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F Hartmann

Publications and source records attributed to F Hartmann.

At least 55 records · Page 3Linked to original sources
PubMed1998

Regional in vivo and in vitro characterization of autonomic innervation in cardiomyopathic human heart.

BACKGROUND: In contrast to healthy volunteers, regional differences of cardiac autonomic innervation have been described through the use of C11-hydroxyephedrine positron emission tomography (HED-PET) in the left ventricles of patients with dilated cardiomyopathy. The goal of the present study was to correlate HED-PET images with biochemical analysis of tissue samples. METHODS AND RESULTS: To assess the significance of altered HED uptake, we used HED-PET to examine eight patients with dilated cardiomyopathy before heart transplantation. After explantation, we measured the density and affinity of uptake1 (3H-mazindol binding) and tissue norepinephrine content as markers of presynaptic function, and we determined beta-receptor density and affinity (3H-CGP 12177 binding) in the corresponding areas of the same patients. The density of uptake1 and norepinephrine content showed marked regional variation, with highest values in the anterior septal wall and lowest in inferoapical and apical areas. Both parameters were closely correlated (r=.65, P=.05). Similarly, uptake1 density or norepinephrine content and HED retention (PET) showed clear correlations (r=.63 and .60, respectively). Uptake1 affinities did not vary significantly and were not correlated to the other parameters. Beta-Adrenergic receptor density showed some, albeit less pronounced, regional variation and was weakly correlated to uptake1 density and local HED retention (r=.38 and .31, respectively). CONCLUSIONS: Uptake1 density and tissue norepinephrine content showed marked regional variation in cardiomyopathic left ventricles. HED-PET is significantly correlated to the density but not the affinity of uptake1 sites in the human heart, suggesting either loss of neurons or downregulation of uptake1 in dilated cardiomyopathy. HED-PET is a valuable marker for alterations of the presynaptic sympathoadrenergic system in humans.

Adult↗
PubMed1998

[A patient with mixed collagen disease, antiphospholipid syndrome and Sjögren syndrome].

CASE REPORT: A 32-year-old female patient is described who suffered from common symptoms such as Raynaud's phenomenon and swollen fingers, high titers of antibodies to U1RNP, SLE-like findings, scleroderma-like findings and polymyositis-like findings. A diagnosis of mixed connective tissue disease (Sharp-syndrome) was established. In addition, the patient had antibodies against cardiolipin, thrombocytopenia, recurrent fetal loss and a history of deep venous thrombosis of her left leg which is typical for an antiphospholipid syndrome. The symptoms dry eyes and dry mouth pointed at secondary Sjögren's syndrome. The diagnosis of these disease entities and the therapeutic regimens are described and discussed.

Adult↗
PubMed1998

[Cardiac sympathetic nerve activity in ischemic heart failure].

The prognosis in patients with heart failure, independent of etiology, is determined mainly by the extent of sympatho-adrenergic stimulation. In the development of heart failure sympathetic cardiac stimulation precedes systemic sympatho-adrenergic activation. Increased concentrations of the neurotransmitter norepinephrine can be found in the myocardium. This is a result of both increased release from sympathetic nerves as well as reduced neuronal reuptake. We were able to show that in advanced heart failure these effects are distributed heterogeneously in the heart. It has been shown experimentally that the effects on sympathetic neurotransmission are similar for both ischemia and heart failure. Therefore, these findings could indicate an important role of sympatholytic measures in patients with ischemia induced heart failure.

Heart↗
PubMed1998

A chromatographic assay for heme oxygenase activity in cultured human cells: application to artificial heme oxygenase overexpression.

