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Biomedical subjects

G Scherer

Publications and source records attributed to G Scherer.

At least 109 records · Page 6Linked to original sources
PubMed1990

No evidence for loss of alleles at 11p in HBV negative hepatocellular carcinomas.

The aim of the present study was to determine whether loss of DNA sequences at the chromosome arm 11p, where presumed tumor suppressor genes are located, might occur in hepatocellular carcinomas (HCCs) of hepatitis B virus (HBV) negative patients. Normal liver and HCC genotypes were compared at 6 loci on 11p with 7 polymorphic probes detecting 10 restriction length polymorphisms (RFLPs). Each of the 8 paired normal-tumor tissue samples was informative for at least three different loci on 11p13-pter. None of them showed loss of constitutional heterozygosity for those markers. The retainment of 11p alleles suggests that mechanisms other than loss of tumor suppressor genes on llp are involved in hepatocarcinogenesis of HBV negative patients.

Alleles↗
PubMed1990

A ZFY-negative 46,XX true hermaphrodite is positive for the Y pseudoautosomal boundary.

Two loci on the short arm of the human Y chromosome have recently been described as candidates for the testis determining factor (TDF); namely, ZFY, and a locus distal to ZFY, near the pseudoautosomal boundary. We have previously reported on seven 46,XX true hermaphrodites and one 45,X mixed gonadal dysgenesis case all presenting with testicular tissue in their gonads in the apparent absence of Y-specific DNA sequences. A reanalysis of these cases shows them all to lack ZFY, but one 46,XX true hermaphrodite carries sequences next to the Y pseudoautosomal boundary. This case provides further evidence for assigning the TDF locus very close to the pseudoautosomal region on Yp.

Base Sequence↗
PubMed1990

Importance of exposure to gaseous and particulate phase components of tobacco smoke in active and passive smokers.

The uptake of tobacco smoke constituents from gaseous and particulate phases of mainstream smoke (MS), inhaled by smokers, and of environmental tobacco smoke (ETS), breathed in by non-smokers, was investigated in two experimental studies. Tobacco smoke uptake was quantified by measuring carboxyhemoglobin (COHb), nicotine and cotinine in plasma and urine and the data obtained were correlated with urinary excretion of thioethers and of mutagenic activity. An increase in all biochemical parameters was observed in smokers inhaling the complete MS of 24 cigarettes during 8 h, whereas only an increase in COHb and, to a minor degree, in urinary thioethers was found after smoking the gas phase of MS under similar conditions. Exposure of non-smokers to the gaseous phase of ETS or to whole ETS at similar high concentrations for 8 h led to identical increases in COHb, plasma nicotine and cotinine as well as urinary excretion of nicotine and thioethers which were much lower than in smokers. Urinary mutagenicity was not found to be elevated under either ETS exposure condition. As shown by our results, the biomarkers most frequently used for uptake of tobacco smoke (nicotine and cotinine) indicate on the one hand the exposure to particulate phase constituents in smoking but on the other hand the exposure to gaseous phase constituents in passive smoking. Particle exposure during passive smoking seems to be low and a biomarker which indicates ETS particle exposure is as yet not available. These findings emphasize that risk extrapolations from active smoking to passive smoking which are based on cigarette equivalents or the use of one biomarker (e.g. cotinine) might be misleading.

Adult↗
PubMed1990

32P-postlabelling analysis of DNA adducts in monocytes of smokers and passive smokers.

In a controlled study, ten male volunteers were subjected to different smoking and passive smoking conditions. After 60 h of strictly controlled nonsmoking, five smokers were exposed to mainstream smoke only, while five nonsmokers were exposed to the gas phase of environmental tobacco smoke (ETS). In a second experiment smokers were mainstream and ETS exposed, while nonsmokers were exposed to complete ETS. Blood was drawn before and after smoking and DNA adducts were analysed from blood monocytes by the 32P-postlabelling assay, using the nuclease P1 enhancement method. We detected DNA adducts in monocytes of all probands. These adducts unrelated to smoking showed interindividual differences but only minor intraindividual changes in four samples of the same donor. After smoking interindividually variable additional adducts were visible in active smokers only. These smoking-related adducts had disappeared after 40 h of nonsmoking and reappeared again in three out of five smokers after the second smoking period. We conclude that smoking causes an interindividually variable pattern of DNA adducts in active smokers. These adducts disappear in less than 2 d, owing to the fast turnover of monocytes in the intravascular system. The effects described could not be observed in heavily exposed passive smokers.

