[The gene plays in a concert. Interview with Dr. H. Müller by Klaus Reinhardt)].
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Genetic Diseases, Inborn↗
Biomedical subjects
H Müller
Publications and source records attributed to H Müller.
[Familial colorectal and breast carcinoma--genetic counseling and presymptomatic diagnosis].
Several types of hereditary cancer can be prevented from progressing to advanced stages by regular surveillance of the person at risk and hence by the early treatment of a developing neoplasia. Genetic counselling of such patients and their relatives is therefore an important task whose value often remains unrecognized. This is especially true for the common forms of hereditary cancer such as breast and colorectal cancer, which aggregate in up to 5% of all patients according to the rules of autosomal-dominant inheritance. Preventive measures are particularly promising in the case of familial cancer because persons at risk are motivated to seek medical help. Genetic counselling is a multifaceted process and involves more than an accurate diagnosis and risk estimate. The counseled patient expects and deserves an open and reasonable answer to his questions about the implications of his/her cancer predisposition or his family history. Accurate diagnosis of the underlying susceptibility is the cornerstone of genetic counselling because most cancers seem to have multiple causes. Different genes located on different chromosomes can independently give rise to the same malignancy. Besides heterogeneity, presymptomatic testing for inherited susceptibilities to cancer raises many issues including therapy, access, intense anxiety, and discrimination.
Adenomatous Polyposis Coli↗
[Gene therapy, gene pharmacology: concepts, fields of application, problems].
Gene therapy represents a new strategy for the treatment of genetic disorders, of viral infections and of cancer. At the present time it is still an experimental phase. However, it is assumed that gene therapy will belong to the spectrum of established therapeutic procedure in the next century. Gene pharmacology is an extension of traditional pharmacology. Chemical agents will be to given to patients with viral infections with the goal to impair the expression of the viral genes. Not only ethical aspects but also biological and medical considerations are hurdles in the realisation of germ-line gene therapy.
Ethics, Medical↗
[Family anamnesis--pedigree analysis].
A thoroughly compiled medical family history is a cheap and beneficial component of the patient's work-up which gives clues for the identification and classification of susceptibilities to genetic disorders. The information can easily be summarized in diagrammatic form. The pedigree is drawn up in accordance with loosely standardize rules whose symbols are described in the accompanying article.
Genetic Predisposition to Disease↗
The degradation of phytic acid in legumes prepared by different methods.
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Cooking↗
CMV antigenemia (the lower matrix protein PP65), a marker for the guidance of antiviral therapy in cytomegalovirus disease after orthotopic heart transplantation.
During CMV viremia, the CMV specific lower matrix protein CMV pp65 can be detected in the nucleus of polymorphonuclear cells. A relationship has been found between the number of CMV pp65 positive cells, the clinical course and the effect of antiviral treatment on CMV disease. From 1990, heart recipients (triple drug therapy) were screened for CMV pp65 (antigenemia, according to the method described by The et al.), anti-CMV-IgM and -IgG. Tests were repeated at least every 4 weeks. Group 1 consisted of 23 patients who had been transplanted at least one year before the introduction of CMV testing as described. Between 1990 and 1992 26 patients were followed up during the first year after transplantation and represent group 2. In group 1, 1184 antigenemia assays were performed and 13 tested positive. In group 2 (1195 tests, 261 positive results), 20 out of the 26 recipients tested positive for CMV pp65. Without preceding evidence of a positive CMV pp65, no rise of IgM or IgG antibodies was observed. The time until the first antigenemia (time from detection until a subsequent test remains negative); 13 were found in group 1, 84 in group 2. In group 2, 46 episodes of antigenemia (mean duration 24.5 +/- 27.1 days) consisted of more than 1 consecutive positive result of the antigenemia assay (4.8 +/- 4.1). During these episodes the white blood cell count was 3460 +/- 1790/mm3. After the episodes, the mean leucocyte count was 6320 +/- 1870/mm3. The detection of CMV antigenemia indicated the initiation of antiviral treatment (hyperimmune globulin and ganciclovir). Therapy was stopped again when the antigenemia assay tested negative again. Antigenemia disappeared in all patients after initiation of antiviral treatment, CMV disease was not observed. CMV antigenemia mainly cumulates within the first year after heart transplantation. Antigenemia directed antiviral therapy does not prevent infection or repeated antigenemia but prevents CMV disease after heart transplantation.