Heme oxygenase (HO) activity oxidizes heme, releasing carbon monoxide; heme iron; and biliverdin, which is converted to bilirubin by biliverdin reductase. Inducible HO-I expression is a marker of oxidative stress in mammalian cells, while noninducible HO-II contributes to basal HO activity. HO-I and HO-II activities are implicated in cellular antioxidant defense mechanisms. We describe a microassay for HO activity in cultured human cells, using high-performance liquid chromatography of biliverdin and bilirubin. The assay is sufficiently sensitive to quantify basal and inducible HO activity in various human cell types. We have established human cell lines overexpressing heme oxygenase-II activity in microsomes using a metallothionein promoter-regulated expression system. Stable transformants treated with ZnCl2 express up to ninefold induction of HO activity. We have constructed human cell lines overexpressing HO-II protein and activity (5-15-fold) in the absence of tetracycline, using the HtTA-1 cell line transfected with tetracycline-regulated expression vectors (Gossen et al., Proc. Natl. Acad. Sci. USA 89, 1992). Functional HO-II overexpressing clones will be useful in investigating anti- or pro-oxidant effects of HO activity during cellular oxidative stress.

Cell Line↗
PubMed1998

Anti-CD16/CD30 bispecific antibodies as possible treatment for refractory Hodgkin's disease.

Fifteen patients with refractory Hodgkin's disease were treated in a phase I/II dose escalation trial with the NK-cell activating bispecific monoclonal antibody HRS-3/A9 which is directed against the Fcgamma-receptor III (CD16 antigen) and the Hodgkin's associated CD30 antigen, respectively. HRS-3/A9 was given four times every 3-4 days starting with 1 mg/m2. The treatment was well tolerated and the maximum tolerated dose was not reached at 64 mg/m2, the highest dose given due to limited amounts of HRS-3/A9 available. Mild to moderate side effects occured in six patients and consisted of fever, pain in involved lymph nodes, and a maculopapulous rash. Median counts of NK-cells and of all lymphocyte subsets were considerably decreased in the patients before therapy and showed no consistent changes under therapy. Eight patients developed human anti-mouse immunoglobulin antibodies, and five patients showed an allergic reaction after attempted retreatment. One complete and one partial remission (lasting 6 and 3 months, respectively), three minor responses (lasting 1 to 15 months), two disease stabilizations (for 2 and 17 months, respectively), and one mixed response were achieved. There was no clearcut dose-side effect or dose-response correlation. Our results encourage further clinical trials with this novel immunotherapeutic approach and emphasize the necessity to reduce the immunogenicity of the murine bispecific antibodies.

Adult↗
PubMed1998

Biochemical markers in the diagnosis of coronary artery disease.

For many years cardiac markers have been used to classify whether chest pain is attributable to acute myocardial infarction or not. However massive, myocardial infarction is frequently preceded by plaque inflammation and local thrombus formation. Novel cardiac markers focus on detection of these more subtle manifestations of coronary artery disease. Detection of inflammation of coronary artery plaques is best achieved by measurement of C-reactive protein and fibrinogen, while thrombus formation may be assessed by testing for fibrin formation and platelet activation. When coronary flow is severely impaired minor myocardial injury will occur and cellular constituents may egress from damaged myocytes. Among the many cardiac markers for myocardial cell necrosis, troponin T revealed the highest sensitivity and cardio-specificity. The superior performance of troponin T has not only refined detection of myocardial cell necrosis but has also improved the risk stratification process and may even facilitate therapeutic decision making in patients with acute coronary syndrome. This review will summarize the characteristics and performance of diagnostic tools used for classification and risk stratification of patients with suspected myocardial injury.

Biomarkers↗
PubMed1997

Treatment of refractory Hodgkin's disease with an anti-CD16/CD30 bispecific antibody.