Adult↗
PubMed1990

Significance of exposure to benzene and other toxic compounds through environmental tobacco smoke.

In order to assess the uptake of benzene from environmental tobacco smoke (ETS) and to estimate its contribution to the total body burden of benzene observed in non-smokers, two experimental studies have been conducted. Controlled exposure to high levels of ETS equivalent to 10 ppm CO for 9 h and 20 ppm for 8 h resulted in a nonsignificant increase in blood benzene levels and a significant increase in exhaled CO, COHb and cotinine in serum and urine. The slightly rising blood concentration of benzene following experimental ETS exposure was paralleled by an increased exhalation of benzene and aromatic hydrocarbons and in contrast to blood levels, this increase was significant. The blood levels of benzene obtained during exposure were comparable to those observed at the time of admission to the laboratory, when biomarkers of ETS uptake, e.g. cotinine in serum and urine, were at the limit of detection, thus demonstrating that these background levels were not from ETS exposure. No difference in the urinary excretion of phenol, the main metabolite of benzene, was found during the experimental periods. The background levels of urinary phenol in unexposed nonsmokers were rather high, demonstrating that phenol excreted in urine must be formed from several endogenous and exogenous precursors. In the light of our findings it is highly questionable whether exposure to benzene from ETS under real life conditions poses a cancerogenic risk to the general population, which is measurable today or in the future by toxicological or epidemiological methods.

Adult↗
PubMed1990

Smoking depresses adipose lipoprotein lipase response to oral glucose.

Adipose tissue lipoprotein lipase was studied in smokers (n = 17) aged 18-47 years and compared with enzyme activity in non-smokers of comparable age (n = 8) and a second time in some of the subjects 5-9 weeks after cessation of smoking (n = 7). Serum cotinine levels served to validate the smoking status of the subjects. Fasting enzyme activity was similar in smokers and non-smokers, when expressed per 10(6) cells, but was significantly increased when normalized for cell size. When lipoprotein lipase was determined in the same individual 4 h after an oral glucose load, a significant decrease (P less than 0.002) occurred in the smokers, while enzyme activity rose in the nonsmokers (P less than 0.02). A tendency for enzyme activity to rise after oral glucose was seen in ex-smokers, which did not reach statistical significance. Even though the mean serum insulin and glucose levels did not differ in the three groups of subjects, the per cent decrease in lipoprotein lipase after oral glucose in smokers was negatively correlated with insulin release into serum in the same subject, i.e., the greater the insulin release, the less the decrease in lipoprotein lipase activity. We would like to propose that the lower body weight in smokers is related to the paradoxical response of adipose tissue lipoprotein lipase to carbohydrate and that the reversal of this behaviour contributes to the weight gain often observed after cessation of smoking.

Adipose Tissue↗
PubMed1990

Dietary influences on urinary excretion of hydroxyphenanthrenes, thioethers and mutagenicity in man.

Our study indicates that large differences in dietary polycyclic aromatic hydrocarbon (PAH) content in humans are not reflected by urinary and faecal excretion of hydroxyphenanthrenes, although significant increases in 3-hydroxybenzo[a]pyrene and 3-hydroxychrysene in faeces were observed after consumption of a diet rich in PAHs. The question therefore arises whether urinary hydroxyphenanthrenes are a reliable marker for exposure to PAHs. As expected, the elevated mutagenicity of the diet rich in PAHs led to increased mutagenic activity in urine. The increased urinary excretion of thioethers after this diet was probably due to its higher thioether content. Therefore, an elevated thioether excretion does not always indicate exposure to electrophilic compounds.

Adult↗
PubMed1990

Identification of a locus which shows no genetic recombination with the autosomal dominant polycystic kidney disease gene on chromosome 16.

