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Biomedical subjects

F Herrmann

Publications and source records attributed to F Herrmann.

At least 91 records · Page 5Linked to original sources
PubMed1990

Effects of recombinant human interleukin-3 in patients with normal hematopoiesis and in patients with bone marrow failure.

In a phase I/II study, 19 patients with advanced tumors but normal hematopoiesis and nine patients with bone marrow failure and prolonged severe cytopenias were treated with recombinant human interleukin-3 (rhIL-3) to assess the toxicity and biological effects of this multipotential hematopoietic growth factor. Doses ranging from 30 micrograms/m2 to 500 micrograms/m2 were administered as subcutaneous bolus injection daily for 15 days. A dose-dependent increase in platelet counts ranging from 1.3-fold at 60 micrograms/m2 to 1.9-fold at 250 micrograms/m2 was induced by rhIL-3 in 15 of 18 evaluable patients with normal hematopoiesis. An increase in reticulocyte counts was observed in 14 patients. The blood leukocyte counts dose dependently increased 1.4- to 3.0-fold. In patients with bone marrow failure, platelet counts increased by a mean of sixfold (range, 1.3-fold to 14.3-fold) in five of eight evaluable patients. Reticulocyte counts increased 4.4-fold in six patients, and neutrophil counts increased by a mean of 3.1-fold in all eight patients. Platelet transfusions could be discontinued after treatment with rhIL-3 in two of three transfusion-dependent patients. Only mild side effects, mainly fever, headache, and flushing, were observed. These results indicate that rhIL-3 functions as a multilineage hematopoietin in vivo in patients with normal bone marrow function and in patients with secondary bone marrow failure.

Adult↗
PubMed1990

Effects of recombinant human interleukin-3 in patients with myelodysplastic syndromes.

In a phase I-II study, nine patients with myelodysplastic syndromes and concomitant severe transfusion-dependent cytopenias were treated with recombinant human interleukin-3 (rhIL-3) to improve hematopoietic function. Doses of rhIL-3 ranged from 250 micrograms/m2 to 500 micrograms/m2 and were given as daily subcutaneous bolus injections for 15 days. Blood leucocyte counts increased 1.3- to 3.6-fold in all nine patients, including neutrophils, eosinophils, lymphocytes, basophils, and monocytes. The mean absolute neutrophil counts increased from 1,350/microL (range, 150 to 2,420) to 2,660/microL (range, 300 to 9,380) (P less than .05) immediately after the end of rhIL-3 therapy and to a maximum count of 4,096/microL (range, 350 to 10,820) (P less than .01). Platelet responses were seen in two of four profoundly thrombocytopenic patients, resulting in discontinuation of platelet transfusion. The requirements for red blood cell transfusion temporarily improved in one patient. Stimulation of plasma cells was evident by a significant increase in serum IgM and IgA levels. Mild side effects (fever, headache, local erythema, and bone pain) were observed in some patients, while transient thrombocytopenia developed in two patients. Disease progression with an increase in blast cells was seen in one patient. These results suggest that rhIL-3 is effective in stimulating hematopoiesis of all lineages in patients with myelodysplastic syndromes and may produce at least short-term hematologic improvement.

Adult↗
PubMed1990

Inducible production of interleukin-6 by human polymorphonuclear neutrophils: role of granulocyte-macrophage colony-stimulating factor and tumor necrosis factor-alpha.

The recent demonstration of the ability of human polymorphonuclear neutrophils (PMN) to secrete various cytokines in response to the granulocyte activator granulocyte-macrophage colony-stimulating factor (GM-CSF) but not to other cytokines, has led to the identification of PMN as biosynthetically active cells. In this study we have investigated the ability of PMN to secrete interleukin-6 (IL-6), a molecule known to be involved in inflammatory reactions. Using RNA blotting analysis and bioassays, we show that PMN could be induced to synthesize transcripts specific for IL-6, indistinguishable in size from IL-6 mRNA produced by activated human macrophages. Consequently, PMN released IL-6-like activity into their culture supernatants that could be neutralized by monospecific anti-IL-6 antibody. Interleukin-6 secretion by PMN, however, required previous stimulation with GM-CSF or tumor necrosis factor-alpha (TNF-alpha), whereas other cytokines, including interleukin-3 (IL-3), granulocyte-CSF (G-CSF), macrophage-CSF (M-CSF), interferon gamma (IFN-gamma), and lymphotoxin (LT), failed to induce IL-6 mRNA accumulation and protein secretion by PMN. Similar to GM-CSF and TNF-alpha, other compounds, including the inhibitor of protein synthesis cyclohexemide (CHX), endotoxin (Escherichia coli-derived lipopolysaccharide), and phorbol myristate acetate (PMA) (but not the chemoattractant N-formyl-methionyl-leucyl-phenylalanine [FMLP]), induced detectable levels of IL-6 transcripts in PMN.

Blotting, Northern↗
PubMed1990

Synthesis of granulocyte colony-stimulating factor and its requirement for terminal divisions in chronic myelogenous leukemia.

In this paper we demonstrate that maturing neoplastic cells from patients with chronic myelogenous leukemia (CML) constitutively produce G-CSF and are also receptive for this molecule. G-CSF functions as an autocrine growth factor in stable phase CML, and thus is responsible for divisions of maturing leukemic cells leading to an expansion of the compartment of mature cells. This observation is well in line with in vivo features of CML in stable phase, i.e., the hyperplasia of the mature granulocyte compartment. In acute blastic phase of CML expression of the G-CSF gene seems to be less common and not related to autonomous blast growth.

