Pharmacokinetics of lithium in brain regions and plasma.
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Biomedical subjects
Publications and source records attributed to H Jung.
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The study was undertaken to establish the clinical and immunological aspects of HBV-mediated membranous glomerulonephritis in children. Out of 54 children with membranous GN treated in the Children's Memorial Hospital 51 children (94.4%) had the disease related to HBV infection. The inhibitory effect of immune complexes: HBsAg-IgG and HBeAg-IgG, isolated from sera of these children on lymphocyte proliferation of blood donors was observed. This may partly explain the status of immune tolerance towards HBV in the infected children.
Chronic thermotolerance was induced in Chinese hamster ovary (CHO) cells by pretreatment at 40 degrees C for various times ranging from 15 min to 16 h. The thermotolerant cells were either exposed to single heat treatments at 43 degrees C or subjected to step-down heating consisting of a priming treatment at 43 degrees C for 90 min followed immediately by a graded test treatment at 40 degrees C. Data evaluation using a mathematical model published previously (H. Jung, Radiat. Res. 106, 56-72, 1986) showed that the rate constants p for the production of nonlethal lesions at 43 and 40 degrees C decreased by a factor of 20 with the duration of the thermotolerance-inducing pretreatment at 40 degrees C and approached exponentially (half-time 1.24 +/- 0.11 h) a minimum value. By contrast, the rate constants c for the conversion of nonlethal lesions into lethal events were not altered by the induction of thermotolerance; this applied to both c (43 degrees C) and c (40 degrees C). After transferring thermotolerant cells (pretreatment at 40 degrees C for 3 h) to 37 degrees C, the rate constants p increased exponentially with time (doubling time 25 +/- 5 h). Similar kinetics for the development and decay of chronic thermotolerance was shown to be applicable also to extended heating at 40 degrees C and to various data from the literature.
Fractionated split-course treatments were given with gaps of different length and the effects on tumor response was studied using the rhabdomyosarcoma R1H of the rat. Total doses of 68, 75 and 82 Gy were applied in 30 fractions (five fractions per week). After four weeks, that is after 20 fractions, treatment was interrupted for one or two weeks followed by another ten fractions. The results were compared to those of continuous treatment given in six consecutive weeks. Tumor response was quantified by TCD37% and net growth delay. The TCD37% increased with increasing duration of the gap. A mean repopulated dose of 0.72 Gy per day was obtained. This corresponds to a doubling time of tumor clonogens of 4.2 days during the gap, which is somewhat slower than the volume doubling time of unperturbed tumors (2.5 days) of the same size. The results obtained for the net growth delay support the results of the TCD37% data. It is concluded that a gap during fractionated radiotherapy leads to poorer results since the dose required for tumor control is enhanced and sparing of normal tissue can only be expected for early but not for late reacting tissues.
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Growth of Escherichia coli 044 K 74 in liquid medium of raised osmotic strength was stimulated by exogenous L-carnitine, crotonobetaine and gamma-butyrobetaine, respectively. L-Carnitine was accumulated within the cells in dependence on the salt concentration of the media. Osmotic stress during aerobic or anaerobic growth with glucose triggered the L-carnitine uptake in E. coli 044 K 74 whereas L-carnitine uptake by cells of this organism grown anaerobically on glycerol/fumarate was only slightly modified. Synthesis of the enzymes metabolizing L-carnitine to gamma-butyrobetaine in glycerol/fumarate growing bacteria was found to be completely repressed by high NaCl-concentrations. Together, these results indicate that most likely the L-carnitine metabolization sequence does not play a role in osmoregulation in E. coli 044 K 74.
The uptake of L-carnitine by Escherichia coli 044 K74 which is able to metabolize L-carnitine to gamma-butyrobetaine under anaerobic conditions was studied. The uptake system of E. coli was induced in the presence of L-carnitine or crotonobetaine. The optimum influx of L-carnitine was found to take place at 37 degrees C in phosphate buffer, pH 7.5. On the basis of the temperature dependence of the uptake rate an activation energy of 53.5 kJ/mol was estimated. The transport of L-carnitine was energy dependent. The kinetics of L-carnitine entry followed the Michaelis-Menten relationship yielding a Km value of 5.3 x 10(-4) M and a Vmax of 154 nmol/min.mg protein. The transport system showed considerable structural specificity for trimethylamine carboxylic molecules. The results suggest that E. coli possesses an inducible, active and carrier-mediated uptake system for L-carnitine.
