred after the first hour of incubation. Newly produced bile acids appeared in the conjugated form with both kinds of hepatocytes. "Control" cells produced only taurine-conjugated, while "treated" cells made both taurine-conjugated and glycine-conjugated bile acids. However, with exogenous taurine (0.5 mM), the latter cells also produced taurine-conjugated bile acids only. With both kinds of cells, cholic and β-muricholic acids, but not dihydroxylated bile acids, appeared as newly formed species during the incubation. Addition of dialyzed rat serum to the incubation did not result in a stimulation of bile acid production, with either kind of hepatocytes. "Treated" cells had a slightly higher content of free cholesterol than control cells; contents of other lipids were not different. Fractional release of bile acids and lipids into the medium did not differ between the two kinds of cells. Triglyceride synthesis from added [14C]palmitate (0.5 mM) was 1.8-fold higher in "treated" than in "control" hepatocytes. Chemicals/CAS: colestyramine, 11041-12-6, 58391-37-0; lipid, 66455-18-3; Bile Acids and Salts; Cholestyramine, 11041-12-6; Lipids; Triglycerides

Chyme concentrations and total recoveries of furazolidone (5 mg/kg body-weight) were determined by a HPLC-method, after oral administration of two different furazolidone formulations to piglets (n = 6) and pre-ruminant calves (n = 8), provided with an ileal re-entrant canula. Additional blood samples were taken from the calves to measure the time dependent plasma levels of furazolidone. In the case of the normal crystalline preparation, the results indicate an almost complete absorption of the drug from the upper parts of the digestive tract. In both species, 96-99% of the dose had been absorbed by the time it reached the end of the ileum. The mean ileal recovery of the newly developed furazolidone formulation in calves and piglets was 14% and 38%, respectively. In calves the observed maximum plasma concentrations of furazolidone after oral application of the sustained release formulation were 14 times lower than with the normal crystalline preparation.

The hepatic angiosarcoma studied was from a male Wistar rat having been exposed to vinyl chloride monomer (VCM) by the oral route for 120 weeks. Widened sinusoids lined by large electron-lucent, spindle-shaped tumor cells and membrane-bound nuclear-free structures were seen in the transitional zone between the tumor mass and the adjacent liver tissue. In areas merely consisting of tumor tissue the tumor cells had a more angular or irregular shape. The origin of the tumor cells is discussed in light of the characteristic differences between endothelial cells and Kupffer cells described in the literature. Although an endothelial origin of the tumor cells could not be established unequivocally, it was concluded that at present there is little reason to doubt such an origin. Chemicals/CAS: vinyl chloride, 75-01-4; Vinyl Chloride, 75-01-4

The effects of the mycotoxin fumonisin B1 (FB1) on the hepatic cytochrome P450 system were investigated in male rats dosed daily by oral gavage with 3 mg FB1 per kg body weight for 9 consecutive days. FB1 treatment resulted in a reduced weight gain. At the same time, CYP2E activity was increased, which is considered to mark the metabolic changes inherent to growth retardation in young rats. Treatment with FB1 also resulted in a selective inhibition of CYP2C11 and to a lesser extent, CYP1A2 in liver microsomes obtained from treated animals, whereas it did not affect significantly the activity of CYP2A1/2A2, CYP2B1/2B2, CYP3A1/3A2 and CYP4A. The significant inhibition of CYP2C11 is considered to reflect a suppressed activity of protein kinase activity resulting from the inhibition of sphingolipid biosynthesis caused by FB1. Copyright (C) 2000 Elsevier Science B.V. Chemicals/CAS: cytochrome P450 3A, 329322-82-9; cytochrome P450, 9035-51-2; dimethylnitrosamine demethylase, 9075-31-4; fumonisin B1, 116355-83-0; pentoxyresorufin dealkylase, 96595-04-9; phenacetin o deethylase, 67724-61-2; protein kinase, 9026-43-1

