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Biomedical subjects

M Heim

Publications and source records attributed to M Heim.

At least 127 records · Page 7Linked to original sources
PubMed1991

Genetic analysis of the interethnic difference between Chinese and Caucasians in the polymorphic metabolism of debrisoquine and codeine.

The Far Eastern and Caucasian populations are strikingly different with respect to the debrisoquine/sparteine hydroxylation polymorphism. The number of poor metabolizers, as defined for Caucasians, is very low among Chinese and Japanese. We investigated the molecular basis for this difference by analysis of the CYP2D6 gene in 115 Chinese subjects, combined with phenotypic classification of codeine and debrisoquine metabolism. A correlation between the rates of metabolism of these two drugs and genotype, as analyzed by RFLP using XbaI, was observed among the Chinese. A high frequency (37%) of alleles indicative of gene insertions (reflected by XbaI 44kb fragments) was recorded in the Chinese, but was not associated with the poor metabolizer phenotype, as it is in Caucasians. PCR amplification of part of the CYP2D6 gene with mutation specific primers for CYP2D6A (29A) and CYP2D6B (29B) allelic variants revealed that the XbaI 44kb fragment in Chinese apparently contains a functional CYP2D6 gene, in contrast to the situation among Caucasians. The results provide a molecular explanation of the interethnic difference in the metabolism of drugs affected by the debrisoquine hydroxylation polymorphism.

Adolescent↗
PubMed1991

Debrisoquine/sparteine hydroxylation genotype and phenotype: analysis of common mutations and alleles of CYP2D6 in a European population.

Four different mutations of the cytochrome P450 CYP2D6 gene associated with the poor metabolizer phenotype (PM) of the debrisoquine/sparteine polymorphism were analyzed by Xba I restriction fragment length polymorphism (RFLP) analysis and a polymerase chain reaction (PCR)-based DNA amplification method in DNA of 394 healthy European subjects; 341 of these were phenotyped by sparteine or debrisoquine administration and urinary metabolic ratios (MR). Our study demonstrates the efficiency of the PCR-test for phenotype prediction; 96.4% of individuals were correctly predicted, i.e., 100% of the extensive metabolizers (EMs) and 86.0% of the poor metabolizers (PMs). In contrast, Xba I RFLP analysis was far less informative, predicting the phenotype in only 26.8% of PMs. By combining both DNA tests, the prediction rate of the PM phenotype increased to 90.6%. A point mutation at a splice-site consensus sequence termed D6-B represented the most common mutant CYP2D6 gene and accounted for more than 75% of mutant alleles. In addition, other known mutations such as D6-D (14%), D6-A (5%), and the rare D6-C mutation bring the identified mutant alleles to greater than 95% of all mutant PM-alleles. Most of Xba I 44-kb alleles were confirmed as mutant alleles carrying the D6-B mutation. However, 9.7% did not have this mutation and may express a functional CYP2D6 gene. Moreover, all Xba I 16 + 9-kb alleles contained the D6-B mutation. Heterozygous EM individuals had a significantly higher MR when compared to homozygous EMs. Genotyping provides an important advantage for investigations of the influence of CYP2D6 activity on drug therapy and its association with certain diseases.

Alleles↗
PubMed1991

A pilot study to investigate whether sport influences psychological parameters in the personality of asthmatic children.

Sixteen asthmatic children were interviewed about the influence of sport activity upon their psychological character. Fourteen additional children with asthma of the same severity who did not take part in any sport served as the control group. The results of this study show that asthmatic children practicing sport have a better self image than the control group, are less anxious and cope better with the disease. They also showed better interfamily relationships. The conclusions of this pilot study indicate that asthmatic children should be encouraged to participate in sport activities, which seem to assist in their general well being.

Adolescent↗
PubMed1991

Pigmented villonodular synovitis.

Pigmented villonodular synovitis (PVS) is an uncommon, usually monoarticular disorder encountered mainly in adults. A boy and a girl, both 7 years old, were referred because of recurrent knee effusions. Both were medically treated for other rheumatic disorders for five years. PVS was diagnosed by arthroscopy and synovectomy was curative in both cases.

Arthroscopy↗
PubMed1991

Immune functions during treatment of growth hormone-deficient children with biosynthetic human growth hormone.

