PubMed Health⌕ Search

Biomedical subjects

H Müller

Publications and source records attributed to H Müller.

At least 19 recordsLinked to original sources
PubMed1992

Hereditary conditions in which the loss of heterozygosity may be important.

Somatic mutations are a common event in multicellular organisms and, therefore, have a significant impact on health. They can lead to either heterozygosity or homozygosity. Since the multistep concept of carcinogenesis presupposes that mutations/deletions of several genes are acquired, the identification and location of the critical genes involved in this sequence is attempted either by the observation of cytogenetic or molecular abnormalities in tumorous tissue or by linkage analysis, or both. The retinoblastoma paradigm of loss of heterozygosity with respect to the loss of the only wild-type allele can be applied to familial neoplasias occurring in all organs as they are summarized in this review. The development of homozygosity in non-malignant tissue has not been extensively investigated. However, its study has contributed to the identification of new genetic phenomena such as parental unidisomy and genomic imprinting.

Genetic Diseases, Inborn↗
PubMed1992

[The significance of the family anamnesis in women with breast carcinoma].

A cancer-related family history was ascertained in 600 women with breast cancer. Prevalence data in the families were compared to the data of the population-based Basel cancer registry. Breast cancer occurrence was increased in first degree female relatives (relative risk: 1.7; 95% confidence interval: 1.4-1.9; p less than 0.0001). Breast cancer risk in relatives decreased with increasing age of the probands. Women at elevated breast cancer risk can be identified by obtaining a family history of breast cancer patients.

Adult↗
PubMed1992

Biogenesis of the yeast vacuole (lysosome). Mutation in the active site of the vacuolar serine proteinase yscB abolishes proteolytic maturation of its 73-kDa precursor to the 41.5-kDa pro-enzyme and a newly detected 41-kDa peptide.

The codon of the catalytic serine in the active site of the vacuolar serine proteinase yscB (PrB) was changed to alanine, yielding the mutant gene prb1-Ala519. Following replacement of the wild-type PRB1 allele with prb1-Ala519, only a 73-kDa molecule was detected by immunoprecipitation with PrB-specific antiserum. The size of the mutant molecule corresponds to the unprocessed cytoplasmic precursor (pre-super-pro-PrB), as detected in sec61 mutants, when translocation into the endoplasmic reticulum is blocked. However, the mutant molecule is completely translocated into the secretory pathway, as indicated by protection from proteinase K digestion in spheroplast lysates in the absence of detergent. When N-glycosylation was inhibited in prb1-Ala519 mutant cells by tunicamycin, a smaller molecule of about 71 kDa appeared consistent with single N-glycosylation and signal-sequence cleavage of the translocated mutant PrB molecule in the endoplasmic reticulum. Thus, the active-site mutation prevents the wild-type processing of the N-glycosylated 73-kDa precursor of PrB to the 41.5 kDa pro-PrB in the endoplasmic reticulum. In order to characterize the processing of wild-type super-pro-PrB in more detail, we generated antibodies against the non-enzymatic superpeptide domain of the 73-kDa precursor expressed in Escherichia coli. We find that, in addition to pro-PrB, a distinct protein (superpeptide) with a mobility of about 41 kDa in SDS/PAGE is generated in the endoplasmic reticulum. Pulse-chase experiments indicate rapid degradation of the 41-kDa superpeptide in wild-type cells. Correspondingly, the superpeptide was virtually undetectable by immunoblotting wild-type cell extracts. In contrast, no degradation of radioactively labeled 41-kDa superpeptide was observed within 60 min in mutant strains deficient in the vacuolar proteinase yscA (PrA), in which maturation of vacuolar pro-PrB to active PrB is blocked. Accordingly, superpeptide antigenic material was readily detected by immunoblotting cell extracts and enriched in vacuolar preparations of PrA deficient mutant cells. These results indicate that the superpeptide and pro-PrB travel to the vacuole, where the superpeptide is rapidly degraded upon pro-PrB activation to PrB. Using purified vacuoles, rapid degradation of the superpeptide was reconstituted in vitro by addition of either mature PrA or mature PrB. However, the PrA-triggered in vitro degradation of the superpeptide required PrB activity, as this process was inhibited in the presence of the PrB inhibitor chymostatin.(ABSTRACT TRUNCATED AT 400 WORDS)

Binding Sites↗
PubMed1992

SEC6 encodes an 85 kDa soluble protein required for exocytosis in yeast.