Lactobacillus strains possess properties that make them attractive candidates as vehicles for oral administration of therapeutics. In this report we describe the construction and analysis of recombinant Lactobacillus casei applicable in oral vaccination against an infectious disease (tetanus) and in oral tolerance induction for intervention in an autoimmune disease, multiple sclerosis. Recombinant L. casei which express surface-anchored tetanus toxin fragment C (TTFC) were generated. Quantitative analysis by flow cytometry demonstrated a high level of cell wall-bound expression of TTFC and immunogenicity was demonstrated by parenteral immunization with whole cell extracts of the recombinants. A series of expression vectors was constructed to secrete human myelin basic protein (hMBP) or hMBP as a fusion protein with β-glucuronidase from Escherichia coli. These heterologous products produced by L. casei were detected in the growth medium and parenteral immunization with this medium evoked antibodies against hMBP, confirming that secretion indeed had occurred. Based on the different localization of the heterologous proteins, lactobacilli expressing surface-anchored TTFC are ideally suited for the induction of antibody responses, whereas lactobacilli that secrete myelin proteins can be used for the induction of peripheral T-cell tolerance. In conclusion, the specific technology described here allows the construction of a wide array of safe live recombinant lactobacilli which may prove to be useful in oral intervention strategies for the prevention of infectious diseases or treatment of autoimmune diseases.

To study the possible reduction by eugenol of the mutagenicity and genotoxicity of benzoja]pyrene (B[a]P) in vivo, the X-lacZ-transgenic mouse strain 40.6 (Muta(TM)Mouse) was used. Male mice were fed a diet containing 0.4% (w/w) eugenol or a control diet for 58 days. On day 10, half of the mice received an i.p. dose of 100 mg/kg b.w. B[a]P. The lacZ mutants were recovered by packaging of DNA isolated from liver into lambda phage, and expressed in E. coli C lacZ- recA-galE- bacteria. In both control mice and mice fed the eugenol diet, B[a]P treatment resulted in a similar, significant increase in lacZ mutant frequency. Eugenol was not mutagenic by itself By 32P-postlabelling analysis of the liver DNA using an analysis method with chromatographic conditions for B[a]P-DNA adducts, no effect of eugenol on the formation of B[a]P-DNA adducts in the λ-lacZ-transgenic mouse was found. By 32P-postlabelling analysis using an alkenylbenzene solvent system the amount of B[a]P-DNA adducts was lower in mice fed the eugenol diet than in mice fed the control diet but the decrease was not statistically significant. However, one spot indicative of an eugenol-associated DNA adduct was detected. The present data provide no evidence for antimutagenic or antigenotoxic potential of eugenol in vivo Furthermore, they suggest genotoxicity in vivo of eugenol per se.

There is accumulating evidence that oxidative modification of LDL is an important step in the process of atherogenesis and that antioxidants may protect LDL from oxidation. We and others have previously shown that ingestion of pharmacological doses of the antioxidant D,L-α-tocopherol (vitamin E), far above the recommended daily intake (ie, 12 to 15 IU/d for adults), increases the oxidation resistance of LDL. In this study, we ascertained the minimal supplementary dose of vitamin E necessary to protect LDL against oxidation in vitro. Twenty healthy volunteers (10 men and 10 women, aged 21 to 31 years) ingested consecutively 25, 50, 100, 200, 400, and 800 IU/d D,L-α-tocopherol acetate during six 2-week periods. No changes were observed in LDL triglyceride content, fatty acid composition of LDL, or LDL size during the intervention. Concentrations of α-tocopherol in plasma and LDL were both 1.2 times the baseline values after the first period (25 IU/d) and 2.6 and 2.2 times, respectively, after the last period (800 IU/d). There was a linear increase in LDL α-tocopherol levels up to an intake of 800 IU/d (r = .79, P < .0001) and a good correlation between α-tocopherol in plasma and LDL (r = .66, P < .0001). Simultaneously, the resistance of LDL to oxidation was elevated dose-dependently (+28% after the last period) and differed significantly from the baseline resistance time even after ingestion of only 25 IU/d. Correlation between α-tocopherol content of LDL and resistance time for all data was r = .57 (P <.0001), whereas the correlation between plasma α-tocopherol and resistance time was r = .69 (P < .0001). The rate of oxidation was decreased significantly at 400 and 800 IU/d (-13% and -17%, respectively). Baseline resistance time was not significantly different between men and women, but propagation rate was higher with LDL from men at baseline and after intake of 25 and 50 IU/d. Minor differences in LDL vitamin E levels and resistance time were found between men and women in response to vitamin E intake. Statistical evaluation of the relations between α-tocopherol content of LDL and resistance time in each of the 20 individual subjects showed strong and significant correlations for 14 individuals, indicating that vitamin E was the most important parameter that determined the oxidation resistance of LDL in these subjects. ANOVA indicated that LDL α-tocopherol content (47%) and interindividual variation (39%) were the most prominent parameters that contributed to the total variance in resistance time. Chemicals/CAS: alpha tocopherol, 1406-18-4, 1406-70-8, 52225-20-4, 58-95-7, 59-02-9; Ascorbic Acid, 50-81-7; Lipid Peroxides; Lipoproteins, LDL; Vitamin E, 1406-18-4