Therapy of neurocysticercosis with cysticidal drugs is frequently complicated by the exacerbation of symptoms that follows the inflammation triggered by the acute destruction of cysticerci. Treatment of such adverse reactions with dexamethasone is highly effective. However, it has been shown that dexamethasone lowers the plasma levels of praziquantel, thus reducing its cysticidal efficacy. We measured plasma levels of albendazole, another strong cysticidal drug, when dexamethasone was given simultaneously. We found that dexamethasone increased the plasma levels of albendazole by about 50% (P less than 0.002); hence, it seems that cysticercosis and the ensuing inflammation can be treated simultaneously with albendazole and dexamethasone without diminishing the efficacy of the cysticidal drug.
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The kinetics of depopulation and repopulation of the solid transplantable rhabdomyosarcoma R1H of the rat following local irradiation with single subcurative X-ray doses of 7.5, 15 and 30 Gy was studied. Several parameters were sequentially measured over a time interval of 4 weeks after irradiation: the ratio of the number of tumour to host cells, and the cellular DNA content of tumour and host cells, were determined by flow cytometry; the amount of DNA per gram of tumour tissue was determined biochemically; the clonogenic fraction of tumour cells was obtained from in vitro colony assay; and the tumour volume was assessed by in situ caliper measurements. From the amount of DNA per gram and the average DNA content per cell, the total number of cells per gram of tumour tissue was obtained. From this and the other parameters measured, the number of clonogenic tumour cells, non-clonogenic tumour cells and nucleated host cells per tumour, as well as their variation with time and dose, could be derived. The results showed that there was a lag period prior to depopulation amounting to 3.8 +/- 1.4, 1.4 +/- 0.8 or 0 +/- 0.7 days for 7.5, 15 or 30 Gy, respectively. The rate of depopulation of non-clonogenic tumour cells increased with dose; the halving times of non-clonogens were 4.7 +/- 1.8, 2.6 +/- 0.7 or 2.1 +/- 0.4 days for the three doses applied. There were no indications that proliferation of doomed cells contributed significantly to tumour growth after irradiation. After lag periods that were similar in length to those prior to depopulation, a massive immigration of host cells was observed. Under certain conditions more than 97 per cent of the cells present in irradiated tumours were found to be of host origin. There was a lag period before the onset of repopulation by clonogenic tumour cells, the length of which increased from 2.7 +/- 0.7 to 5.0 +/- 0.8 or 6.3 +/- 1.0 days for 7.5, 15 or 30 Gy, respectively. The initial rate of repopulation increased with radiation dose; after the end of the lag period the doubling time of clonogenic tumour cells (in controls amounting to 3.7 +/- 0.2 days) was 3.1 +/- 0.1, 2.1 +/- 0.1 and 1.1 +/- 0.1 days for the three doses applied.(ABSTRACT TRUNCATED AT 400 WORDS)
Albendazole or praziquantel were measured in plasma and cerebrospinal fluid (CSF) in 29 patients with neurocysticercosis. Mean levels of albendazole in plasma were 0.918 microgram/ml and in CSF were 0.392 microgram/ml and levels of praziquantel were 1.640 micrograms/ml in plasma and 0.398 microgram/ml in CSF, after doses of 15 and 50 mg/kg, respectively. Drug concentrations in CSF were 43% for albendazole and 24% for praziquantel. The drug levels obtained for both drugs showed ample individual variations that were not related to age, sex, presence of inflammation in the subarachnoid space, or therapeutic effectiveness; such variations seem to be due to individual differences in pharmacokinetics. Both drugs were effective and the doses currently used of each drug seem to be optimal for therapy of neurocysticercosis.