Immune functions, including cell surface markers, interleukin-2 receptor levels and responses of lymphocytes to mitogenic stimulation were evaluated in seven growth hormone deficient children ages 4-15 years, during treatment with biosynthetically derived human growth hormone. Treatment resulted in a decrease in % B cells and in % T total cells and also decreases in most individual patients' mitogen responses and interleukin-2 receptor levels. Most of the changes noted were transient and similar to those previously demonstrated during pituitary-derived human growth hormone treatment. Although not resulting in overt clinical manifestations in our patients, we think that potential interactions between growth hormone and immune functions need to be considered by physicians treating children with growth hormone.

Adolescent↗
PubMed1991

Cyclic-alternating versus response-oriented chemotherapy in small-cell lung cancer: a German multicenter randomized trial of 321 patients.

To test whether alternating chemotherapy is a favorable treatment modality in small-cell lung cancer (SCLC), 334 patients were randomized to receive either fixed cyclic-alternating treatment with ifosfamide/etoposide (IE), cyclophosphamide, doxorubicin, and vincristine (CAV), or response-oriented treatment with IE therapy up to maximal response and subsequently an immediate switch to CAV. In both arms, six cycles were given in 3-week intervals. After chemotherapy, patients with limited-stage disease received chest irradiation with 45 Gy. Prophylactic cranial irradiation with 30 Gy was applied to all complete responders. No maintenance therapy was given to patients with complete response. Minimum follow-up was 2 years. Of 321 assessable patients, the overall response rate was 70% for cyclic alternating and 77% for response-oriented treatment. Complete remission (CR) rates were 26% versus 26%. The median survival times were 9.7 months for cyclic-alternating versus 10.7 months for response-oriented treatment; the 2-year survival rates were 11% versus 9%. In limited-stage disease (LD) patients, there was a median survival of 12.5 months versus 12.3 months and a 2-year survival rate of 21% versus 18%. In extensive-stage disease (ED) patients, median survival was 8.5 versus 9.1 months, and the 2-year survival rate 3% versus 4%. From these results, we conclude that the cyclic-alternating treatment according to the hypothesis of Goldie et al has no advantage in comparison to a sequential treatment strategy with an immediate switch to a second-line protocol at the time no further response to first-line therapy is seen. Our major aim in the treatment of SCLC is to administer an active regimen at any time during the course of treatment regardless of whether sequential or alternating therapy is used.

Adult↗
PubMed1990

Donor leukocyte transfusions for treatment of recurrent chronic myelogenous leukemia in marrow transplant patients.

Three patients with hematologic relapse after bone marrow transplantation for chronic myelogenous leukemia were treated with interferon alpha and transfusion of viable donor buffy coat. All had complete hematologic and cytogenetic remission, which persisted 32 to 91 weeks after treatment. In two patients graft-versus-host disease developed and was treated by immunosuppression. These results are an example of adoptive immunotherapy without cytoreductive chemotherapy or radiotherapy in human chimeras.

Adult↗
PubMed1990

Multiple mutations of the human cytochrome P450IID6 gene (CYP2D6) in poor metabolizers of debrisoquine. Study of the functional significance of individual mutations by expression of chimeric genes.

The debrisoquine/sparteine-type polymorphism is a clinically important inherited variation of drug metabolism characterized by two phenotypes, the extensive metabolizer and the poor metabolizer (PM). Five to 10 percent of individuals in Caucasian populations are of the PM phenotype and have deficient metabolism of debrisoquine and over 25 other drugs. Our previous studies have revealed absence of cytochrome P450IID6 protein and aberrant splicing of IID6 premRNA in livers of PMs. Moreover, two mutant alleles of the P450IID6 gene locus (CYP2D6) were identified by restriction fragment length analysis to be associated with the PM phenotype. However, the mutations of the CYP2D6 gene causing absent P450IID6 protein have not been defined. Here we report the cloning and sequencing of two types of mutant alleles of CYP2D6 isolated from genomic libraries of three PM individuals. One allele (29-A) was characterized by a single nucleotide deletion in the 5th exon with consequent frameshift and was observed in one individual only. The other type of mutant allele (29-B) was present in all three PM individuals and its sequence contained multiple mutations, notably four base changes causing amino acid changes in exons 1, 2 and 9, and a point mutation at the consensus sequence of the splice site of the 3rd intron. To understand the significance of the individual mutations, chimeric genes were constructed between the wild-type IID6 gene and the mutant 29-B allele or site-specific mutations were introduced into the IID6-cDNA and these DNA constructs were transiently expressed in COS-1 cells. The mutations in exon 1 resulted in a functionally deficient IID6 protein and the mutation at the splice site in absent IID6 protein, whereas the mutations in exons 2 and 9 were of no consequence for IID6 function. Only the mutation at the splice site thus explains the absence of P450IID6 protein in livers of PM individuals and appears to be a common cause of polymorphic drug oxidation.