Plant sterols and their saturated derivatives, known as stanols, reduce serum cholesterol when consumed in amounts of approximately 2 g per day. Stanol fatty acid esters have been developed as a highly fat-soluble form that may lower cholesterol more effectively than stanols. Stanol esters occur naturally in human diets, but at levels far below those known to lower cholesterol. The present study was conducted to assess the safety of stanol esters upon subchronic ingestion at levels comparable to or exceeding those recommended for lowering cholesterol. Two stanol fatty acid ester preparations, wood-derived stanol esters and vegetable oil-derived stanol esters, were fed to groups of 20 male and 20 female Wistar rats for 13 weeks, at dietary concentrations of 0, 0.2, 1, and 5% total stanols (equivalent to 0, 0.34, 1.68, and 8.39% wood-derived stanol esters and 0, 0.36, 1.78, and 8.91% vegetable oil-derived stanol esters). Both preparations were well tolerated as evidenced by the absence of clinical changes or major abnormalities in growth, food and water consumption, ophthalmoscopic findings, routine hematological and clinical chemistry values, renal concentrating ability, composition of the urine, appearance of the feces, estrus cycle length, organ weights, gross necropsy findings, and histopathological findings. Plasma cholesterol and phospholipids were slightly decreased in males fed the stanol esters. In both sexes, plasma levels of plant sterols were decreased whereas those of stanols tended to increase. Fecal excretion of sterols, including cholesterol, and stanols was markedly increased in the stanol ester groups. Compared to controls, male rats fed stanol esters showed somewhat lower liver weights and more pronounced glycogen depletion. These hepatic changes were considered to reflect an altered nutritional condition and not a pathological condition. Plasma levels of vitamin E, vitamin K1, and, to a lesser extent, vitamin D were decreased in males and females fed the high-dose diets. Hepatic levels of vitamins E and D showed similar changes (vitamin K1 in the liver was not determined). For both preparations, the mid-dose level (1% total stanols in the diet) was a no-observed-adverse-effect level. This dietary level provided approximately 0.5 g total stanols/kg body wt/day.

The drug salbutamol (SBL) is a β-agonist that may be used illegally as an animal growth promoter. SBL is also a good example of a drug which is excreted in the form of glucuronides and sulfates. Such metabolites cause complexities in analysing for the presence of drug residues. In the majority of cases a process of deconjugation and sample clean-up is required prior to analysis. This is both time consuming and causes some loss of accuracy. In this study, the urine of calves treated with SBL orally for 3 d was collected during and after medication. Samples were assayed before and after hydrolysis by two different methods, radioimmunoassay (RIA) and a newly developed biosensor immunoassay (BIA). Some samples were also analysed by GC-MS. The results clearly showed that both screening assays (RIA and BIA) found high concentrations of SBL residues throughout the study. This was especially true in the BIA method. It was also demonstrated that urine sample analysis without the need for deconjugation or clean-up could be achieved. Results obtained by GC-MS tended to be an order of magnitude lower than the corresponding screening test results. This work showed that biosensor based veterinary drug residue testing procedures can be developed which can generate results in real time without the need for time consuming sample preparation.

