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A Risch

Publications and source records attributed to A Risch.

30 records · Page 2Linked to original sources
PubMed1998

Impact of adduct determination on the assessment of cancer susceptibility.

The characterization of genetic determinants for cancer susceptibility is important for understanding disease pathogenesis and for preventive measures. There is growing evidence that a group of predisposing polymorphic genes exists, such as those involved in carcinogen metabolism and repair, which may increase cancer in certain environmentally exposed subjects, even those exposed only to low levels of carcinogens. In developing preventive strategies, it is therefore necessary to identify these vulnerable members in our society, particularly those suffering from an unfortunate combination of high carcinogen exposure, cancer-predisposing genes and lack of protective (dietary) factors. Thus, molecular epidemiology faces the difficult task of analyzing carcinogen-exposed individuals for a combination of genotypes associated with cancer susceptibility. Once identified, combinations of cancer-predisposing genes can then be used as intermediate risk markers rather than taking cancer as an endpoint. In case-control studies, simultaneous measurements were carried out in each subject to determine exposure/early effect markers, e.g. polycyclic aromatic hydrocarbons (PAH)-DNA adducts, and susceptibility markers, e.g. genetic polymorphism, in drug-metabolizing enzymes related to cytochrome P450 1A1 (CYP1A1) and glutathione S-transferase (GSTM1) genes. The genotype dependence of human lung (+)-anti-benzo[a]pyrene diol-epoxide (BPDE)-DNA adducts in lung cancer patients was examined. BPDE-DNA adduct levels in bronchial tissue of smokers with high pulmonary CYP1A1 inducibility (by immunohistochemistry) and GSTM1 inactive were approximately 100-fold higher than in subjects with an active GSTM1 at similar smoking dose. Further genetic analyses confirmed that the combination of CYP1A1 homozygous mutants and GSTM1 inactive leads to high levels of BPDE-DNA adducts in human lung of smokers and white blood cells of PAH-exposed coke oven workers. Thus, BPDE-DNA adduct levels resulting from the "at risk" genotype combinations may serve as markers to identify high-risk subjects among smokers and individuals occupationally and/or environmentally exposed to PAH.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1998

[Remifentanil-propofol anesthesia in vertebral disc operations: a comparison with desflurane-N2O inhalation anesthesia. Effect on hemodynamics and recovery].

OBJECTIVE: To ascertain whether there is a difference between total intravenous anaesthesia with propofol (P) and remifentanil (R) and inhalational anaesthesia with desflurane (D) and nitrous oxide (N) with regard to haemodynamic reactions, recovery profile and postoperative analgesic demand in patients scheduled for elective microsurgical vertebral disc resection. METHODS: 50 patients (ASA I-II, 18-65 years) were randomly assigned to receive total intravenous anaesthesia with propofol and remifentanil or inhalational anaesthesia with desflurane and nitrous oxide. After standardised induction of anaesthesia in both groups (1 microgram.kg-1 remifentanil, 1.5 mg.kg-1 propofol 0.1 mg.kg-1 cisatracurium), anaesthesia was maintained in the D/N group with desflurane in 50% N2O. The patients of the P/R group received a constant infusion of 2 mg.kg-1.h-1 propofol and a constant infusion of 0.5 microgram.kg-1.min-1 remifentanil, which was reduced after 15 min by 50%. The administration of desflurane and the infusion of the anaesthetics were adjusted to maintain a surgical depth of anaesthesia. At the end of surgery the anaesthetics were discontinued and early emergence from anaesthesia was assessed by measuring time to spontaneous ventilation (VT > 4 ml/kg), tracheal extubation, opening of the eyes and stating correct name and data of birth. The frequency of analgesics and total demand for analgesics were determined using patient-controlled analgesia and recorded for 2 h postoperatively. In addition the pain level of the patients was measured on a visual analogue scale and the incidence of postoperative shivering, nausea and vomiting was noted. RESULTS: Patients anaesthetised with desflurane responded to tracheal intubation and skin incision with increasing blood pressure and showed higher heart rates than patients anaesthetised with propofol and remifentanil, but there were no other haemodynamic differences between the groups in response to surgical stimuli. There were significantly shorter times to spontaneous ventilation (3.2 vs. 6.3 min), extubation (3.8 vs. 9.5 min), eye opening (3.0 vs. 11.5 min) and giving name and date of birth (4.8 vs. 14.3 min) in patients anaesthetised with remifentanil and propofol than in those receiving desflurane and nitrous oxide. In addition, patients anaesthetised with remifentanil and propofol had a greater incidence of postoperative shivering. There were no significant differences between the two groups in the patients' pain scores, analgesic demand and incidence of nausea and vomiting. CONCLUSION: Patients anaesthetised with propofol and remifentanil have significantly shorter emergence times than patients anaesthetised with desflurane and nitrous oxide. The low incidence of postoperative pain after microsurgical vertebral disc resections requires no large-scale analgesic therapy, even after total intravenous anaesthesia including remifentanil.