The major site for mutations leading to autosomal dominant polycystic kidney disease (ADPKD) is at the PKD1 locus, previously mapped to 16p13. Three additional probes have now been mapped within an existing array of genetic markers flanking this locus. One of these, CMM65b (D16S84), shows no recombination with PKD1 in 201 informative meioses. The others, Fr3-42 (D16S21) and EKMDA2 (D16S83), are shown to be the closest telomeric flanking markers. Somatic cell hybrids containing derivative chromosome 16s were used to construct a physical map of the region. Cosmid overlap cloning of the D16S84 region allowed a t(16;1) translocation breakpoint to be mapped at the molecular level, orientating the extended D16S84 locus with respect to the chromosome. The new markers and physical map described here provide an improved framework for attempts to clone the PKD1 region and to identify polycystic kidney disease mutations.

Animals↗
PubMed1989

Analysis of two 47,XXX males reveals X-Y interchange and maternal or paternal nondisjunction.

Two cases of 47,XXX males were studied, one of which has been published previously (Bigozzi et al. 1980). Analysis of X-linked restriction fragment length polymorphisms revealed that in this case, one X chromosome was of paternal and two were of maternal origin, whereas in the other case, two X chromosomes were of paternal and one of maternal origin. Southern blot analysis with Y-specific DNA probes demonstrated the presence of Y short arm sequences in both XXX males. In one case, the results obtained pointed to a paracentric inversion on Yp of the patient's father. In situ hybridization indicated that the Y-specific DNA sequences were localized on Xp22.3 in one of the three X chromosomes in both cases. The presence of Y DNA had no effect on random X inactivation. It is concluded that both XXX males originate from aberrant X-Y interchange during paternal meiosis, with coincident nondisjunction of the X chromosome during maternal meiosis in case 1, and during paternal meiosis II in case 2.

Adolescent↗
PubMed1989

Duplication of an Xp segment that includes the ZFX locus causes sex inversion in man.

Two 46,XY females with tandem duplications of an X short arm segment were studied by cytogenetic and Southern blot analysis. The results show that the duplicated segment in each case included the Xp21.2-Xp22.2 interval, resulting in a double dose of ZFX on the single active X chromosome. The results from our two cases, in conjunction with those reported by other workers, lead us to conclude that the duplication is the reason for the sex inversion. If ZFY and ZFX are indeed sex-determining gene loci, these findings favour a model of sex determination characterized by antagonistic interaction between these genes.

Chromosome Banding↗
PubMed1989

Localization of Y chromosome sequences and X chromosomal replication studies in XX males.

By in situ hybridization, Y-specific DNA sequences were localized on Xp22.3-Xpter of one of the two X chromosomes in all of eleven XX males studied. In nine of the cases the presence of the Y-specific DNA did not affect random X inactivation in fibroblasts. Fibroblasts of the other two cases showed a preferential inactivation of the Y DNA-carrying X chromosome. In only one of these two exceptions blood lymphocytes could also be studied, and here, random inactivation of the Y DNA-carrying X chromosome occurred. Furthermore, the gene dosage of steroid sulfatase (STS) was examined by Southern blot analysis. In ten of the cases including the one showing random X-inactivation in lymphocytes but not in fibroblasts, a double dosage of the STS gene is present. The remaining case with non-random inactivation shows a single STS gene dosage. This case was reported previously to have STS enzyme activity in the male range. It is assumed that, as a consequence DNA sequences may result in the preferential inactivation of the Y DNA-carrying X chromosome.

Arylsulfatases↗
PubMed1989

Gene mapping on mouse chromosome 8 by interspecific crosses: new data on a linkage group conserved on human chromosome 16q.