The SEC6 gene encodes a protein required for an event leading to fusion of post-Golgi vesicles with the plasma membrane in Saccharomyces cerevisiae cells. The gene was cloned by complementation of the temperature-sensitive growth defect of a sec6-4 strain. The nucleotide sequence was determined and the longest open reading frame was found to encode an 85 kDa protein of 733 amino acids. The Sec6 protein is predicted to be hydrophilic and is found predominantly in the soluble fraction of a yeast lysate, in a species that sediments with a coefficient of 14S. No extensive homology was found with known proteins of the database. Gene disruption and marker rescue experiments indicate that SEC6 is a single copy gene essential for growth. Overproduction of Sec6p does not suppress any of the other late-acting sec mutants, yet sec6-4 does display synthetic lethality with sec8-9, suggesting that the two gene products may fulfill inter-related functions.

Amino Acid Sequence↗
PubMed1992

Role of Lys 558 and Lys 869 in substrate and inhibitor binding to the murine band 3 protein: a study of the effects of site-directed mutagenesis of the band 3 protein expressed in the oocytes of Xenopus laevis.

The effect of mutation of either Lys 558 or Lys 869 or both on mouse erythroid band 3 protein (AE1)-mediated 36Cl- efflux and its inhibition by pyridoxal 5-phosphate (P5-P), DNDS and H2DIDS were studied. Regardless of the mutation, band 3 was always capable of executing Cl- self-exchange. P5-P (5 mM, pH 7.6) produced irreversible inhibition in the wild type (KK) and in the mutant in which Lys 558 (NK) or Lys 869 (KM) had been replaced by asparagine (N) or methionine (M), respectively. However, when both residues were replaced, mutant (NM), irreversible inhibition could no longer be achieved. This shows that P5-P is capable of producing inhibition with either one of the lysine residues, 558 or 869. Inhibition by DNDS changed dramatically upon mutation. The Ki app increased from 6.0 microM in the wild type (KK) to 23 microM in the mutant NK, to 73 microM in the mutant KM and to 474 microM in the double mutant NM. The Km value for activation of the transport system by varying the substrate concentration by isosmotic substitution of Cl- with SO4(2-) decreased from 42 mM in the wild type (KK) to 11.3 mM in the mutant NM. The results show that both Lys 558 and Lys 869 are involved in the maintenance of the structure of the overlapping binding sites for stilbene disulfonates and the substrate Cl-. In the double mutant NM, H2DIDS is no longer able to produce irreversible inhibition at pH 7.6. This is evidently related to the replacement of Lys 558 (pK 8.2) by Asn 558 in this mutant (see Bartel, D., Lepke, S., Layh-Schmitt, G., Legrum, B., Passow, H., 1989. EMBO J. 8:3601-3609). However, at pH 9.5, some irreversible inhibition could still be observed. This suggests that the other lysine residue (pK 10.8) that is known to be involved in covalent binding with the second isothiocyanate group of H2DIDS is still present, and hence, not identical to Lys 869, which had been substituted by a methionine residue. However, this result remains inconclusive since after mutagenesis, the H2DIDS may produce inhibition at a site that is not normally involved in H2DIDS binding.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1992

Relation between leukocyte counts and cortisol secretion in CML patients undergoing combined TNF alpha/IFN alpha therapy.