Adult↗
PubMed1998

[Evaluation of lactate measurement in blood and plasma with biosensor technology: a comparison of methods].

UNLABELLED: The introduction of biosensor technology for near bedside measurement of plasma lactate concentrations has been a promising step for critical care profiling. However, methodological drawbacks and relevant inaccuracy have been reported. With the advent of a new biosensor (Chiron Diagnostics) and a revised NOVA Biomedical device, accuracy was expected to be improved. The goal of the present investigation was to evaluate the accuracy of both methods. METHODS: Two devices (System 860, Chiron Diagnostics; StatProfile 9, NOVA Biomedical) were simultaneously analysed using 9 biosensors in both fresh frozen plasma and citrated whole blood. The results were compared with an established photometric method (Lactat PAP, Analyticon). Measurements were performed as duplicates (n = 1120) before and after the addition of 1 molar sodium lactate solution (2-24 mmol/L). For the estimation of between-day precision commercially available aqueous and serum-based quality controls were analysed daily over a period of 60 days. RESULTS: Reproducibility in blood was 2.6 +/- 2.8% (Chiron), 4.1 +/- 4.0% (NOVA) and 1.5 +/- 2.1% (Analyticon), in plasma respectively 2.1 +/- 2.4%, 2.1 +/- 2.9% and 1.0 +/- 1.1%. Mean inaccuracy in plasma presented to be -0.2 +/- 16.4% (plasma) and +7.2 +/- 13.1% (blood) for Chiron, +9.4 +/- 18.4% and +18.7 +/- 16.7% for NOVA, and -37.8 +/- 18.2% and -27.5 +/- 17.6% for Analyticon. Calculated between-day-precision (variation coefficients mean values) was 11.5 +/- 4.9% (Chiron) and 14.0 +/- 5.9% (NOVA). CONCLUSION: Although accuracy of lactate concentrations obtained with biosensor technology has improved (mean 0-18%), the variability of the results still poses a problem (mean 13-18%). Therefore, from the methodological point of view, interpretation of a single lactate value requires caution when applying to the critically ill, particularly with view to threshold values, and should be considered vis-à-vis other options.

Biosensing Techniques↗
PubMed1997

[The "TAS-Analyzer"].

Explore the source record for details and available documents.

Evaluation Studies as Topic↗
PubMed1997

Mapping AAC1, AAC2 and AACP, the genes for arylamine N-acetyltransferases, carcinogen metabolising enzymes on human chromosome 8p22, a region frequently deleted in tumours.

Arylamine N-acetyltransferases (NATs) are encoded at two loci on 8p22, a region subject to deletions in bladder tumours. The two functional genes (AAC1 and AAC2 alias NAT1 and NAT2) without introns in the coding region, encode enzymes which metabolise carcinogens, including bladder carcinogens. They are both multi-allelic and certain alleles have been implicated as susceptibility factors in bladder cancer. There is a third N-acetyltransferase gene, a pseudogene, AACP alias NATP, which we show is also located on chromosome 8 at the p22 region. We have mapped a series of YAC clones (ICI and CEPH) containing the NAT genes and the markers D8S21, an RFLP marker, and D8S261, a microsatellite marker. We show that D8S21 is a portion of the coding region of AAC2. The order of genes in this region, covering some 2 Mb, is TEL-D8S261-AAC1-AACP-AAC2 (D8S21)-CEN. The restriction map also illustrates that there are likely to be other expressed genes in the region through the identification of CpG islands.

Arylamine N-Acetyltransferase↗
PubMed1996

Arylamine N-acetyltransferase in erythrocytes of cystic fibrosis patients.

Sulphamethoxazole, a substrate of human arylamine N-acetyltransferase, is used in the treatment of cystic fibrosis patients, who metabolise the drug rapidly. Increased metabolic clearance of sulphamethoxazole has been suggested to account for this rapid metabolism. Arylamine N-acetyltransferase type 1 is expressed in erythrocytes and leucocytes and the activity in erythrocytes is shown to contribute approximately 99% of the activity of arylamine N-acetyltransferase type 1 in blood cells. Arylamine N-acetyltransferase type 1 activity in erythrocytes from 16 adult cystic fibrosis patients and 19 age-matched controls were compared. Although there is a variation in erythrocyte arylamine N-acetyltransferase type 1 activity within each group, no difference was found when the two groups were compared. All individuals from the cystic fibrosis and control groups were investigated for certain allelic variants of the arylamine N-acetyltransferase type 1 gene (NAT1). Only one copy of a mutant NAT1 allele (NAT1*11) was found. The heterozygous NAT1 individual is a cystic fibrosis patient with a low level of erythrocyte arylamine N-acetyltransferase type 1 activity. A second distinct arylamine N-acetyltransferase isozyme, arylamine N-acetyltransferase type 2, is encoded at the multi-allelic NAT2 locus. There was no correlation between erythrocyte arylamine N-acetyltransferase-1 activity and NAT2 alleles present in either the cystic fibrosis or control groups. The distribution of NAT2 alleles was very similar in the two groups. The increased clearance of sulphamethoxazole in cystic fibrosis patients appears unlikely to be due to erythrocyte arylamine N-acetyltransferase type 1 activity or to inheritance of alleles at either the NAT1 or NAT2 loci.

