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Biomedical subjects

C Müller

Publications and source records attributed to C Müller.

At least 361 records · Page 20Linked to original sources
PubMed1995

Polymorphism of human minor histocompatibility antigens: T cell recognition of human minor histocompatibility peptides presented by HLA-B35 subtype molecules.

To investigate the polymorphism of human minor histocompatibility (mH) antigens, PBLs from 23 Japanese individuals and 25 German individuals with HLA-B35 were studied by using four human mH antigen-specific, HLA-B35-restricted CTL clones. The CTL clones killed PHA-stimulated PBLs from all 23 Japanese individuals. On the other hand, they killed the PHA-stimulated PBLs from 19 of 25 German individuals and partially killed the PHA-stimulated PBLs from three German individuals (CTL weakly sensitive cell line); those from another three individuals (CTL-resistant cell line) were not killed by the CTL clones. All of three CTL weakly sensitive cell lines carry HLA-B*3503 molecules, whereas the three CTL-resistant cell lines carry HLA-B*3502, B*3507, and B*3508 molecules. The cytotoxicity of the CTL clones for three CTL weakly sensitive cell lines was enhanced by stimulation of human mH peptides isolated from HLA-B*3501 molecules purified from C1R-B*3501 cells. Small amounts of human mH peptides were isolated from B*3503 molecules purified from these three CTL weakly sensitive cell lines. Taken together, these results indicate that weak recognition by the CTL clones of three CTL weakly sensitive cell line results from a small amount of the human mH peptides presented by B*3503 molecules. The CTL-resistant cell line carrying B*3507 loaded with the human mH peptides was killed by four CTL clones, whereas the cell lines carrying B*3502 or B*3508 loaded with the peptides were not. The human mH peptides were not isolated from B*3507 molecules purified from the cell lines expressing this subtype, whereas small amounts of the human mH peptides were isolated from B*3502 and B*3508 molecules purified from the cell lines expressing the subtypes. These results indicate that failure of the CTL recognition of the cell line carrying B*3507 is due to a lack of human mH antigens in this cell line. The failure of the CTL recognition of the cell lines carrying B*3502 and B*3508 is not explained by only the amount of the human mH peptides binding to these B35 subtype molecules because the amount of the human mH peptides eluted from B*3502 and B*3508 molecules purified from the cell lines carrying these B35 subtypes is almost the same as that eluted from B*3503 molecules purified from the cell lines carrying B*3503.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗
PubMed1995

Localization and organization of phenol degradation genes of Pseudomonas putida strain H.

The genetic organization of the DNA region encoding the phenol degradation pathway of Pseudomonas putida H has been investigated. This strain can utilize phenol or some of its methylated derivatives as its sole source of carbon and energy. The first step in this process is the conversion of phenol into catechol. Catechol is then further metabolized via the meta-cleavage pathway into TCA cycle intermediates. Genes encoding these enzymes are clustered on the plasmid pPGH1. A region of contiguous DNA spanning about 16 kb contains all of the genetic information necessary for inducible phenol degradation. The analysis of mutants generated by insertion of transposons and cassettes indicates that all of the catabolic genes are contained in a single operon. This codes for a multicomponent phenol hydroxylase and meta-cleavage pathway enzymes. Catabolic genes are subject to positive control by the gene product(s) of a second locus.

Amino Acid Sequence↗
PubMed1995

Loss and degradation of enzyme-bound heme induced by cellular nitric oxide synthesis.

We report here that, like nonheme iron, protein-bound intracellular heme iron is also a target for destruction by endogenously produced nitric oxide (NO). In isolated rat hepatocytes NO synthesis results in substantial (approximately 60%) and comparable loss of catalase and cytochrome P450 as well as total microsomal heme, and decreased heme synthetic (delta-aminolevulinate synthetase and ferrochelatase) and increased degradative (heme oxygenase) enzymatic activities. The effect is reversible, and intact cytochrome P450 apoproteins are still present, as judged by heme reconstitution of isolated microsomes. The effects on delta-aminolevulinate synthetase and heme oxygenase are likely to be secondary to heme liberation, while the effects on ferrochelatase appear to be a direct effect of NO, perhaps destruction of its nonheme iron-sulfur center.