Alleles↗
PubMed1990

Genotyping of poor metabolisers of debrisoquine by allele-specific PCR amplification.

A method for genotyping poor metabolisers of debrisoquine is based on specific polymerase chain reaction (PCR) amplification of parts of mutant genes for hepatic cytochrome P450IID6. Analysis by restriction fragment length polymorphism allowed identification of only 25% of poor metabolisers, but when it was combined with allele-specific PCR over 95% of poor metabolisers could be identified. The PCR method also allowed the identification of heterozygous carriers of mutant alleles.

Base Sequence↗
PubMed1990

Which X-ray views are required in juvenile ankle trauma?

Although ankle sprains are probably the most common injury in adolescent sports people, epiphyseal injuries are missed on the presumption of a ligamentous tear. The risk of damaged ligaments has been overemphasized while the potentially dangerous epiphyseolysis has been understressed. An oblique X-ray of the ankle joint is indicated prior to "stress" pictures.

Ankle Injuries↗
PubMed1990

Human arylamine N-acetyltransferase genes: isolation, chromosomal localization, and functional expression.

N-Acetylation by hepatic arylamine N-acetyltransferase (NAT, EC 2.3.1.5) is a major route in the metabolism and detoxification of numerous drugs and foreign chemicals. NAT is the target of a common genetic polymorphism of clinical relevance in human populations. We have used our recently isolated rabbit cDNA rnat to clone three human NAT genes from human leukocyte DNA. None of the three genomic coding sequences was interrupted by introns. Two genes, designated NAT1 and NAT2, each possessed open reading frames of 870 bp. Both genes have been assigned to human chromosome 8, pter-q11. Following transfection they were transiently expressed in monkey kidney COS-1 cells. NAT1 and NAT2 gave rise to functional NAT proteins, as judged by their NAT enzyme activity with the arylamine substrate sulfamethazine. Western blots with NAT-specific antisera detected proteins of apparent molecular weight of 33 and 31 kD in NAT1- and NAT2-transfected cultures, respectively. The product of NAT2 had an identical apparent molecular weight as that of NAT detected in human liver cytosol. The deduced amino acid sequence of NAT2 also contained 6 peptide sequences which had previously been determined from tryptic peptides of the polymorphic NAT purified from human liver. These data suggest that NAT2 encodes the polymorphic NAT protein. The third gene, NATP, had multiple deleterious mutations and did not encode a functional NAT protein; it most likely represents a pseudogene.

Acetyltransferases↗
PubMed1990

The correlation between low birth weight and learning traits in senior school pupils--a retrospective survey.

The purpose of this study was to establish whether a correlation exists between childrens birth weight and their scholastic achievements in high school. This correlation has previously only been investigated only in primary school children and it was felt that it would be interesting to observe whether schooling changed the known status. The records of 718 children were reviewed and there appears to be a statistically significant disability for low birth weight children in the study of exact sciences and foreign languages whilst no significant differences were noted in the humanities and sport.

Adolescent↗
PubMed1990

[Bright light therapy in schizophrenic diseases].

20 patients with schizophrenic disorders, displaying a depressive syndrome, were given bright-light therapy, and compared with 11 patients treated by means of partial deprivation of sleep. Against a figure of 27% in the case of sleep-deprivation, syndrome remittance was 55% in the case of bright-light therapy. Psychometric data were obtained by use of three external-assessment schemes (HAMD, BPRS, and NOSIE) and two self-assessment procedures (TSD, POMS). As depressive syndromes improve under bright-light therapy, schizophrenic symptoms also recede, which suggests close syndromatologic links in the sense of a universal genesis of psychoses.

Antidepressive Agents↗