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Biomedical subjects

M Deckert

Publications and source records attributed to M Deckert.

At least 73 records · Page 4Linked to original sources
PubMed1994

High levels of functional endopeptidase 24.11 (CD10) activity on human thymocytes: preferential expression on immature subsets.

Although it is now well established that cells of the immune system express most of the exopeptidases described so far, little information is available concerning the identification and the characterization of the peptidases associated with the surface of human thymocytes. In the present study we have focused on CD10 expression on thymocytes using both FACS and enzymatic analysis. Unfractionated intact human thymocytes were shown to express significant levels of CD10-specific enzymatic activity, as assessed by the hydrolysis of the neutral endopeptidase (NEP) substrate Suc-Ala-Ala-Phe-pNA and of D-Ala2-Leu-enkephalin, a typical NEP substrate. CD10 activity was abolished by specific NEP inhibitors, including thiorphan, retrothiorphan and phosphoramidon. Moreover, high performance liquid chromatography (HPLC) analysis showed that intact thymocytes and purified NEP hydrolysed thymopentin, a thymic factor known to induce the maturation of prothymocytes into thymocytes. Finally, CD 10/NEP was preferentially associated with CD3- CD3low and immature CD4- CD8- thymocytes. The data demonstrate for the first time that human thymocytes express functional NEP and suggest a role for this enzyme in the maturation of human thymocytes.

CD3 Complex↗
PubMed1993

Interleukin-2 in combination with interferon-alpha and 5-fluorouracil for metastatic renal cell cancer.

Recent clinical trials for the biological therapy of solid tumours have used recombinant human cytokines in combination with conventional chemotherapy. In patients with progressive metastatic renal cell carcinoma, we established a three-drug combination comprising interferon-alpha (IFN-alpha), interleukin-2 (IL-2) and 5-fluorouracil (5-FU), using a regimen which allows outpatient therapy. Treatment consisted of 8 weeks each of IFN-alpha [6-9 MU/m2 once to three times weekly subcutaneously (sc)] combined sequentially with IL-2 (5-20 MU/m2 thrice weekly sc for 4 weeks) and 5-FU [750 mg/m2 intravenously (i.v.) weekly for 4 weeks]. Among the first 35 patients treated, there were 4 complete (11.4%) and 13 partial responders (37.1%), with an overall objective response rate of 48.6% (95% confidence interval 32-66%). Regressions occurred in local relapse, in lung, lymph node, bone, pleural, renal and thyroid metastases. Median response duration was calculated at 7+ months. An additional 13 patients (37.1%) were stable throughout therapy and thereafter (median of 6+ months). Response rate of this three-drug combination regimen compared favourably with single agent IFN-alpha (objective response rate approximately 16%) and against the sc IFN-alpha/IL-2 combination (objective response rate approximately 28%). Systemic toxicity was mild to moderate with no severe 5-FU-related mucositis and no dose-limiting adverse effects of sc IL-2. While the exact mechanisms of the potentially additive or synergistic effects of 5-FU and IFN-alpha/IL-2 remain to be established in more detail, it appears that the sequential use of IFN-alpha/IL-2 and IFN-alpha/5-FU in metastatic renal carcinoma further enhances the therapeutic index of IFN-alpha/IL-2-based biological therapy. Based on the present data, combined biochemotherapy may be a promising new approach to the therapy of advanced renal cancer.

Adult↗
PubMed1993

Limited efficacy of interferon-alpha and vinblastine as second line biochemotherapy regimen in patients with progressive metastatic renal cell carcinoma.