Arginine↗
PubMed1995

The role of perforin-expression by granular metrial gland cells in pregnancy.

The pregnant uterus of humans and rodents contains a population of granulated lymphoid cells, which, in the mouse, are called granular metrial gland (GMG) cells and have been described to express high levels of perforin. Since there is evidence for cytolytic activity of these cells and since perforin is a crucial effector molecule for the lytic action of cytotoxic T cells and natural killer cells, we evaluated the function of perforin in the pregnant uterus by using perforin-deficient mice. Perforin-deficient female mice were found to reproduce as efficiently as normal control females when bred either with syngeneic or allogeneic males. However, perforin-deficient mice differed from normal mice in that the frequency of GMG cells was significantly higher within maternal blood spaces and within several compartments of the feto-maternal interface. Proliferating GMG cells, identified by [3H] thymidine incorporation, were observed during more advanced stages of pregnancy when compared to normal controls. In contrast to normal mice, perforin-deficient mice did not display GMG cells attached to degenerating trophoblasts; instead perforin-deficient GMG cells were often observed in association with small maternal lymphocytes. In addition, the lack of transmission of lymphocytic choriomeningitis virus from infected pregnant perforin-deficient mice to the fetuses argued against a role of perforin expression by GMG cells in prevention of virus transmission from the mother to the fetus. Our data indicate that functional perforin is not necessary for successful pregnancies. The morphological changes in the pregnant uterus of perforin-deficient mice might, however, point to a certain, as-yet undefined function of perforin in the uterus of pregnant normal mice, which is functionally compensated in perforin-deficient mice.

Animals↗
PubMed1995

Fas (CD95) expression on CD4+ T cells from HIV-infected patients increases with disease progression.

Active T cell suicide (apoptosis) is supposed to be involved in the CD4+ T cell depletion in the course of HIV infection. We investigated the expression of the apoptosis-related antigen Fas on CD4+ T cells from 25 HIV-positive individuals (CDC I-III) and 8 HIV-negative controls by two-colour flowcytometry. In addition, we evaluated: total CD4 count, HIV p24 antigen concentration in serum after immune complex dissociation, and clinical course of infection in HIV-positive individuals. We found a significant increase in mean Fas expression on CD4+ T cells from HIV-positive individuals compared to HIV-negative individuals (85.84 +/- 14.92% vs. 64.28 +/- 7.59%, P < 0.001). Within the HIV-positive group the increase in Fas expression was correlated with the decline in CD4 count (r = -0.76, P < 0.001), p24 antigen concentration in serum, after immune complex dissociation (r = 0.67, P < 0.001), and CDC stage (r = 0.73, P < 0.001). The upregulation of Fas antigen on CD4 cells is associated with CD4 depletion and other virological and clinical marker of disease progression in HIV infection.

Adult↗
PubMed1995

Phase I/II trial of dexverapamil, epirubicin and granulocyte/macrophage-colony-stimulating factor in patients with advanced pancreatic adenocarcinoma.