Acrylonitrile is a monomer used extensively as a raw material in the manufacturing of acrylic fibers, plastics, synthetic rubbers, and acrylamide. It has been classified as a probable human carcinogen according to the results of numerous chronic rat bioassays. The present report summarizes the toxicity data on acrylonitrile and reviews available data concerning the mechanism (genetic versus epigenetic) by which acrylonitrile is carcinogenic in rats. From the evaluation of the relevant toxicity data, it can be concluded that acrylonitrile is indeed carcinogenic to rats after either oral or inhalational exposure. However, information on other mammalian species is lacking, and, moreover, the exact mechanism of the carcinogenic process is unclear. Therefore, it is recommended to conduct an additional long-term inhalation carcinogenicity study with acrylonitrile in mice, as well as studies into the mechanism by which acrylonitrile induces (brain) tumors in rats (genetic versus epigenetic). Chemicals/CAS: Acrylonitrile, 107-13-1; Carcinogens; Mutagens

An HPLC assay with tandem mass spectrometric detection in the positive-ion Turbo-Ion-Spray((TM)) (TISP) mode for the fast and sensitive determination of perifosine ((I), D-21266) in human plasma was developed, utilising the structural analogue, miltefosine ((II), D-18506), as internal standard. Automated solid-phase extraction of diluted plasma samples, based on 250-μl plasma aliquots, at pH 6.5, allowed a reliable quantification of perifosine down to 4 ng/ml. Injection of 200 μl of plasma extracts onto a 100x3 mm normal-phase analytical column at a flow-rate of 0.5 ml/min provided retention-times of 2.4 and 2.1 min for perifosine (I) and the internal standard (II), respectively. The standard curves were linear from 4 to 2000 ng/ml using weighted linear regression analysis (1/Y2). The inter-assay and intra-assay accuracies for the calibration standards were within +0.9% and -0.2%, exhibiting precisions (C.V.) of ±6.5 and ±7.3%, respectively. Up to 100 unknowns may be analysed each 24 h per analyst. Copyright (C) 1999 Elsevier Science B.V.

A study was executed to investigate the relation between the use of fluoride tablets by children in the age period 1.5-6 yr on the one hand and the caries experience at the age of 6 and 15 yr and the prevalence of fluorosis at the age of 15 yr on the other hand. The year of birth of the child, the motivation of the mother to engage in preventive dental behavior, the level of her school education and her place of birth were taken into account as possible confounding factors. A significant relation was found between the use of fluoride tablets and the prevalence of fluorosis. The most important predicting factor for the caries experience of the child was the mother's motivation to engage in preventive dental behavior. An effect of fluoride tablets on the caries experience could not be demonstrated. Chemicals/CAS: Sodium Fluoride, 7681-49-4

The oral toxicity of γ-cyclodextrin (γ- CD) was examined in a 13-week feeding study in which four groups of four male and four female Beagle dogs received γ-CD in the diet at concentrations of 0 (control), 5, 10, or 20%. No treatment-related changes were noted in behavior or appearance of the dogs and no mortalities occurred. Transient diarrhea occurred in some dogs of the 5 and 10% dose groups and in all dogs of the 20% dose group. However, all dogs remained in good health and gained weight. During the last 6 weeks of the study, the males of the 20% dose group gained less weight, but body weights were not significantly re duced in comparison to controls. Food intakes and food efficiencies were comparable among all groups. No treatment-related differences were observed with respect to ophthalmoscopic examinations, hematological parameters, clinicochemical analyses of the plasma, and semiquantitative urine analyses. Only the urinary pH was slightly below control levels in males of the 20% dose stoup. No abnormalities were seen at necropsy that could be attributed to treatment. The organ weight data revealed some cecal enlargement in the 10 and 20% dose groups. Relative ovary weights were significantly increased in the 10 and 20% groups but this was probably a result of an unusually low ovary weight in the controls. An increase of relative liver weights in males of the 10 and 20% dose groups also was considered to lack toxicological relevance because it was not associated with changes in plasma liver enzyme levels or histopathological changes. On microscopic examination, no treatment-related effects were observed in any of the various organs and tissues. In conclusion, transient diarrhea, cecal enlargement, and a slightly increased acidity of the urine were the only treatment-related effects reported. These changes are well-known physiological responses to the presence of increased amounts of undigested, fermentable carbohydrates in the lower got. At the high applied intakes an incomplete digestion of γ- CD and/or a partial inhibition of pancreatic amylase by γ-CD could account for these effects. It is concluded that daily γ-CD consumption of up to 20% in the diet (approximately 7.7 g/kg body wt in male and 8.3 g/kg body wt in female dogs) was tolerated without any toxic effects. Chemicals/CAS: Amylases, EC 3.2.1.-; Cyclodextrins; gamma-cyclodextrin, 17465-86-0; gamma-Cyclodextrins; Lactose, 63-42-3