We report on thirty-four patients with metastatic renal cell carcinoma who were treated with a combination of subcutaneous recombinant interferon-alpha and intravenous vinblastine upon progression after previous antineoplastic therapy. Pretreatment included chemotherapy (n = 3), hormonal therapy (n = 6) and immunotherapy (interleukin-2/interferon-alpha, n = 25). In this study, treatment courses consisted of subcutaneous doses thrice weekly of recombinant interferon-alpha at 6 million U/m2 (20 patients, group 2), respectively. Treatment was given over 8 consecutive weeks. Additionally, in all patients, vinblastine was administered intravenously at a dose of 6 mg/m2 in weeks 2, 5 and 8. Of 14 patients treated in group 1, one had a partial response for 6 months (overall response rate 7.14%; 95% confidence interval, 0.18-33.87%), and four had disease stabilization (median duration, 5.0 months). Of 20 patients treated in group 2, there was one patient who achieved a complete response (response duration, 34+ months); in addition, two patients had a partial response (median response duration, 10.5+ months; overall response rate, 15%; 95% confidence interval 3.21-37.89%), and 13 patients exhibited disease stabilization (median duration 5.9+ months). Response rates showed no significant differences when comparing treatment results in patients in group 1 vs group 2. In contrast, significantly less patients treated in group 2 had progressive disease (p = 0.024), as compared to patients in group 1. This treatment combination was overall well tolerated with low to moderate systemic toxicity. In addition, there were no significant differences in frequency or intensity of therapy-related systemic toxicities when comparing patients in group 1 and group 2, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Expansion of peripheral blood natural killer cells correlates with clinical outcome in cancer patients receiving recombinant subcutaneous interleukin-2 and interferon-alpha-2.

Natural killer (NK) cells are believed to contribute to the clinical efficacy of cancer immunotherapy using recombinant interleukin-2 (rIL-2) in humans. In previous trials of high-dose i.v. rIL-2, however, no correlation has been established between circulating NK cells and treatment response. Between January 1989 and October 1990, we treated a total of 47 outpatients with advanced tumors using low-dose s.c. rIL-2 and interferon-alpha-2 (rIFN-alpha). Therapy consisted of a 2-day rIL-2 pulse at 18 million IU/m2/day, followed by 6 weeks of rIL-2 (3.6 x 10(6)-4.8 x 10(6) IU/m2/day x 5 days/week) and rIFN-alpha (5 x 10(6)-6 x 10(6) U/m2 x 3/week). Before and after therapy, we phenotypically evaluated circulating lymphocytes and correlated them with clinical response. During 6-week therapy, peripheral blood lymphocytes bearing the CD56 (NK-cell-associated) surface antigen were increased significantly (p < or = 0.005) in treatment responders [complete response (CR) and partial response (PR), n = 10; 3.8-fold] and stable disease (SD) patients (n = 20; 2.1-fold), while patients with progressive disease (PD, n = 17) exhibited no significant expansion of circulating NK cells (p > 0.1). After one 6-week treatment cycle, CR/PR patients had significantly more peripheral NK cells, when compared with patients in SD (1.6-fold) and PD (1.9-fold) (p < 0.04). The overall number of circulating lymphocytes was also increased upon therapy (1.6-fold; p < or = 0.001), but remained independent of response (p > 0.4). These data demonstrate that s.c. rIL-2 and s.c. rIFN-alpha produce a significant increase in peripheral blood NK cells; this expansion correlates significantly with treatment response in advanced tumor patients receiving long-term combination immunotherapy at outpatient doses.

Antigens, CD↗
PubMed1993

Increased urinary loss of high density lipoproteins in albuminuric insulin-dependent diabetic patients.