Fifteen patients with refractory Hodgkin's disease were treated in a phase I/II trial with the natural killer (NK)-cell-activating bispecific monoclonal antibody HRS-3/A9, which is directed against the Fc(gamma)-receptor III (CD16 antigen) and the Hodgkin's-associated CD30 antigen, respectively. Median counts of NK cells and of all lymphocyte subsets were considerably decreased in the patients before therapy. HRS-3/A9 was administered 4 times every 3 to 4 days, starting with 1 mg/m2. The treatment was well tolerated, and the maximum tolerated dose was not reached at 64 mg/m2, the highest dose administered because of the limited amounts of HRS-3/A9 available. Side effects were rare and consisted of fever, pain in involved lymph nodes, and a maculopapulous rash. A total of 9 patients developed human antimouse Ig antibodies, and 4 patients developed an allergic reaction after attempted retreatment. A total of 1 complete and 1 partial remission (lasting 6 and 3 months, respectively) [corrected], 3 minor responses (1 to 11+ months), and 1 mixed response were achieved. There was no clear-cut dose-side effect or dose-response correlation. Our results encourage further clinical trials with this novel immunotherapeutic approach and emphasize the necessity to reduce the immunogenicity of the murine bispecific antibodies.

Adolescent↗
PubMed1997

[Oncology '96].

Explore the source record for details and available documents.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Effects of the tyrosine-kinase inhibitor geldanamycin on ligand-induced Her-2/neu activation, receptor expression and proliferation of Her-2-positive malignant cell lines.

Geldanamycin belongs to the family of benzoquinoid ansamycin tyrosine-kinase inhibitors. We have examined its effects on Her-2/neu kinase activity, protein expression level, and proliferation of Her-2+ malignant cells. In SK-BR-3 breast-cancer cells, short-time treatment with geldanamycin completely abrogated gp30-ligand-induced activation of Her-2 without a change of receptor-expression level. Longer treatment of intact cells with geldanamycin induced decreased steady-state Her-2 autophosphorylation activity, which correlated with reduction of Her-2 protein expression and phosphotyrosine content of several proteins. The decrease was time- and dose-dependent, starting after 1 hr at 100 nM concentration and reaching completion by 24 hr. The reduction of the Her-2 protein level probably resulted from increased degradation, since the Her-2 mRNA level remained constant. Geldanamycin effects were not specific for Her-2, since the non-receptor tyrosine-kinase fyn was inhibited equally. In contrast to these results, protein-kinase-C activity was not affected. In 3 other malignant cell lines expressing different amounts of Her-2 (SK-BR-3 > SK-OV-3 > OVCAR3 > MCF7), geldanamycin also effectively reduced Her-2-kinase activity proportionally to the decrease of protein expression. In contrast, in a [3H]-thymidine-uptake assay, cell growth was meaningfully inhibited by geldanamycin at nanomolar concentrations only in SK-BR-3 (IC50 2 nM) and MCF7 (IC50 20 nM), while OVCAR3 was only moderately sensitive (IC50 2 microM) and SK-OV-3 was clearly resistant to geldanamycin. In direct comparison with herbimycin A, another benzoquinoid ansamycin that has been more thoroughly characterized, the biologic effects of geldanamycin were more pronounced.

Adenocarcinoma↗
PubMed1997

Successful collection of peripheral blood progenitor cells in patients with acute myeloid leukaemia following early consolidation therapy with granulocyte colony-stimulating factor-supported high-dose cytarabine and mitoxantrone.

We evaluated the feasibility of collecting peripheral blood progenitor cells (PBPC) in patients with acute myeloid leukaemia (AML) following two cycles of induction chemotherapy with idarubicin, cytarabine and etoposide (ICE), and one cycle of consolidation therapy with high-dose cytarabine and mitoxantrone (HAM). Thirty-six patients of the multicentre treatment trial AML HD93 were enrolled in this study, and a sufficient number of PBPC was harvested in 30 (83%). Individual peak concentrations of CD34+ cells in the blood varied (range 13.1-291.5/microl; median 20.0/microl). To reach the target quantity of 2.5 x 10(6) CD34+ cells/kg, between one and six (median two) leukaphereses (LP) were performed. The LP products contained between 0.2 x 10(6) and 18.9 x 10(6) CD34+ cells/kg (median 1.2 x 10(6)/kg). Multivariate analysis showed that the white blood cell count prior to HAM and the time interval from the start of HAM therapy to reach an unsupported platelet count > 20 x 10(9)/l were predictive for the peak value of CD34+ cells in the blood during the G-CSF stimulated haematological recovery. In 16 patients an intraindividual comparison was made between bone marrow (BM) and PBPC grafts. Compared to BM grafts, PBPC grafts contained 14-fold more MNC, 5-fold more CD34+ cells and 36-fold more CFU-GM. A CD34+ subset analysis showed that blood-derived CD34+ cells had a more immature phenotype as indicated by a lower mean fluorescence intensity for HLA-DR and CD38. In addition, the proportion of CD34+/Thy-1+ cells tended to be greater in the PBPC grafts. The data indicate that sufficient PBPC can be collected in the majority of patients with AML following intensive double induction and first consolidation therapy with high-dose cytarabine and mitoxantrone.