Adult↗
[Normal blood serum levels of pheasants--total proteins and protein fractions].
Examinations of 908 blood serum samples of pheasants were carried out in order to estimate the total protein content and 544 serum samples were tested due to estimation of protein fractions by means of electrophoretic separation. Great variations were found in all tested groups. During hatch the serum protein level was low and increased with advancing age. The percentage of albumines decreased with advancing age but the total level was relatively constant. Alpha-, beta- and gammaglobulines increased steadily from the first day of life up to the age of one year. While the beta globulines still increased up to two years the gamma-globulines dropped somewhat. The diagnostic use of the estimation of protein level in pheasants is meaningful only as a complementary procedure with other diagnostic measurements.
Aging↗
Cytomegalovirus after heart transplantation: definitions for the guidance of antiviral therapy.
Besides the current classification of cytomegalovirus (CMV) infection and disease we defined "CMV antigenaemia" as the marker for initiation of antiviral therapy (CMV hyperimmune globulin 2 ml/kg/d and ganciclovir 1000 mg/d), and "episodes of CMV antigenaemia"(the time from detection of antigenaemia until a subsequent antigenaemia assay tested negative again) indicated the time period of antiviral treatment. Patients were at highest risk for antigenaemia at day 38.2 +/- 20.9 after heart transplantation. We observed 50 episodes of antigenaemia in 18 patients. The mean duration was 7.3 +/- 6.4 days. No antigenaemia associated symptoms and no anti-CMV IgM was observed without preceding evidence of antigenaemia. Antigenaemia-associated symptoms and antigenaemia disappeared after antiviral therapy was initiated. Our therapy did not prevent CMV infection, but despite the repeated evidence of active CMV infection, no patient suffered CMV disease.
Antigens, Viral↗
[Treatment of tumor pain with flupirtine. Results of a double-blind study versus tramadol].
STUDY DESIGN: In a multicentric double-blind trial, flupirtine was compared with tramadol in the treatment of cancer pain. METHODS: Over a period of four weeks, 4 (-6) capsules containing either 100 mg flupirtine (n = 35) or 50 mg tramadol (n = 36) were taken daily in accordance with a fixed time schedule. Severity of pain was scored on a weekly basis using a five-stage verbal scale. RESULTS: Initially comparable in the two groups, pain was more markedly reduced after four weeks of treatment with flupirtine than after tramadol, the need for additional analgesic drugs also being less in the flupirtine group. The final general assessment by the attending doctors of the results achieved was "good" to "very good" in 63% of the patients on flupirtine, and in 46% of those on tramadol. Undesired effects were observed in 6% of the flupirtine patients and in 19% of those taking tramadol.
Adult↗
Apoptosis is not involved in the hypersensitivity of Fanconi anemia cells to mitomycin C.
A striking feature of Fanconi anemia (FA) cells is their hypersensitivity towards crosslinking agents such as mitomycin C (MMC). In this study, we have shown that treatment of lymphoblastoid cells with MMC resulted in nuclear fragmentation, chromatin condensation, and DNA degradation, which is characteristic of apoptosis. The level of DNA fragmentation 48 hours after MMC treatment reached approximately 33% in both control and FA cells. In addition, 24 hours after drug addition a decrease in the number of cells in the G2/M phase of the cell cycle was seen. This coincided with the appearance of apoptotic cells in the sub-G1 phase, indicating that once the cells had passed through G2/M, apoptosis occurred. The number of apoptotic cells increased to 60% 96 hours after MMC treatment. The number of apoptotic cells increased to 60% 96 hours after MMC treatment. The onset and level of apoptosis was found to be identical in FA and control cell lines, indicating that the FA defect does not lead to abnormal apoptotic cell death.
Apoptosis↗
Reentrant Meissner effect in the organic conductor kappa -(BEDT-TTF)2Cu
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Journal Article↗
[Polycythemia in the late metastasis of an erythropoietin-producing renal-cell carcinoma].