During long-term interferon alpha-2b (IFN) therapy of Philadelphia chromosome-positive chronic myelogenous leukemia (CML) patients, short-term effects of tumor necrosis factor alpha (TNF) on peripheral leukocyte counts, as well as cortisol and corticotropin (ACTH) release were studied. TNF (40-160 micrograms/m2) was given as a 2-h infusion on 5 consecutive days every 3 weeks, in addition to s.c. daily IFN injections (4 mio U/m2), to four (two male/two female) patients, who had been treated for more than 8 months with IFN and additionally for 0-7 months with TNF. Leukocyte counts, cortisol, and ACTH were determined at 30-min intervals between 4 p.m. and midnight. Profiles were determined the day before and on day 1 of TNF therapy. Leukocyte numbers decreased 30 min after start of TNF administration and increased 30-60 min later with a rebound until the next TNF application. The increase of leukocyte counts was due mostly to neutrophil granulocytes. ACTH levels increased 30 min, cortisol 60 min, and leukocyte counts 90 min after start of TNF infusion. Metopirone, an inhibitor of cortisol synthesis given to one patient, suppressed the TNF-induced stimulation of cortisol secretion and subsequent increase of leukocyte counts, while ACTH blood levels were enhanced. It was concluded that leukocyte count increases after TNF/IFN administration might be related to TNF-evoked cortisol secretion.

Adrenocorticotropic Hormone↗
PubMed1992

Sub-acute effects of interferon-alpha 2 on adrenocorticotrophic hormone, cortisol, growth hormone and prolactin in humans.

This study investigated the chronic effects of interferon-alpha 2 (IFN-alpha 2) on hormonal secretion in humans. Six patients suffering from chronic hepatitis B or C infection received SC doses of 3 million IU IFN-alpha 2 three times a week for 4 mo. Each patient was examined for hormone secretion four times: the day before initial IFN-alpha 2 administration (day 0), the day of the first injection (day 1), and 4 wk after start of IFN therapy on days 27 (without IFN administration) and 28 (with IFN administration). Adrenocorticotrophic hormone (ACTH), cortisol, growth hormone (hGH), and prolactin (PRL) were measured in plasma samples drawn at 30-min intervals between 1600h and 2400h. Acute administration of IFN-alpha 2 stimulated the release of ACTH to 423% (p = 0.02 vs. day 0) and cortisol to 393% (p = 0.01 vs. day 0) of control values in each patient. In five of the six patients, the plasma levels of hGH were higher on day 1 than on day 0. IFN-alpha 2 did not affect the secretion of prolactin. On day 27, the plasma levels of the four hormones were similar to the baseline levels on day 0. When IFN-alpha 2 was given on day 28, there were no significant differences in the release of ACTH (135% of control, p = 0.4) or cortisol (124% of control, p = 0.5) in comparison to day 27. These findings indicate that IFN-alpha 2 stimulation of hormone release is restricted to specific hormones.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗
PubMed1992

Staged chest closure in pediatric cardiac surgery preventing typical and atypical cardiac tamponade.

Chest closure after cardiac surgery occasionally results in cardiac compression leading to circulatory failure. In shunt-dependent circulation, the arterial oxygen saturation may decrease significantly due to the increase in pulmonary vascular resistance caused by chest closure. Temporary patch implantation with delayed sternal closure facilitates circulatory and/or pulmonary stabilization (temporary chest wall patch plasty, TCWPP). Between July 1986 and June 1991, 42 patients underwent staged chest closure (TCWPP) after open heart surgery for congenital lesions (4.9% of 854 patients). TCWPP was performed when either primary hemodynamic deterioration or an increase in cyanosis (palliative procedures only) followed by hemodynamic deterioration occurred during attempted or shortly after sternal closure. Overall mortality was 40.4% (17/42). It was 32.3% (11/34) when the patch was inserted primarily at the end of the operation. If the patch was inserted emergently 4-24 h postoperatively, mortality was 75% (6/8). Definite chest closure was performed from 4 h to 6 days (mean 72 h) postoperatively. In 2 patients closure had to be performed emergently (single ventricles); 7 patients died before chest closure. One mediastinal microbiology examination was positive. Deep sternal infection necessitating operative revision occurred in one other patient. In conclusion, TCWPP may considerably lower mortality of the illest patients after surgery for complex congenital heart disease. A timely decision as to the performance of staged chest closure is mandatory. This procedure rarely causes infection. We now apply this technique liberally, by cardio-mediastinal size judgement in over 30% of our TCWPP candidates even without a prior trial of primary closure.