Acute Disease↗
PubMed1997

Radioimmunotherapy targeting of HER2/neu oncoprotein on ovarian tumor using lead-212-DOTA-AE1.

UNLABELLED: The specificity, toxicity and efficacy of lead (212Pb) radioimmunotherapy were evaluated in nude mice bearing the SK-OV-3 human ovarian tumor cell line expressing the HER2/neu proto-oncogene. METHODS: The therapeutic agent used was the tumor-specific anti-HER2/neu monoclonal antibody AE1 conjugated to 212Pb, 212Bi being the daughter and thus the source of the alpha-particle and beta emissions. A bifunctional derivative of tetraazacyclododecanetetraacetic acid (p-SCN-Bz-DOTA) was used to couple 212Pb to the anti-HER2/neu monoclonal antibody AE1. The chelating agent did not alter the binding affinity to its antigenic target or the pharmacokinetics and tissue distribution of the AE1 antibody. Toxicity and therapeutic efficacy of 212Pb-AE1 were evaluated in nude mouse ascites or solid tumor models, wherein SK-OV-3 cells were administered i.p. or s.c., respectively. RESULTS: The dose-limiting acute toxicity after i.v. administration of 212Pb-AE1 was bone marrow suppression, which was observed at doses above 25 microCi. Therefore, doses of 10 and 20 microCi were used in efficacy trials. The i.p. administration of 212Pb-AE1 3 days after i.p. tumor inoculation led to a significant (P2 = 0.015) prolongation of tumor-free survival. In a second model, i.v. treatment with 212Pb-AE1 3 days after s.c. tumor inoculation prevented subsequent tumor development in all animals treated with 10 or 20 microCi of 212Pb-AE1 (P2 = 0.002 compared to control groups). This efficacy in the adjuvant setting was antibody specific because treatments with equivalently labeled control antibody or unlabeled AE1 antibody or no treatment were less effective. The rate of growth of small (mean tumor volume, 15 mm3) SK-OV-3 tumors was modestly inhibited. However, tumor growth was not inhibited in mice bearing larger (mean tumor volume, 146 mm3) SK-OV-3 tumors by the administration of a single dose of 10 or 20 microCi of 212Pb-AE1. CONCLUSION: Lead-212-AE1 as an intact radiolabeled monoclonal antibody may be of only modest value in the therapy of bulky solid tumors due to the short physical half-life of 212Pb and time required to achieve a useful tumor-to-normal tissue ratio of radionuclide after administration. However, the radiolabeled monoclonal antibody may be useful in therapy of tumors in the adjuvant setting. Furthermore, 212Pb may be of value in select situations, including treatment of leukemia, intercavitary therapy or strategies that target vascular endothelial cells of tumors.

Animals↗
PubMed1996

Treatment of Hodgkin's disease with bispecific antibodies.

Bispecific monoclonal antibodies (Bi-MAbs) with dual specificity for tumor-associated antigens (TAA) and a triggering molecule of an immunologic effector cell, respectively, open the possibility to specifically target to and activate cytotoxic effector cells (macrophages, T-cells, NK cells) at the tumor site. Using appropriately designed Bi-MAbs and unstimulated human NK cells and T-cells, respectively, we were able to cure SCID mice xenografted with human Hodgkin's tumors. This approach was also effective in disseminated tumors and when treatment was delayed until three weeks after the inoculation of the tumor, thus establishing this approach as the most effective model of an immunomodulating therapy of human neoplasms. Early observations with an ongoing phase I/II study with CD16/CD30 Bi-MAb in patients with refractory Hodgkin's disease confirm the expected low toxicity. If these observations can be confirmed in larger clinical studies, effector cell activating Bi-MAbs could become an important weapon in the remaining fight for the conquest of Hodgkin's disease.