The pathophysiological mechanisms resulting in hyperlipidaemia in albuminuric insulin-dependent diabetic patients are largely unknown. Increased non-specific hepatic protein synthesis as a response to urinary protein loss, has been proposed. However in that case it is unexplained why the plasma concentration of the high density lipoprotein (HDL) subfraction, in contrast to all other lipoprotein subfractions, is normal or even reduced in albuminuric patients. We studied the urinary excretion of HDL-cholesterol in 26 insulin-dependent diabetic patients matched according to sex and age into three groups. I: normal urinary albumin excretion (< 30 mg 24 h-1; n = 8); II: incipient nephropathy (urinary albumin excretion in the range of 30-300 mg 24 h-1; n = 7); and III: clinical nephropathy (urinary albumin excretion > 300 mg 24 h-1; n = 11). Eight normal subjects served as controls. Lipoproteins in urine were separated by ultracentrifugation, and the daily urinary loss of HDL-cholesterol was 1.30 mumol (0.83-2.21) (median and range) in controls, 1.27 mumol (0.56-2.59) in group I, 1.39 mumol (0.55-1.97) in group II and 4.02 mumol (1.33-42.12) in group III (p < 0.01). More than 95% of cholesterol in urine was found in the HDL-fraction. The plasma concentrations of total cholesterol, very low density lipoprotein cholesterol, low density lipoprotein cholesterol and triglyceride were 21-94% higher in patients with clinical nephropathy compared with normal controls and group I.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

CD58 and CD59 molecules exhibit potentializing effects in T cell adhesion and activation.

We have generated stable Chinese hamster ovary (CHO) cell transfectants expressing either CD58 or CD59 or both molecules to compare their respective parts played in T cell adhesion and activation. Using a rosetting assay, we have shown the following: 1) The CD59 molecule was directly responsible for adhesive interaction between human T cells and CD59+ CHO transfectants. CD59-mediated adhesion induced 12 +/- 2% (mean +/- SEM, n = 25) of rosettes. 2) The CD58 molecule expressed on CD58+ CHO transfectants induced 29 +/- 6% (mean +/- SEM, n = 8) of rosettes. 3) Double transfected CD58+CD59+ CHO cells formed up to 80% of rosettes, largely exceeding the sum of rosettes formed by single transfectants, thus disclosing at least an additive and possibly a synergic action of both molecules in mediating adhesion to T cells. Culturing purified human T cells in the presence of fixed CHO transfectants and submitogenic doses of PHA + rIL-1 alpha showed that: 1) CD59+ CHO transfectants induced sevenfold T cell proliferation enhancement, demonstrating the direct involvement of the CD59 molecule in T cell activation; 2) CD58+ CHO transfectants induced 20-fold T cell proliferation increase; and 3) the enhancement induced by CD58+CD59+ CHO cells was more than 40-fold. These results suggest that CD58 and CD59 molecules present on the surface of accessory cells might exert synergic function in T cell adhesive interactions and in the stimulation of T cell activation.

Animals↗
PubMed1992

CD59 molecule: a second ligand for CD2 in T cell adhesion.

The T cell surface molecule CD2 forms, with its counter-receptor CD58 (LFA-3), a powerful adhesion/activation pathway. There is some evidence that CD2 might bind more than a single ligand. Chinese hamster ovary cells (CHO) expressing human CD59 after cDNA transfection (CD59+CHO) form rosettes with human T cells; these rosettes are inhibited in a dose-dependent fashion by the CD59 monoclonal antibody (mAb) H19 and by the CD2 mAb O275 known to block natural rosettes, but not by the CD2R mAb D66, a poor rosette blocker. CD2+CHO transfectants form rosettes with human erythrocytes; these rosettes are inhibited by the CD59 mAb H19 in addition to CD2 mAb O275 and CD58 mAb; murine thymoma cells expressing human CD2 form rosettes with CD59+CHO cells that again are blocked by CD59 H19 and by CD2 O275 mAb. In a marked contrast with H19, two others CD59 mAb, YTH 53.1 and MEM 43, which react with a different epitope on CD59, led to a 50%-70% increase of the number of cells forming rosettes. In addition to rosette experiments, the binding of 125I-labeled CD59 molecules to CD2+CHO cells was specifically inhibited by unlabeled CD59 molecule and CD2 mAb. Furthermore, the binding of CD59 molecules to resting T cells induced expression of CD2R epitopes. These results directly show that CD2 binds CD59 and that subtle molecular changes occur upon binding.

Animals↗
PubMed1991

Melibiose permease of Escherichia coli: mutation of aspartic acid 55 in putative helix II abolishes activation of sugar binding by Na+ ions.