The toxicity of γ-cyclodextrin (γ-CD), a cyclic polymer of eight α-1,4-linked glucopyranosyl units with potential applications as a food ingredient, was examined in a 2-week pilot study followed by a 13-week oral toxicity study in Wistar rats. In the 2-week study, the test substance was administered to groups of 5 male rats at dietary levels of 0, 5, 10, 15, and 20%. In the 13-week study, groups of 20 rats/sex received diets with 0, 1.5, 5, or 20% γ-CD. In each study, a comparison group receiving a diet with 20% lactose also was included. The 13-week study also included satellite groups of 10 rats/sex for the control and 20% γ-CD groups. These satellite groups were kept on a standard, cereal-based rodent diet for a 4-week recovery period after termination of the treatment period. Parameters measured during the two studies were clinical signs, body weights, food and water intake, clinicochemical parameters, organ weights, and gross observation at necropsy. In the 13-week study, ophthalmoscopic and hematological examinations, urine and feces analyses, and histopathological examination of standard organs and tissues were conducted. There were no treatment-related mortalities in either study. Soft stools and, in the 13-week study,infrequent occurrences of diarrhea were noted in the lactose group at the beginning of treatment. Among the γ-CD groups, soft stools occurred in only a few animals of the high-dose groups (≤10% γ-CD) during the first few days of treatment. Mean body weights tended to be slightly reduced in males of the 20% γ-CD and 20% lactose groups. However, food efficiency was not affected by treatment except in the 13-week study in males of the 20% γ-CD group during the first week of treatment. The hematological examinations and the semiquantitative urinalyses (conducted in the 13-week study) and the clinicochemical investigations (both studies) did not reveal any changes that could be attributed to γ-CD treatment. Except for a slight cecal enlargement, which is commonly observed in rodents upon ingestion of incompletely absorbed carbohydrates, organ weights did not exhibit relevant changes as a result of γ-CD treatment. On histopathological examination (13-week study), no treatment-related abnormalities were found. In conclusion, the ingestion of γ-CD for 13 weeks at dietary levels of up to 20% (corresponding to intakes of 11.4 and 12.7 g/kg body wt/day for male and female rats, respectively) was well tolerated and did not produce any signs of toxicity. Chemicals/CAS: Cyclodextrins; gamma-cyclodextrin, 17465-86-0; gamma-Cyclodextrins; Lactose, 63-42-3

The embryotoxicity/teratogenicity of γ-cyclodextrin (γ-CD) was examined in Wistar Crl:(WI)WU BR rats. γ-CD was fed at dietary concentrations of 0, 1.5, 5, 10, and 20% to groups of 25 pregnant female rats from day 0 to 21 of gestation. A comparison group received a diet with 20% lactose. The additions to the diet of γ-CD and lactose were made at the expense of pregelatinized potato starch. Body weight and food and water intake were recorded during the treatment period. The rats were killed on day 21 and examined for standard parameters of reproductive performance. The fetuses were examined for signs of toxic and teratogenic effects. Generally, γ-CD was well tolerated and no deaths occurred in any group. Weight gain and food consumption were similar in all groups during gestation, except for a slightly reduced food intake in the 20% γ-CD group from day 0 to 16. Water intake was similar in all γ-CD groups; in the lactose group, it was significantly higher than in the control group. Reproductive performance was not affected by the γ-CD treatment. Examination of the fetuses for external, visceral, and skeletal alterations did not reveal any fetotoxic, embryotoxic, or teratogenic effects of γ-CD. In conclusion, no adverse effects were observed at γ-CD intakes of up to about 20% of the diet (approximately 11 g/kg body wt/day). Chemicals/CAS: Cyclodextrins; gamma-cyclodextrin, 17465-86-0; gamma-Cyclodextrins; Teratogens