An 85-year-old woman had a right-sided renal cell carcinoma removed 20 years ago. At haemoglobin concentration. Two years ago she had a syncope, at which time the haemoglobin concentration was 16.9 g/dl. Ultrasound and computed tomography (CT) revealed an extensive retroperitoneal space-occupying lesion, which however was not investigated further, and no therapeutic consequences were drawn. An erythrocytosis (7.5 x 10(6)/microliters) and elevated haemoglobin concentration (> 20 g/dl) were found when she was examined after a fall in which she had sustained only minimal injury. The retroperitoneal mass had slightly increased in size. Histological examination of a CT-guided fine-needle biopsy revealed metastases of the hypernephroid carcinoma. The serum erythropoietin concentration was increased (42.4 U/l) and failed to increase even after repeated venesections, indicating erythropoietin production by the late metastases of the renal cell carcinoma. There was no evidence for any systemic haematological disease. Six months after the diagnosis of metastases the patient died at home, presumably of a cerebrovascular accident.
Aged↗
Cyclin D1 protein expression and function in human breast cancer.
Cyclin D1 is a cell-cycle regulator essential for G1 phase progression and a candidate proto-oncogene implicated in pathogenesis of several human tumour types, including breast carcinomas. In spite of the accumulating genetic evidence, however, there are no data regarding abundance and properties of the cyclin D1 protein in breast cancer. We now report aberrant nuclear overexpression/accumulation of the cyclin D1 protein in about half of the 170 primary breast carcinoma specimens analyzed by monoclonal antibody immunohistochemistry, indicating that the frequency of cyclin D1 abnormalities may be considerably higher than previously deduced from DNA amplification studies. A comparison of the expression patterns in matched lesions at different stages of tumour progression revealed that the cyclin D1 protein aberration appears to reflect a relatively early event and that, when acquired by a tumour, it is maintained throughout breast cancer progression including metastatic spread. In both tumour tissues and breast cancer cell lines, the abundance of this protein shows characteristic variations consistent with a cell-cycle oscillation and the peak levels expressed in G1. In all 7 cell lines whose retinoblastoma (Rb) protein is mutant or complexed to SV40 T antigen, exceptionally low levels of cyclin D1 protein and mRNA were found. Antibody-mediated and anti-sense oligonucleotide knockout experiments demonstrate the requirement for the cell-cycle regulatory function of cyclin D1 in breast cancer lines with single or multiple copies of the gene and reveal the absence of such a requirement in the cell lines with Rb defects. Our data are consistent with the notion that the emerging "Rb-cyclin D1 pathway" represents a frequent target of oncogenic abnormalities in breast cancer.
Base Sequence↗
Cyclin D1 expression is regulated by the retinoblastoma protein.
The product of the retinoblastoma susceptibility gene, pRb, acts as a tumor suppressor and loss of its function is involved in the development of various types of cancer. DNA tumor viruses are supposed to disturb the normal regulation of the cell cycle by inactivating pRb. However, a direct function of pRb in regulation of the cell cycle has hitherto not been shown. We demonstrate here that the cell cycle-dependent expression of one of the G1-phase cyclins, cyclin D1, is dependent on the presence of a functional Rb protein. Rb-deficient tumor cell lines as well as cells expressing viral oncoproteins (large tumor antigen of simian virus 40, early region 1A of adenovirus, early region 7 of papillomavirus) have low or barely detectable levels of cyclin D1. Expression of cyclin D1, but not of cyclins A and E, is induced by transfection of the Rb gene into Rb-deficient tumor cells. Cotransfection of a reporter gene under the control of the D1 promoter, together with the Rb gene, into Rb-deficient cell lines demonstrates stimulation of the D1 promoter by Rb, which parallels the stimulation of endogenous cyclin D1 gene expression. Our finding that pRb stimulates expression of a key component of cell cycle control, cyclin D1, suggests the existence of a regulatory loop between pRb and cyclin D1 and extends existing models of tumor suppressor function.
Base Sequence↗
Prospective randomized clinical study in general surgery comparing a new low molecular weight heparin with unfractionated heparin in the prevention of thrombosis.