Animals↗
PubMed1995

Expression of type A and B tumor necrosis factor (TNF) receptors on melanoma cells can be regulated by dbc-AMP and IFN gamma.

Local administration of high-dose r-TNF alpha with IFN gamma in the limbs of melanoma patients has proved to be a very promising treatment. To understand the role played by the effect of TNF on melanoma cells in tumor destruction, we have investigated the expression of TNF-receptors in melanoma cells using monoclonal antibodies specific for the type-A (75-kDa) and the type-B (55-kDa) TNF receptors. Flow cytometric analysis of cultured melanoma cells indicated the presence of both types of receptor. Quantificative differences in the relative levels of receptors were observed for different cells lines, although the type-B receptor was generally more strongly expressed. Similar results were obtained by immunohistochemistry on cryosections from tumor samples. Positive staining of variable intensity was observed for the type-B TNF-receptor in a high percentage of tumor cells. The type-A TNF-receptor was also detected, but with a weaker staining. The total TNF-binding activity of cultured melanoma cells, as measured by binding of 125I-labeled TNF alpha, was up-regulated between 2- and 4-fold by incubation of cells with activators of protein kinase A or IFN gamma. Treatment of cultured melanoma cells with dbc-AMP resulted in a selective induction of type-A TNF-receptors, without affecting the type-B receptor level. In contrast, IFN gamma was able to induce either type of receptor in a cell-line-dependent fashion. Addition of TNF alpha to melanoma cells induced the activation of the nuclear transcription factor kappa B, as measured in an electrophoretic mobility shift assay, thus indicating the biological significance of the TNF-receptors on these cells.

Base Sequence↗
PubMed1995

Comparison between high dose 5-aminosalicylic acid and 6-methylprednisolone in active Crohn's ileocolitis. A multicenter randomized double-blind study. German 5-ASA Study Group.

BACKGROUND: The value of 5-aminosalicylic acid (5-ASA) in Crohn's disease (CD) is still under discussion. In a previous study 2 g 5-ASA per day were inferior to a standard glucocorticoid treatment with 6-methylprednisolone (6-MPred) (Can J Gastroenterol 1990; 4: 446-51). In the present study we tested whether in active CD response rates to 4.5 g 5-ASA/day were not different from those to 6-MPred. METHODS: Multicenter randomized double-blind double-dummy trial. 34 patients with active CD (CDAI > 150) were included. 17 patients were in the 5-ASA group (Salofalk, 4.5 g/day), 17 patients in the 6-MPred group (Urbason, initial dose 48 mg/day, weekly tapering). Duration of treatment was 8 weeks. Main outcome measure was remission of CD (CDAI < 150) and decrease of at least 60 points. RESULTS: Both groups were comparable with respect to demographic and clinical parameters. The median CDAI decrease in the 5-ASA group was 85, in the 6-MPred group 122 (p = 0.7437). The median AUC of the CDAI in the 5-ASA group was 1027, in the 6-MPred group 950 (p = 0.137). The median AUC of the CDAI per treatment day was 22.94 in the 5-ASA group, and 17.33 in the 6-MPred group (p = 0.0555). On an intention-to-treat basis remission rates after 8 weeks were 40.0% in the 5-ASA group and 56.3% in the 6-MPred group (p = 0.5867). CONCLUSIONS: Response rates to 5-ASA or 6-MPred were not significantly different although there was a trend towards a higher efficacy of 6-MPred. 5-ASA may be considered as alternative treatment in patients with activer CD who are intolerant to or refuse glucocorticoids.

Adult↗