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The N-oxidation of carcinogenic arylamines to form N-hydroxy arylamines has long been regarded as a necessary metabolic step for conversion to proximate carcinogenic derivatives. In contrast, arylamine ring-oxidation has been generally considered to be an important detoxification mechanism. Both enzymatic reactions are carried out in the liver and usually involve the cytochrome P-450 monooxygenases. Studies on the metabolic oxidation of certain arylamines have indicated that the relative charge density on nitrogen versus ring-carbon atoms for a nitrenium/carbenium ion-enzyme intermediate correlates with the relative proportion of N-versus ring-hydroxylated products that are formed. A further examination of this approach now shows that positive charge density on the nitrogen, as estimated by Hückel molecular orbital calculations, is consistent with the formation of N-hydroxy arylamines from aniline, 4-aminoazobenzene, 2-naphthylamine, 4-aminobiphenyl, 2-aminofluorene, and 6-aminochrysene, but not from 1-naphthylamine, 1-aminopyrene, 6-aminobenzo[a]pyrene, or 7-aminobenz[a]anthracene. Since greater positive charge on the arylamine nitrogen implies a greater charge localization during the transition state of the enzyme-substrate complex, we envisioned that higher oxidation potentials for arylamines, which might be expected to correlate inversely with the ease of total oxidation, would instead be predictive of the relative extent of N-oxidation.(ABSTRACT TRUNCATED AT 250 WORDS)
The effect of the activated c-Ha-ras oncogene on invasiveness and formation of spontaneous metastases was studied using the rhabdomyosarcoma R1H of the rat. R1H tumor cells which are able to grow in vitro and produce tumors upon subcutaneous injection in syngeneic WAG/Rij rats were transfected with the c-Ha-ras (EJ) oncogene and the neomycin gene for selection. Two R1H cell lines harboring and expressing the human c-Ha-ras oncogene, one cell line containing the neomycin gene only, and the parent R1H cell line were compared. The expression of the transfected c-Ha-ras oncogene was assessed by Northern blot analysis and by flow cytometry using antibodies against ras p21. No difference in tumor growth rate and morphology was observed for the transfected and untransfected cell lines. Tumor volume doubling time was about 2 days in R1H-ras as well as in R1H parent tumors. Formation of spontaneous metastases was tested by excising the tumors when they had reached a volume of 2 cm3; after that the animals were observed up to 12 months. The excised tumors still contained and expressed the transfected ras oncogene as proved by Southern blot analysis and antibody staining using anti-ras p21. In contrast to most previous work on ras-transfected tumorigenic cells the R1H-ras tumors did not acquire invasive growth potential or increased metastatic capacity.
Traffic accident occurrence in Switzerland has undergone a positive development, in spite of the fact that the number of motor vehicles in use and the overall driving performance have increased. The main features of accident occurrence are illustrated, alcohol and driving too fast being the most frequent accident causes. The construction of a motorway network, the use of safety-belts and the introduction of general speed limits play the most important part in the positive development of accident occurrence.
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Carnitine dehydratase from Escherichia coli 044 K74 is an inducible enzyme detectable in cells grown anaerobically in the presence of L(-)-carnitine or crotonobetaine. It has been purified 500-fold to electrophoretic homogeneity by chromatography on phenyl-Sepharose, hydroxyapatite, DEAE-Sepharose, second phenyl-Sepharose and finally gel filtration on a Sephadex G-100 column. During the purification procedure a low-molecular-weight effector essential for enzyme activity was separated from the enzyme. The addition of this still unknown effector caused reactivation of the apoenzyme. The relative molecular mass of the apoenzyme has been estimated to be 85,000. It seems to be composed of two identical subunits with a relative molecular mass of 45,000. The purified and reactivated enzyme has been further characterized with respect to pH and temperature optimum (7.8 and 37-42 degrees C), equilibrium constant (Keq = 1.5 +/- 0.2) and substrate specifity. The enzyme is inhibited by thiol reagents. The Km value for crotonobetaine is 1.2.10(-2) M. gamma-Butyrobetaine, D(+)-carnitine and choline are competitive inhibitors of crotonobetaine hydration.