A large conserved linkage group exists on mouse chromosome 8 and human chromosome 16q, including the loci for chymotrypsinogen B (Ctrb), haptoglobin (Hp), lecithin:cholesterol acyltransferase (Lcat), metallothionein-1,-2 (Mt-1,-2), tyrosine aminotransferase (Tat), and uvomorulin (Um). Using cloned gene probes, these six loci were mapped in M. m. domesticus X M. spretus interspecific crosses relative to a number of chromosome 8 anchor loci resulting in the gene order Es-1,Es-9-Mt-1,-2-Got-2-Es-2,Es-7,Lcat,Um-Hp,Tat,Ctrb-e. These results complement earlier studies and redefine the conserved segment on mouse chromosome 8, previously defined by the Hp-Tat interval, by the 24-cM interval between Mt-1,-2 and the conserved locus for adenine phosphoribosyltransferase, Aprt, mapped at 25 cM from Es-1 by T. B. Nesterova, P. M. Borodin, S. M. Zakian, and O. L. Serov (1987, Biochem. Genet. 25: 563-568). Within this segment, the gene order appears the same in man and mouse. While map distances between HP-TAT,HP-CTRB, and TAT-CTRB of respectively 7, 11, and 9 cM have previously been measured in man, no crossovers between Hp, Tat, and Ctrb were observed in over 100 meioses in the mouse.

Animals↗
PubMed1989

Biomonitoring after controlled exposure to environmental tobacco smoke (ETS).

A rough estimation of the amounts of tobacco smoke components taken up by active and passive smoking suggests that, in the case of passive smoking, gas phase constituents in ETS are of greater relevance than particle-bound substances. Since this aspect is of importance for the risk evaluation of passive smoking, it was decided that it should be investigated further in a series of exposure studies with human volunteers. The ETS exposure conditions were characterized by measuring tobacco smoke components such as carbon monoxide (CO), nitrogen oxides (NOx), nicotine, formaldehyde, tobacco-specific nitrosamines (N-nitrosonornicotine (NNN), 4-methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), benzo(a)pyrene (BaP) and particulate matter in the air of the exposure room. The biomonitoring covered carboxyhemoglobin (COHb), thioethers and mutagenic activity in urine. These parameters were compared to those observed after controlled active smoking. It was found that urinary thioether excretion increased in non-smokers after extremely high ETS exposure. This effect could be attributed to gas phase ETS components. Urinary mutagenicity was not measurably increased in non-smokers under these conditions. This indicates that in passive smoking, as opposed to smoking, the gas phase might be more important in terms of possible effects than the particulate matter. It would, therefore, be misleading to make extrapolations based on the burden of smoking to establish the burden of passive smoking.

Adult↗
PubMed1989

Regional assignment of the human loci for uvomorulin (UVO) and chymotrypsinogen B (CTRB) with the help of two overlapping deletions on the long arm of chromosome 16.

Using cDNA probes for the human uvomorulin (UVO) and rat chymotrypsinogen B (CTRB) genes, we have analyzed two overlapping interstitial deletions on human chromosome 16q by Southern blot analysis. One deletion, with breakpoints at 16q22.1 and 16q22.3, results in loss of the UVO locus. The second deletion, whose breakpoints are at 16q22.1 and 16q23.2, leads to loss of the CTRB locus. Therefore, UVO resides between both proximal deletion breakpoints within band 16q22.1, whereas CTRB is located between both distal breakpoints at 16q22.3 and 16q23.2.

Blotting, Southern↗
PubMed1988

The human tyrosine aminotransferase gene: characterization of restriction fragment length polymorphisms and haplotype analysis in a family with tyrosinemia type II.

Deficiency in hepatic tyrosine aminotransferase (TAT) causes tyrosinemia type II, an autosomal recessively inherited disorder. Using a TAT cosmid clone, we have identified an MspI restriction fragment length polymorphism (RFLP) 5' to the TAT gene, with allele frequencies of 0.63 and 0.37. Analysis of the cloned maternal and paternal TAT alleles from a patient with tyrosinemia type II led to the identification of a HaeIII RFLP at the 3' end of the TAT gene, with allele frequencies of 0.94 and 0.06. The two RFLPs are 27 kb apart and in no allelic association. From haplotype frequencies, a polymorphism information content (PIC) value of 0.44 was obtained. The two RFLPs have allowed the unambiguous identification of the mutant TAT alleles in the patient's pedigree by haplotype analysis.

Amino Acid Metabolism, Inborn Errors↗