Adolescent↗
PubMed1995

Xenogenetics in multifactorial disease susceptibility.

Susceptibility to multifactorial disease includes both genetic and environmental components. These two aspects of susceptibility are interlinked through genetic control of an individual's response to the environment. As a first step in identifying disease susceptibility genes that influence the response of an individual to foreign compounds (xenobiotics), it is necessary to study disorders in which there is an identified environmental trigger. Establishing a DNA resource from individuals with known environmental exposure ('a xenogenetic register') for diseases with an established environmental aetiology is an essential step in beginning to understand how environmental factors contribute to the susceptibility to polygenic diseases. A complementary approach to identification of environmental factors is suggested using a comparison of genetically homogeneous subdivisions of individuals with polygenic diseases where there is no clue to the environmental trigger.

Animals↗
PubMed1995

Slow N-acetylation genotype is a susceptibility factor in occupational and smoking related bladder cancer.

Bladder cancer is a common multifactorial disease and is known to be associated with occupational exposure to arylamines. Smoking is also a recognised contributory environmental cause. Occupational bladder cancer has previously been associated with slow acetylation by N-acetyltransferase (NAT) in humans in phenotyping studies, but more recently there has been some controversy regarding this issue. NAT is an enzymic activity involved in the metabolism of arylamines, and its 'classical' polymorphism is due to multiple alleles at the NAT2 locus. A genotyping approach has been used to investigate NAT2 type in a population of 189 Caucasian bladder cancer patients attending a clinic at a hospital in Birmingham. Genomic DNA was prepared from a blood sample donated by each of the patients and was used in the polymerase chain reaction with primers specific for all NAT2 alleles. Restriction fragment length polymorphism analysis was used to determine which alleles were present. Results have been compared to those from an age-matched non-malignant Caucasian control population (59 individuals) from the same region. Occupational and smoking history was determined by questionnaire and a significant excess of genotypic slow acetylators is found in those groups of bladder cancer patients exposed to arylamines as a result of their occupation or who are cigarette smokers. A higher proportion of slow acetylators is also found in those bladder cancer patients without identified exposure to arylamines when compared to the non-malignant controls. Slow NAT genotype is therefore a contributory risk factor in bladder carcinogenesis which acts through influencing individual response to environmental carcinogens.

Acetylation↗
PubMed1994

Chromosomal localization of human genes for arylamine N-acetyltransferase.

Arylamine N-acetyltransferase is encoded at two loci, AAC-1 and AAC-2, on human chromosome 8. The products of the two loci are able to catalyse N-acetylation of arylamine carcinogens, such as benzidine and other xenobiotics. AAC-2 is polymorphic and individuals carrying the slow-acetylator phenotype are more susceptible to benzidine-induced bladder cancer. We have identified yeast artificial chromosome clones encoding AAC-1 and AAC-2 and have used the cloned DNAs as fluorescent probes for in situ hybridization. The hybridization patterns allow assignment of AAC-1 and AAC-2 to chromosome 8p21.3-23.1, a region in which deletions have been associated with bladder cancer [Knowles, Shaw and Proctor (1993) Oncogene 8, 1357-1364].

Arylamine N-Acetyltransferase↗
PubMed1992

Genotyping human polymorphic arylamine N-acetyltransferase: identification of new slow allotypic variants.

Arylamine N-acetyltransferase catalyses the N-acetylation of primary arylamine and hydrazine drugs and chemicals. N-acetylation is subject to a polymorphism and humans can be categorized as either fast or slow acetylators according to their ability to N-acetylate polymorphic substrates in vivo. Previously, slow acetylation has been linked to four distinct polymorphic N-acetyltransferase (pnat) alleles each of which contains one or more point mutations within the coding region of the pnat gene. One new rare slow variant of pnat has been identified by cloning and sequencing the pnat DNA from an individual whose NAT phenotype was determined by in vivo acetylation of the polymorphic substrate sulphamethazine. This allele, designated S1c, differs from the wild type fast allele at nucleotide positions 341 and 803. A second new rare slow allotypic variant, designated S3, has been identified by resistance of the pnat specific DNA to digestion with the restriction enzymes Fok I and Bam HI. A method of genotyping individuals for the arylamine N-acetyltransferase (NAT) polymorphism is presented which correctly predicts the phenotype of greater than 95% (21 of 22) of individuals as measured by the extent of acetylation of sulphamethazine in urine. This refined genotyping method was applied to a clinical population of 48 Caucasians with classical or definite rheumatoid arthritis each receiving daily between 150 and 500 mg of the anti-rheumatic drug, D-penicillamine. There is no difference in the N-acetyltransferase phenotype of the individuals who developed proteinuria and the control group with no adverse effects.

Adult↗