Adolescent↗
PubMed1992

Sec8p and Sec15p are components of a plasma membrane-associated 19.5S particle that may function downstream of Sec4p to control exocytosis.

The SEC8 and SEC15 genes are essential for exocytosis in the yeast Saccharomyces cerevisiae and exhibit strong genetic interactions with SEC4, a gene of the ras superfamily. The SEC8 gene encodes a hydrophilic protein of 122 kD, while the temperature-sensitive sec8-9 allele encodes a protein prematurely truncated at 82 kD by an opal stop codon. The Sec8p sequence contains a 202 amino acid region that is 25% identical to the leucine rich domain of yeast adenylate cyclase that has been implicated in ras responsiveness. Fractionation, stability, and cross-linking studies indicate that Sec8p is a component of a 19.5S particle that also contains Sec15p. This particle is found both in the cytosol and peripherally associated with the plasma membrane, but it is not associated with secretory vesicles. Gel filtration studies suggest that a portion of Sec4p is in association with the Sec8p/Sec15p particle. We propose that this particle may function as a downstream effector of Sec4p, serving to direct the fusion of secretory vesicles with the plasma membrane.

Amino Acid Sequence↗
PubMed1992

Morphological changes of cultured endothelial cells after microinjection of toxins that act on the cytoskeleton.

Clostridium novyi alpha-toxin and C. difficile toxins A and B (all 200 to 300 kDa) and C. botulinum C2-I toxin (50 kDa) caused a delayed and persistent retraction and rounding of microinjected cells. Microinjected phalloidin acted fast and reversibly. Unlike C2-I toxin, phalloidin passed through the intercellular junctions. Specific antitoxin applied to the medium did not prevent the action of microinjected C. novyi or C. difficile toxin B. Microinjected antitoxin protected against the toxins applied with the medium or injected into the same cells.

Bacterial Proteins↗
PubMed1992

[Immunohistochemical in situ demonstration of cytokines in Hodgkin and non-Hodgkin lymphoma].

Primary biopsies from 149 patients with malignant lymphomas were examined by histological and immunohistochemical techniques. Twenty eight cases were classified as Hodgkin's disease and 121 as non-Hodgkin's lymphomas. The immunohistochemical distribution of cytokine expression (Il-1 alpha, Il-1 beta, Il-6 and TNF-alpha) was demonstrated in neoplastic cells and in tumor-associated macrophages (TAM). Neoplastic cells showed mostly weak positivity for TNF-alpha in 40% of Hodgkin's disease and in 20% of T cell lymphoma cases. Two groups of malignant lymphomas were established which differed in the numbers of cytokine expressing TAM. The first group consisted of malignant lymphomas which contained large quantities of cytokine-possessing TAM. In the second group significantly lower frequencies of cytokine expressing TAM were found. In both groups high and low grade malignant lymphomas were encountered. There was a significantly positive correlation between the number of Il-6 possessing TAM and the proliferation of lymphoma cells in only the non-Hodgkin's lymphomas. Our results suggest a paracrine tumor growth stimulating mechanism which is created by a self perpetuating cytokine production loop. A supposed cytokine produced by neoplastic cells dependent from their proliferative activity may induce Il-6 secretion by TAM. Il-6 in turn may stimulate the proliferation of the lymphoma cells without maturation thus leading to a self-sustaining growth.

Antibodies↗
PubMed1992

[Tumor proliferation, MDR phenotype and tumor associated t-lymphocytes in non-Hodgkin's lymphomas].