A prospective, randomized, controlled clinical trial was performed comparing the antithrombotic efficacy of the low molecular weight heparin LMWH 21-23, (Braun) with an unfractionated heparin in elective general surgical patients over an observation period of 7 postoperative days. A total of 230 patients were admitted: 103 (group I) received low molecular weight heparin and 100 (group II) low-dose unfractionated heparin treatment given subcutaneously. In group I 41 patients (46%) were operated on for malignant disease and in group II 54 patients (54%). Due to the large amount of great abdominal procedures the intra- and perioperative application of hydroxyethyl starch was allowed for volume substitution. None of the patients died due to fatal pulmonary embolism. In group I four patients revealed positive 125I-labeled fibrinogen uptake (3.9%); two patients belonged to the hydroxyethyl starch subgroup. In group II five patients displayed a positive fibrinogen uptake (5%); two belonged to the hydroxyethyl starch subgroup. The results of the hemostaseological investigations (e.g., prothrombin time, activated partial thromboplastin time, thrombin clotting time, fibrinogen, antithrombin III, protein C, plasminogen, alpha 2-antiplasmin, tissue-type plasminogen activator, plasminogen activator inhibitor) revealed no statistically significant differences between groups I and II or their subgroups, although a tendency to prolonged clotting times was observed. The antifactor Xa activity values, however, displayed a statistically significant difference between the two groups (P < 0.05). The antifactor Xa activity measured up to 0.16 U/ml for the low molecular weight heparin (group I) and 0.05 U/ml for the unfractionated heparin (group II) in the postoperative period.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
[Different opioids in patients at cardiovascular risk. Comparison of central and peripheral hemodynamic adverse effects].
Efficient analgesia may be the major objective in the cardiovascular risk patient following myocardial infarction, acute occlusion of peripheral vessels, or dissection/perforation of major abdominal vessels. It was the purpose of the study to investigate the haemodynamic and respiratory side effects of eight different opioids in 57 circulatory risk patients prior to major vascular surgery. METHODS. Patients were randomly allocated to eight groups, each receiving a different opioid within a clinical, equipotent dose range (buprenorphine, fentanyl, morphine, nalbuphine, pentazocine, pethidine, tramadol, alfentanil). A complete haemodynamic and blood gas status was obtained prior to as well as 5, 10, 15, and 20 min following opioid administration. Monitoring included a complete invasive haemodynamic and blood gas status. Statistical evaluation was performed by 1- and 2-factorial ANOVA (P < 0.05). RESULTS. Significant time effects (changes from baseline at the time of measurement) were observed for heart rate and total peripheral resistance, while significant group (group-specific differences in the course of values at the different times of measurements) and time effects were noted for mean pulmonary artery pressure, pulmonary capillary wedge pressure, stroke volume index, and PaO2. No major effects were observed following morphine, fentanyl, alfentanil, tramadol, and nalbuphine. Buprenorphine caused distinct respiratory depression accompanied by an increase in pulmonary vascular tone. Pentazocine and pethidine caused a significant increase in MPAP and peripheral vascular resistance while pethidine also produced marked respiratory depression. CONCLUSIONS. For interpretation of the results, factors such as respiratory depression, histamine release, secretion of endogenous catecholamines, and hypoxia-induced pulmonary vasoconstriction have to be discussed. Tramadol, an opioid with moderate potency, seems to offer some advantages due to its minor cardiovascular and respiratory side effects.
Aged↗
Mutational analysis of the first 14 exons of the adenomatous polyposis coli (APC) gene.
In the present study, the polymerase chain reaction single strand conformation polymorphism (PCR-SSCP) technique has been applied to the mutation analysis of the adenomatous polyposis coli (APC) gene. We examined the first 14 exons of the APC gene in 46 polyposis coli patients. Five germline mutations were observed, including a single-nucleotide substitution and small (1-4 bp) deletions leading, in 4 cases, to a stop codon. A missense mutation in exon 3 and a 1 bp deletion in exon 4 of the APC gene were observed in patients presenting with the attenuated form of FAP.
Adenomatous Polyposis Coli↗