A group of 28 previously untreated patients with locally advanced or metastatic adenocarcinoma of the pancreas were entered in this phase I/II study. Treatment consisted of oral dexverapamil 1000-1200 mg/day for 3 days, epirubicin given as an intravenous bolus injection on day 2 with a starting dose of 90 mg/m2, and 400 micrograms granulocyte/macrophage-colony-stimulating factor (GM-CSF) administered subcutaneously from day 5 through 14. Epirubicin dose escalation levels were 90, 105, 120 and 135 mg/m2. Consecutive cohorts of 4-8 patients were planned at each dose level. Treatment cycles were repeated every 3 weeks. Haematological toxicity, specifically granulocytopenia constituted the dose-limiting toxicity with a maximum tolerated dose of 120 mg/m2 for epirubicin. Despite routine supportive therapy with GM-CSF, 4, 2, and 5 patients experienced grade 4 granulocytopenia during their first two treatment courses at levels of 105, 120, and 135 mg/m2 respectively. Non-haematological toxicity was uncommon, generally modest, and did not demonstrate a clear relationship with the anthracycline dose. Dexverapamil-related cardiovascular symptoms occurred frequently, but they never resulted in serious toxicity requiring active medical intervention or permanent discontinuation of therapy. Of the 28 patients, 9 achieved partial reponses to this therapy. The recommended dose of epirubicin for this regimen with dexverapamil and GM-CSF is 120 mg/m2 every 3 weeks. Therapeutic results suggest this regimen to be an effective and tolerable treatment strategy in pancreatic cancer, which should be evaluated further.

Adenocarcinoma↗
PubMed1995

Increased in vitro production and serum levels of the soluble lipopolysaccharide receptor sCD14 in liver disease.

Elevated concentrations of lipopolysaccharide have been found in serum of patients with severe parenchymal liver disease and its toxic effect is thought to involved in hemodynamic disturbances seen in cirrhosis. A soluble form of the receptor (sCD14) for lipopolysaccharide is present in serum and is released by stimulated macrophages, indicating macrophage activation. We investigated sCD14 serum levels and in vitro production by lipopolysaccharide stimulated peripheral blood monocytes in patients with various liver diseases. In acute viral hepatitis serum sCD14 levels were significantly higher during the first 2 weeks after onset of jaundice (n=11; 3.6 +/- 0.9 microg /ml (mean +/- SD)) than in healthy control individuals (n=52; 2.5 +/- 0.7 microg/ml; p<0.001). These elevated serum levels corresponded to enhanced in vitro production of sCD14 by lipopolysaccharide-stimulated peripheral blood monocytes (n=11; 365 +/- 262 ng/ml) as compared to control monocytes (n=52; 228 +/- 74 ng/ml; p=0.02). Similarly, patients with alcoholic cirrhosis had significantly increased sCD14 serum levels (n=31; 4.5 +/- 3.2 microg/ml; p<0.001) and in vitro sCD14 production by lipopolysaccharide-stimulated monocytes (291 +/- 153 ng/ml; p=0.014). Serum sCD14 levles correlated with the severity of disease (Child A: 2.6 +/- 1.0 microg/ml; Child B: 4.4 +/- 2.1 microg/ml; Child C: 7.8 +/- 5.1 micro/ml; Anova: p=0.001). Patients with chronic viral hepatitis had only slightly elevated serum sCD14 levels (n=17; 2.9 +/- 0.7 microg/ml; p=0.01) and increased in vitro production of sCD14 by peripheral blood monocytes (320 +/- 128 ng/ml; p<0.001). The elevated serum concentration of sCD14 in alcoholic cirrhosis and acute and chronic viral hepatitis points to an incrased macrophage activation in these diseases. sCD14 from serum is able to associate with cells not expressing membrane CD14, such as endothelial cells, allowing those cells to bind and respond to lipopolysaccharide. Elevated levels of sCD14 could in this way contribute to the toxic effects of lipopolysaccharide in severe liver disease.

Adult↗
PubMed1995

Isolation of atypical mycobacteria from tap water in hospitals and homes: is this a possible source of disseminated MAC infection in AIDS patients?

