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- Segerbäck, Dan, 1950-
(författare)
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In vivo dosimetry of some alkylating agents as a basis for risk estimation
- 1985
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The present study concerns in vivo dosimetry of ultimate electrophilic reagents as a step in risk estimation of mutagenic and carcinogenic chemicals. The level of reaction products with nucleophilic groups in macromolecules could be used for dose determination. Hemoglobin adducts were studied in mice and rats with regard to suitability for dose monitoring using radiolabelled chemicals (methyl methanesulfonate, dimethylnitrosamine, ethylene oxide, ethene, methyl bromide, 2,2-dichlorovinyl dimethyl phosphate, N-methyl-N-nitrosourea and N-(2-hydroxyethyl)-N-nitrosourea). The adducts formed were shown to be eliminated with a rate corresponding to the life-span of the erythrocytes. This stability makes it possible to use the accumulated degree of alkylation of hemoglobin as a measure of dose at chronic exposure. The predominant reactive nucleophilic groups in hemoglobin were found to be cysteine, N-terminal valine, histidine and carboxylic groups. Each alkylating agent gave a characteristic pattern of products. This pattern may in principle be used for identification of exposure to unknown chemicals. The dose in the erythrocytes, calculated from the degree of hemoglobin alkylation, was compared with the dose in different organs, calculated from the degree of alkylation of guanine-N^-7 in DNA. For small, uncharged compounds, soluble in both water and lipids, the dose was approximately the same in the erythrocytes as in other organs. Hemoglobin dosimetry could therefore be used for estimation of doses to DNA in other organs for such compounds. Other compounds give, for different reasons, an uneven dose distribution that has to be determined in experimental animals when using hemoglobin dosimetry in man for risk estimation. Risk coefficients for alkylating agents expressed in relation to the effect of gamma radiation have been determined (by others) in several test systems. On the basis of these coefficients and of dose determinations in mice attempts at risk estimation were performed for ethene and dichlorvos.
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- Hed, Helen M. E., 1955-
(författare)
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Opportunity for natural selection in Sweden : a study of childhood mortality and differential reproductivity
- 1986
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Opportunity for natural selection in human populations has so far mainly been studied on anthropological data for tribal populations or on census data for nations. The present study is mainly based on data on individual lifehistories but also, for part of the longitudinal study, on census data. Six of the populations, Nedertorneå, Tuna, Svinnegarn, Trosa, Locknevi and Fleninge are parishes. These sets of data covers the period 1800-1850 as defined by the birthyears of the women. The data for the longitudinal study are derived from two sources, a biography over all clergymen in the diocese of Linköping, covering the period 1600-1845, and material published by the National Swedish Central Bureau of Statistics (SCB) that covers the period 1750-1980. For each subpopulation data on childhood mortality and female fertility has been collected and from these data Crow's index of opportunity for natural selection has been calculated. The original index has also been modified in order to estimate the importance of childlessness in relation to the total index.The study shows that for the periods and the populations studied, there is a considerable opportunity for natural selection both through mortality and through differential fertility and that, during our century, differential fertility has become the main asset for natural selection, as mortality has been reduced to very low levels. It is also obvious that childlessness is an important factor as regards natural selection in human populations. The cross-sectional study shows significant differences between the populations for all components of the index. The longitudinal study covers when, the two sets of data are combined, a period of over 350 years, 1600-1980. Over this period changes in index of opportunity for natural selection have occured but these changes are not very drastic as compared to other longitudinal studies. However, within a separate region there can be drastic changes in index between decades and there are large differences between regions.Mortality and fertility patterns have been studied from different angles. With the exception for the census data, each woman in the study has be followed from 16 to 40 years of age and each of her children (if any) has be followed from birth to 16 years of age or death, if prior. Therefore it was possible to obtain distributions for age at first childbirth, sibship size, succesful sibship size, childhood mortality by age at death, female mortality, and childlessness, total and marital. In some cases a study of sex ratio at birth and at 16 years of age, and birth intervals, have been made. Statistical analysis of the results shows significant differences between populations for all tests that have been applied. The Linköping data was analysed for differences between periods. Significant differences were found for all of the parameters with the exception of female mortality.
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- Jakobsson, A H, et al.
(författare)
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Chromatin bodies in multidrug resistant hybrid cells have centromeres and originate from homogeneously staining regions.
- 1989
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Ingår i: Anticancer research. - 0250-7005. ; 9:2, s. 267-71
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Tidskriftsartikel (refereegranskat)abstract
- Antikinetochore antibodies from patients with the CREST syndrome of scleroderma were used as probes to study homogeneously staining regions (HSRs) in multidrug resistant (MDR) mouse tumor cells, and chromatin bodies (CBs) in MDR mouse-hamster hybrid cells. In one mouse tumor line the C-band positive HSR showed antigenic properties and displayed many weekly fluorescent spots, i.e. it contained kinetochore proteins. The immunofluorescence pattern of the HSR could also be observed in interphase nuclei. The C-band positive CBs of the hybrid cells had active centromeres, as shown by double kinetochore spots. These results support our hypothesis that CBs originate from C-band positive HSRs.
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- Levan, G, et al.
(författare)
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Selective gene amplification in mammalian cells
- 1984
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Ingår i: Hereditas. - : Wiley-Blackwell Publishing, Inc.. - 0018-0661. ; , s. 278-
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Konferensbidrag (refereegranskat)abstract
- Selective gene amplification in mammalian cells is now recognized as a common cellular response to selection in a number of different toxic drugs, such as methotrexate (MTX). coformycin, PALA, hydroxyurea (HU), vincristine (VCR). colcemid (COL) and actinomycin D (AMD). Recently, we have studied SEWA murine tumor cells in culture exhibiting the pleiotropic drug resistance (PDR) phenotype. Cells subjected to stepwise selection in AMD, VCR or COL all develop double minute chromosomes (DM), which are a cytogenetic expression of gene amplification. These lines overproduce a 21 K acidic soluble protein and show a high degree of cross resistance, which is typical for the PDR phenotype. Other workers have shown that cells with this phenotype exhibit a shift in membrane-bound glycoproteins from 90- 100 K to 150-170 K. Thus, it is likely that several genes are involved in the development of the PDR phenotype. We have isolated a fraction highly enriched in DM from an AMD-resistant SEWA subline. DNA was extracted from this fraction, and several DM-specific DNA-probes were developed. These probes were used to study independently derived SEWA sublines resistant to AMD, VCR, COL, MTX and HU. The results showed that the investigated amplified DNA-segments in AMD-, VCR-. and COL-resistant lines exhibited a high degree of sequence sequence homology, indicating that basically the same segment was amplified in the 3 inductions. In contrast. the amplified DNA-segments in MTX- and HU-resistant lines that do not show the PDR phenotype, displayed no sequence homology to the probes used.
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