An aspartic residue (Asp55) located in the putative transmembrane alpha-helix II of the melibiose(mel) permease of Escherichia coli was replaced by Cys using oligonucleotide-directed, site-specific mutagenesis. Although D55C permease is expressed at 0.7 times the level of wild type permease, the mutated mel permease loses the ability to catalyse Na+ or H+ coupled melibiose transport against a concentration gradient. (3H) p-nitrophenyl-alpha-D-galactoside (NPG) binding studies demonstrated that D55C permease binds the sugar co-substrate but Na+ (or Li+) ions do no longer enhance the affinity of D55C permease for the co-transported sugar. In addition sugar binding on D55C permease but not on wild type permease is inactivated by sulfhydryl reagents and the inhibition protected by an excess of melibiose. These observations suggest 1) that the negatively-charged Asp55 residue, expected to be within the membrane embedded domain near the NH2 extremity of mel permease, is in or near the Na(+)-binding site and 2) that the cation and sugar binding sites may be overlapping.

Aspartic Acid↗
PubMed1991

Toxoplasma encephalitis of immunocompetent and nude mice: immunohistochemical characterisation of Toxoplasma antigen, infiltrates and major histocompatibility complex gene products.

The experimental infection of immunocompetent and immunodeficient athymic mice with an avirulent encephalitogenic Toxoplasma strain (DX strain) was employed to study the ensuing encephalitic process by use of histological and immunocytochemical methods. In the acute phase of the infection Toxoplasma cysts and tachyzoites were accompanied by an infiltrate composed of macrophages, CD4+ and CD8+ T cells. In the chronic stage a granulomatous encephalitis developed. In contrast to immunocompetent NMRI mice, athymic nude NMRI mice died 3 weeks post-infection because of a generalized toxoplasmosis with predominant involvement of the brain. A salient feature of murine Toxoplasma encephalitis was up-regulation of class I and II major histocompatibility complex (MHC) gene products. Class I antigen was widely expressed on microglial cells and astrocytes. Class II antigen was only expressed on microglial cells despite a considerable astrogliosis. Our results indicate a differential expression of MHC-determined antigens on brain cells in acute and chronic murine Toxoplasma encephalitis.

Animals↗
PubMed1991

Possible genetic defects in regulation of glycosaminoglycans in patients with diabetic nephropathy.

The hypothesis of genetic defects in glycosaminoglycan (GAG) regulation among patients with insulin-dependent diabetes mellitus (IDDM) and nephropathy was assessed by studies in tissue cultures of fibroblasts obtained from 7 patients with normal urinary albumin excretion, 11 patients with diabetic nephropathy, and 6 nondiabetic control subjects. The incorporation of [2H] glucosamine and [35S] sulfate into hyaluronic acid (HA), chondroitin sulfate and dermatan sulfate (CS + DS), and heparan sulfate (HS) was measured in cells, matrix, and medium and related to micrograms of tissue protein. Large interindividual variations were seen in all three groups, and the incorporation of [3H] glucosamine into HA, CS + DS, and HS and [35S] sulfate into CS + DS and HS were not significantly different between the three groups. However, the fractional incorporation of [3H]glucosamine into HS was significantly reduced in diabetic patients with nephropathy compared with control subjects. This was the case not only when related to the total amount of GAGs (P = 0.014) but also when related to HA (P = 0.014). No significant difference was seen between control subjects and normoalbuminuric diabetic patients. The degree of N-sulfation of HS was not significantly different between the experimental groups. The results suggest that patients with diabetic nephropathy may suffer from deficiencies of coordinate regulation in the biosynthesis of GAG in fibroblasts, which may lead to a reduced density of HS in the extracellular matrix. If these changes reflect alterations in the biosynthesis of GAG from endothelial, myomedial, and mesangial cells, this observation may be relevant for the pathogenesis of severe diabetic complications.