Infections caused by mycobacteria other than tuberculosis (MOTT), especially Mycobacterium avium complex (MAC), are common in AIDS patients, but rare in immunocompetent persons. The route of transmission is unknown, but tap water could provide a possible source of infection: MAC was isolated from tap water in the U.S.A. but this has not been reported in Germany. We therefore investigated tap water in Berlin for the presence of mycobacteria and compared radiometric (Bactec) and standard plate culture methods processing large volumes of water samples. The Bactec method yielded equal results compared to standard methods but had the advantage of easy handling. Mycobacteria were isolated from 50/118 (42.4%) samples and from 21/30 (70%) sites. The most frequently isolated species was Mycobacterium gordonae (from 28% samples and from 53.3% sites); MAC was isolated from two samples only (1.7%).

AIDS-Related Opportunistic Infections↗
PubMed1995

Nitric oxide and intracellular heme.

Figure 2 depicts a working hypothesis for these results. Activation of .NO synthesis results in nitrogen oxide-induced loss of protein-bound heme from CYP proteins, which remain relatively intact. This heme liberation results in a decrease in heme synthesis (decreased ALAS) and an increase in heme degradation (increased HO). In addition, .NO synthesis results in direct inhibition of ferrochelatase, which further contributes to inhibition of heme synthesis. There also appears to be a mechanism to repair or resynthesize CYP after .NO synthesis is inhibited. Finally, a result of this effect may be protection against cellular injury, since increased HO is an important response against cellular injury from a variety of insults.

Animals↗
PubMed1995

Reduced mitogenic stimulation of peripheral blood mononuclear cells as a prognostic parameter for the course of breast cancer: a prospective longitudinal study.

Immunosuppression has been often associated with the course of malignant diseases. In the present study, the proliferation of peripheral blood mononuclear cells (PBMCs) in response to mitogenic stimulation with phytohaemagglutinin (PHA) was assessed prospectively in 90 patients with stage I-III breast cancer. Whereas PHA-induced proliferation of PBMCs derived from patients with breast cancer preoperatively was significantly decreased when compared with data obtained in healthy control individuals (P < 0.001), the degree of the defect in PHA-induced proliferation of PBMCs depended upon the tumour burden as manifested by tumour size and axillary lymph node involvement (P < 0.003 in each case). PHA-induced proliferation of PBMCs dropped significantly in patients who received adjuvant chemotherapy consisting of cyclophosphamide, methotrexate and fluorouracil (CMF) after an observation period of 6 months (P < 0.01), but not in patients under adjuvant treatment with tamoxifen only. After an additional 6 months (i.e. 12 months after surgery), PHA-induced proliferation of PBMCs was similar in patients after adjuvant chemotherapy with CMF and in those receiving continued adjuvant tamoxifen treatment (P > 0.1), but in all patients still significantly decreased as compared with healthy controls (P < 0.001). When data obtained preoperatively and after 12 months were compared, it was found that out of 23 patients whose PBMCs had experienced a drop in their PHA-induced proliferation, 14 (61%) had developed metastatic disease within the subsequent 24 months (i.e. 36 months after surgery). In contrast, out of 59 patients whose PBMCs showed an increase in their PHA-induced proliferation within the first 12 months after surgery, only one (2%) presented with disease progression. We thus conclude that PHA-induced proliferation of PBMCs derived from patients with breast cancer depends upon the tumour load and is a good clinical predictor for the further course of the disease.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1995

HBV and HCV genome in peripheral blood mononuclear cells in patients undergoing chronic hemodialysis.

Patients undergoing chronic hemodialysis are at risk for infection with hepatitis B virus (HBV) and hepatitis C virus (HCV). As peripheral blood mononuclear cells (PMNC) are known to be susceptible to infection of both HBV and HCV, assessment of viral genomes in those cells could uncover occult infections not detected by serologic methods or virus determination in serum. We investigated all 67 patients undergoing chronic hemodialysis at a single dialysis unit by PCR for the presence of HBV or HCV genomes in serum as well as in PMNC. None of the 67 patients was HBsAg positive or showed HBV-DNA in serum, but in 5 patients HBV-DNA in PMNC was detected as the only marker of HBV-infection; those patients were also anti-HBc negative. In 9 patients HCV-RNA was positive in serum; in 5 of those patients it was also found in PMNC. Three of these infected patients were negative for anti-HCV. One other patient had no anti-HCV or HCV-RNA in serum, but was positive for HCV-RNA in PMNC. Thus, in 6 patients (8.9%) undergoing chronic hemodialysis we found evidence of infection with HBV or HCV by detecting viral genomes in PMNC without the presence of viremia, antigenemia or specific viral antibodies in serum. The detection of viral genomes in PMNC could be useful in the positive identification of additional potentially infectious patients.