In this study we examined the P170-expression (mdr-phenotype) in 42 non-Hodgkin's Lymphomas with variant entities immunohistochemically with the mab JSB1. The mdr-phenotype was related to the tumor proliferation as measured by Ki67-expression and AgNOR numbers. Furthermore the mdr-phenotype was related to the tumor associated T-lymphocytes. The mdr-phenotype showed no relation to histological type and the proliferation of the tumor. There was a positive correlation between the mdr-phenotype and CD2-reactive lymphocytes. There was also a significant positive correlation between CD4-reactive lymphocytes and the mean number of AgNOR's. Possibly P170-expression and proliferation of the tumor cells have a lymphotactic effect on T-lymphocytes. The latter could promote tumor progression by means of paracrine mechanisms.

CD4 Antigens↗
PubMed1992

[Human mammary carcinoma. A model for the relationship between tumor proliferation, tumor-associate macrophages, and prognostic factors].

As compared with the lymphatic system, the mononuclear phagocyte system (MPS) represents the older defense system in the course of evolution. Organisms with defective or with no lymphocytic function are able to live for a certain time while metazoa cannot develop and exist without cells capable of phagocytosis. It is known that up to 80% of the mass of malignant experimental tumors may consist of macrophages. The biological relevance of these tumor-associated macrophages (TAM), however, is contested to date. Besides well-known tasks in specific and non-specific defense, the cells of the MPS possess nutritive functions. The different functions of TAM have been essentially examined in animal experiments in vivo and in vitro up to now. These studies have shown, e.g., that TAM of different phenotypes to some extent are assigned to different functions and that each tumor or tumor cell line has a specific TAM pattern. The available number of monoclonal antibodies (MAB) able to recognize different groups of human macrophages has only increased in the recent past. This also provided evidence of the phenotypic heterogeneity of macrophages in the human system. On the other hand, there is little knowledge to date of the possible biological cause of the presence of numerous macrophages also in the stroma of malignant tumors in man and on the functional relevance of particular macrophage phenotypes. In the present studies, the phenotypic pattern of tumor-associated cells was examined by immunohistochemistry in the model of human mammary carcinoma, using 18 monoclonal antibodies (Ki-M1-8, Leu-M1-3, Leu-M5, EBM11, CD1, anti-transferrin receptor [TFR], anti-MHC I, anti-MHC II or anti HLA-DR) and one polyclonal antibody (anti protein-S100). The first part of the study contains a semiquantitative evaluation of 216 cases of mammary carcinoma. The analytical results are correlated with established prognostic factors available in the case of malignant tumors in general and in that of mammary carcinomas in particular (age, menopausal status of patients, axillary lymph node and estrogen/progesterone receptor status, size of tumor, tumor type according to WHO, degree of malignancy according to histopathological and nuclear grading). As tumor parameters of absolute biological relevance, proliferating activity (Ki67) and MHC phenotype of tumor cells and amount or types of tumor-associated lymphocytes (TAL) are examined in order to analyze their correlation with prognostic factors and their importance in the tumor-macrophage system.(ABSTRACT TRUNCATED AT 400 WORDS)

Antibody-Dependent Cell Cytotoxicity↗
PubMed1992

[New methods for diagnosing infection in pregnancy].

Maternal infections during pregnancy are of special relevance because of the risk of transmission to the fetus. Besides serological methods of diagnosing acute maternal infection, new approaches to assess fetal involvement have been made by invasive procedures, such as ultrasound-guided fetal blood sampling or amniocentesis. The most relevant infections in pregnancy are briefly reviewed with their incidence, consequences of fetal infection, and standard diagnostic procedures. Immunological methods are handicapped by the immaturity of the fetal immune system; direct culture is complicated and time-consuming. The application of molecular biological methods to directly identify the RNA- or DNA-sequences of the infectious agent may be an alternative. Two methods, polymerase-chain-reaction (PCR) and in-situ hybridization (ISH) are explained. Broad clinical use is still hindered by problems in specificity and quantitative accuracy. Nevertheless, successful diagnosis of most of the relevant infections in pregnancy by these molecular biological methods, is published, and discussed in a review of the recent literature.

Cytomegalovirus Infections↗