Adult↗
PubMed1990

[Health hazards due to lead in an an accumulator-production plant of the Suhl district].

In a lead accumulator producing factory the health risk of workers has been studied for more than 30 years by means of measuring the lead concentration at the working places for many years and by carrying out several exposure tests on the 22 workmen. At most workshop places the maximum allowable concentration was considerably exceeded. In many workmen the concentration of lead in the blood and the delta aminolevulinic acid in the urine were increased above the control values. Since 1955 six occupational diseases have been diagnosed which demonstrates the high health risk.

Air Pollutants, Occupational↗
PubMed1989

Determination of the proliferative potential of human brain tumors using the monoclonal antibody Ki-67.

The proliferative activity of 133 human tumors of the nervous system was investigated by means of immunohistochemistry using the monoclonal antibody Ki-67 in order to evaluate the usefulness of this method for histopathological tumor grading. Ki-67 recognizes a proliferation-associated nuclear antigen present in human cells during all active phases of the cell cycle but absent in the G0 phase [Gerdes J, Schwab U, Lemke H, Stein H (1983) Int J Cancer 31:13-20]. In 28 WHO grade I and II gliomas of all major types Ki-67 indices were generally low with mean values ranging from less than 1% in pilocytic astrocytomas to 4.2% in grade II oligodendrogliomas. Individual cases of grade II astrocytomas and oligodendrogliomas had, however, values up to 8.5%. In 13 primary anaplastic gliomas of WHO grade III consistently higher statistical means were obtained with values ranging from 8.6% for anaplastic astrocytomas to 14.2% for anaplastic mixed gliomas. Interestingly, 18 WHO grade IV glioblastomas demonstrated a mean value of only 7%, which is probably due to the pronounced phenothypic heterogeneity in this tumor group. This heterogeneity results in enormous intra- and intertumor variability in Ki-67 indices (range less than 1%-22.1%). Investigation of 17 recurrent gliomas revealed mean values for Ki-67 ranging from 1.7% for three WHO grade II astrocytomas up to 48.5% obtained in two highly anaplastic recurrent astrocytomas corresponding to WHO grade IV. Other tumors of the nervous system evaluated included 9 medulloblastomas (mean 17.9%, range 5.0%-42.0%), 17 benign meningiomas (mean 1.1%, range 0%-5%), 15 metastatic carcinomas (mean 16.5%, range less than 1%-46.0%), and individual tumors of various types. Our results indicate that Ki-67 immunohistochemistry can add useful additional information for histopathological grading which, by supplementing and refining the traditional WHO grading system, might lead to a better assessment of the biological behaviour of human tumors of the nervous system.

Antibodies, Monoclonal↗
PubMed1989

Immunohistochemical determination of protein kinase C expression and proliferative activity in human brain tumors.

Protein kinase C (PKC), the major receptor for phorbol ester tumor promotors, is a phospholipid- and calcium-dependent phosphorylating enzyme which plays an important role in the intracellular signal transduction necessary for a variety of basic cellular functions including the control of cell proliferation. To determine the expression of PKC in human neurogenic tumors we investigated 121 tumors of the human nervous system by means of immunohistochemistry using the monoclonal antibody C5. The results were compared with immunohistochemical staining for intermediate filament proteins, desmoplakins, and the proliferation-associated nuclear antigen Ki-67. Besides strong staining of normal and reactive astrocytes, C5 immunoreactivity was consistently observed in tumor cells of all types of gliomas. However, the fraction of C5 positive tumor cells varied between the different tumor types with astrocytomas and subependymomas demonstrating the strongest immunoreactivity. In the other gliomas, especially those of higher malignancy, a considerable heterogeneity in C5 expression could be observed. There was a tendency for the percentage of C5 immunostained tumor cells being lower in high-grade gliomas compared to low-grade ones and comparison with Ki-67 staining frequently revealed an inverse relationship between proliferative activity and C5 immunoreactivity. Besides the gliomas we found 3 of 7 neurinomas and 6 of 18 meningiomas which were partially C5 positive. All other tumors investigated including medulloblastomas and metastatic carcinomas were C5 negative. Our results thus indicate that immunohistochemistry for PKC using the monoclonal antibody C5 could be an useful aid for histopathological tumor classification in neuro-oncology.