Adult↗
PubMed1995

Incidence of hypertrophic cardiomyopathy in hypothyroidism.

In 13 consecutive severely hypothyroid patients no sign of endocrine cardiomyopathy in the form of asymmetric septal hypertrophy (ASH) could be disclosed by M-mode and two-dimensional (2D) echocardiography on examination prior to thyroxine replacement therapy. In previous investigations ASH was demonstrated to be almost invariably present in untreated hypothyroidism irrespective of thyrotropin levels. Consequently application of positive inotropic and afterload reducing agents that may invoke deleterious effects in ASH has been considered hazardous in hypothyroidism even when indicated by concurrent other heart disease. Determination of exact confidence limits reveals that the proportional incidence of hypothyroid hypertrophic cardiomyopathy could not exceed 24.7% with 95% probability. We conclude that ASH is not necessarily inherent in hypothyroidism.

Adult↗
PubMed1995

Silent myocardial ischemia in hypothyroidism.

In some patients with severe hypothyroidism thyroxine replacement therapy precipitates or aggravates angina pectoris, whereas in other patients angina pectoris is ameliorated or even disappears. The reason for this paradox is unknown. It has been attributed either to reversible endocrine cardiomyopathy in the form of asymmetric septal hypertrophy (ASH) or reversible anatomical narrowing of the coronary arteries. The results of a recent investigation, in which myocardial performance was surveyed by radionuclide ventriculography throughout early thyroxine replacement therapy in severe hypothyroidism, were compatible with the presence of reversible coronary dysfunction rather than of ASH. The aim of the present investigation was to confirm these findings. In six severely hypothyroid patients, without echocardiographic evidence of ASH or evidence of concomitant coronary artery disease (CAD), exercise and redistribution tomographic myocardial thallium-201 imaging (SPECT) was performed before thyroxine replacement therapy and repeated after 10 days and again after 2 months during therapy. In four patients substantial regional perfusion defects were demonstrated after exercise that were normalized at rest both before, and in one subject also after 10 days, on thyroxine. With restoration of euthyroidism, exercise and redistribution SPECT were normal in every patient. Determination of exact confidence limits reveals that the proportional incidence of myocardial perfusion defects in hypothyroidism, indicating myocardial ischemia, will at least be 22% with 95% probability. Despite the relatively low specificity of SPECT it seems pertinent to conclude that impaired myocardial perfusion as assessed by SPECT probably is due to reversible coronary dysfunction inherent in the hypothyroid state, and that this is not an infrequent manifestation of severe hypothyroidism.

Adult↗
PubMed1995

Prophylaxis of alcohol withdrawal syndrome in alcohol-dependent patients admitted to the intensive care unit after tumour resection.

Prophylaxis of alcohol withdrawal syndrome (AWS) in alcohol-dependent patients shortens the duration of stay in the intensive care unit (ICU). The objective of this study was to assess the effect of four different prophylactic regimens on the duration of ICU stay, prevention of AWS and rate of major intercurrent complications in alcohol-dependent patients admitted to the ICU after tumour resection. A total of 197 alcohol-dependent patients, diagnosed by the Diagnostic and Statistical Manual of Mental Disorders (third revised edition) with a daily ethanol intake of 60 g, were allocated randomly to one of the following regimens which were commenced on admission to the ICU: flunitrazepam-clonidine, chlormethiazole-haloperidol, flunitrazepam-haloperidol or ethanol. The duration of ICU stay, prevention of AWS, incidence of tracheobronchitis and major intercurrent complications such as pneumonia, sepsis, cardiac disorders, bleeding disorders and death were documented. On admission, patients did not differ significantly in age, APACHE II and multiple organ failure scores. ICU stay, incidence of AWS, severity of AWS (revised clinical institute withdrawal assessment for alcohol scale > 20) and major intercurrent complication rate did not differ significantly between groups. Although there was no advantage in any of the four regimens with respect to the primary outcome measures, pulmonary and cardiac patients were not included in the study. Patients in the chlormethiazole-haloperidol group had a significantly increased incidence of tracheobronchitis (P = 0.0023), probably because of an increased incidence of hypersecretion.

Adrenergic alpha-Agonists↗
PubMed1995

Beta-carbolines in chronic alcoholics undergoing elective tumor resection.

The prevalence of chronic alcoholism in patients with carcinomas of the upper digestive tract exceeds 60%. The patient's history and laboratory markers, preoperatively, are often not sensitive or specific enough to detect alcohol-dependent patients, preoperatively, who are at risk of developing alcohol withdrawal syndrome (AWS) during their postoperative intensive care unit (ICU) stay. Previously, it was found that plasma norharman was elevated in chronic alcoholics, suggesting marker characteristics for chronic ethanol misuse and possibly alcohol dependence. We investigated whether beta-carbolines (i.e., harman and norharman) were different between chronic alcoholics and nonalcoholics with carcinoma, and how the levels change in alcohol-dependent patients during their hospital stay. Ninety-seven patients with oral, pharyngeal, laryngeal, or esophageal carcinomas were evaluated regarding their drinking habits. Sixty patients were transferred to the ICU following tumor resection. Chronic alcoholics met the DSM-III-R and ICD-10 criteria for alcohol dependence or chronic alcohol abuse/harmful use. The daily ethanol intake in chronic alcoholics was > or = 60 g. Blood samples were collected on admission to the hospital, preoperatively, on admission to the ICU and on days 2, 4, and 7 in the ICU. Harman and norharman were determined by HPLC. Elevated norharman was found in chronic alcoholics on admission to the hospital, whereas harman did not differ between groups. On admission, the area under the receiver operating characteristics curve was significantly larger for carbohydrate-deficient transferrin and preoperatively for norharman. The preoperative norharman levels were significantly correlated with the period of mechanical ventilation and the length of ICU stay. Postoperatively, norharman decreased in all patients, except a group of 11 alcohol-dependent patients who developed AWS during their ICU stay. The finding that elevated norharman levels were found in chronic alcoholics on admission to the hospital and preoperatively supports the view of a specific marker for alcoholism. Preoperative norharman was superior to carbohydrate-deficient transferrin and was associated with a prolonged ICU stay and a prolonged period of mechanical ventilation. Further studies are required to determine whether norharman aids in the preoperative diagnosis of chronic alcohol misuse with respect to the prevention of postoperative complications.

Adult↗
PubMed1995

A new, peroral non-radioactive vitamin B12 absorption test compared with the Schilling test.

The results of a non-radioactive, peroral absorption test have been compared with the results of the traditional Schilling test in 31 cobalamin-deficient patients. The non-radioactive test is simple to perform, is less costly than the Schilling test and seems to give reliable results. The non-radioactive test should be performed after cobalamin treatment, but not until the plasma cobalamin value has declined to below 450 pmol/l. Normal Schilling test was noted in one-third of the patients, while normal non-radioactive test was noted in only one-fifth of the patients. The results reveal some discrepancies between the two tests regarding the response to intrinsic factor. In the non-radioactive test without intrinsic factor, the great variation in values may reflect varying secretion of intrinsic factor, possibly secondary to infestation with Helicobacter pylori. "False normal" Schilling test seems to be more common than previously believed.

Administration, Oral↗