Adult↗
PubMed1989

Epidermal growth factor receptor expression and growth fraction in human tumours of the nervous system.

100 tumours of the human nervous system were investigated by means of immunohistochemistry in order to determine the expression of epidermal growth factor receptor (EGFr) and the proliferative activity as evaluated by demonstration of the proliferation-associated Ki-67 antigen. Epidermal growth factyr receptor immunoreactivity was present in 79% (23/29) of the high-grade malignant gliomas examined but in only 9% (2/22) of the low-grade gliomas. Besides the gliomas, EGFr-expression was detectable in smaller amounts in most (13/15) meningiomas, in one anaplastic neurinoma and in individual tumour cells of one medulloblastoma. In addition, EGFr-expression was found in 50% (6/12) of metastatic carcinomas. Seven of eight medulloblastomas, two cerebral primitive neuroectodermal tumours (PNETs), three benign neurinomas, one ganglioneuroma, one metastatic intracerebral malignant melanoma, three spinal plasmacytomas and one immunocytoma showed no detectable EGFr-expression. Our results indicate that (1) the expression of EGFr in human tumours of the nervous system depends on the histological tumour type and (2) in the glioma group is related to the grade of malignancy. A close correlation between EGFr-expression and proliferative activity as evaluated by Ki-67 staining could not, however, be established.

Cell Division↗
PubMed1989

Endotheliomatous meningioma with coalescing microcysts, presenting as an hypodense lesion with ring enhancement on computed tomography.

Computed tomography (CT) revealed a hypodense intracranial tumour that showed a slight ring enhancement and a peripheral tumour nodule. Although this suggested a cystic astrocytoma, angiography identified a meningeal tumour. Microscopical examination demonstrated a cystic endotheliomatous meningioma. Neuropathological and intraoperative findings suggested that the meningioma was an intermediate form between the microcystic and macrocystic types, illustrating the evaluation from the former to the latter.

Cysts↗
PubMed1989

Comparison of ultracentrifugation and a precipitation method for high-density lipoprotein cholesterol quantitation in insulin-dependent diabetic patients.

We compared sodium phosphotungstic acid and magnesium chloride precipitation method for high-density lipoprotein (HDL) cholesterol quantitation with the ultracentrifugation method in 64 insulin-dependent diabetic patients with plasma triglyceride less than 3 mmol/l. The cholesterol content of HDL after precipitation of very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) was 86% +/- 3% of the cholesterol content of HDL (q greater than 1.063) determined after ultracentrifugation at q = 1.063 (1.33 +/- 0.05 mmol/l vs 1.55 +/- 0.06 mmol/l; p less than 0.001). HDL cholesterol determined after precipitation closely correlated to HDL cholesterol determined after ultracentrifugation (r = 0.97; p less than 0.001). The absolute difference between the HDL cholesterol values obtained by the two methods was correlated to HDL cholesterol (ultracentrifugation) (r = 0.75; p less than 0.001), but it was not correlated to VLDL cholesterol, LDL cholesterol, triglyceride, HbA1c, blood glucose or serum albumin. LDL cholesterol calculated by use of Friedewald's formula was 108% +/- 4% of the cholesterol content of LDL (q = 1.019 to 1.063), determined after ultracentrifugation, but the calculated and the ultracentrifugally determined LDL cholesterol values were closely correlated (r = 0.98; p less than 0.001). These results suggest that during sodium phosphotungstic acid and magnesium chloride precipitation of plasma from diabetic patients, a constant fraction of HDL cholesterol is co-precipitated, resulting in a systematic difference in HDL cholesterol quantitation when compared with the ultracentrifugation method.

Adolescent↗