Antigens, CD↗
PubMed1990

Mechanisms of differential regulation of interleukin-6 mRNA accumulation by tumor necrosis factor alpha and lymphotoxin during monocytic differentiation.

In the present report we compare the capacity of two related cytokines, tumor necrosis factor (TNF) alpha and lymphotoxin (LT), to modulate mRNA levels of interleukin-6 (IL-6) in cells representing different stages of monocytic differentiation including the human leukemia cell lines HL 60, U 937, THP-1, MonoMac 1 and peripheral blood monocytes. We show that the capacity of TNF alpha and LT to induce IL-6 mRNA accumulation increases as monocytic differentiation proceeds with TNF alpha being more potent than LT, suggesting that alternate pathways may be used by differentiating cells to control expression of IL-6. In contrast, in monocytes which constitutively synthesize IL-6 transcripts, TNF alpha and LT treatment had opposite effects on levels of IL-6 mRNA accumulation. In these cells TNF alpha enhanced steady state levels of IL-6 transcripts due to mRNA stabilization, whereas LT shortened IL-6 mRNA half-life, most likely due to induction of a RNA destabilizer since LT-mediated downregulation of levels of IL-6 mRNA in monocytes could be prevented by inhibition of protein synthesis. Neither TNF alpha nor LT altered IL-6 mRNA accumulation by interfering with preexisting transcription factors since both TNF alpha and LT required de novo protein synthesis to exert their effects.

Blotting, Northern↗
PubMed1990

N-ras gene point mutations in childhood acute lymphocytic leukemia correlate with a poor prognosis.

Ras genes can be altered by point mutations at critical portions of their coding regions to acquire transforming ability in vitro. These point mutations have been detected in a variety of human malignancies. However, their relevance for the clinical and biologic behavior of the subgroups of patients exhibiting these mutations in unclear. We analyzed 100 patients with childhood acute lymphocytic leukemias (ALLs) for point mutations of exons 1 and 2 of all three ras genes (H-ras, K-ras, and N-ras) by polymerase chain reaction and a combination of oligonucleotide hybridization and direct DNA sequencing. A 6% incidence of N-ras gene mutations was detected, all of which occurred at different nucleotides of codons 12 or 13 of N-ras. When correlating presence of ras mutations with the clinical and biologic features and the clinical outcome of these cases, a significantly higher risk for hematologic relapse (P = .01) and a trend toward a lower rate of complete remission (P = .07) was noted. The two groups did not differ in any of the known high-risk factors of ALL. These results suggest that presence of an N-ras mutation in children with ALL may be an independent predictor for worse clinical outcome and therefore may have therapeutic implications; further studies to confirm these findings are required because of the small number of patients with N-ras mutations.

Antigens, CD↗
PubMed1990

[Incidence of goiter and thyroiditis in chronic inflammatory rheumatism].

In our investigations 201 patients with rheumatoid arthritis show in 127 cases according 63.2% (123 women = 71.1%; 4 women = 14.3%) and 32 patients with collagen diseases in 11 cases according 34.4% (11 women = 43.3%) a goiter. In comparison to a control group with a goiter incidence of 29.5% in women (168 out of 570 women), we found in female patients with rheumatoid arthritis or collagen diseases a clearly higher prevalence of goiter. But there was no difference of goiter frequency between the small groups of men. A second aim of our study was to investigate, whether an increased occurrence of the hypertrophic kind of Hashimoto's thyroiditis is to find in patients with rheumatic diseases, because of a possible association of two immunological induced affections. The results of sonographical, immunological and cytological examinations of the thyroid gland suggested no high responsibility of Hashimoto's thyroiditis for the goiter frequency in rheumatism. Only in three out of 201 investigated patients with rheumatoid arthritis (1.5%) we were able to diagnose this disease. In comparison to a rheumatologically healthy population out of the same catchment area (HT-frequency less than 0.5%), indeed the morbidity rate in rheumatic patients seems to be 3 times higher. But for a goiter frequency of altogether 63.2% in this disease the Hashimoto's thyroiditis is only of very small importance. Other causes such as pharmacotherapy with goitrogenic antirheumatic drugs, conditions of iodine deficiency, disposition and probably also an increase of thyroid growth stimulating immunoglobulins may be alone or in combination or a much higher degree responsible for goiter development in patients with rheumatoid arthritis or collagen diseases.

Adolescent↗
PubMed1990

Cytokine-stimulation of prostaglandin synthesis from endogenous and exogenous arachidonic acids in polymorphonuclear leukocytes involving activation and new synthesis of cyclooxygenase.

Peripheral blood-derived human polymorphonuclear leukocytes (PMNL) can be induced to synthesize prostaglandin E2 (PGE2) from endogenous and exogenous arachidonic acid (AA) when exposed to agents such as human recombinant (hr) granulocyte-macrophage (GM) colony-stimulating factor (CSF), hr tumor necrosis factor-alpha, hr granulocyte (G)-CSF, lipopolysaccharide and the chemoattractant N-formyl-methionyl-leucyl-phenylalanine. Treatment of PMNL with hr macrophage (M)-CSF and interleukin 3, however, did not result in detectable PGE2 synthesis. Cytokines stimulated PGE2 production during two distinct time intervals, an early peak of PGE2 that was detectable at 20 min and a late one detectable after 4 h. Inhibition of protein synthesis by cycloheximide (CHX) had virtually no effect on the early increase of PGE2 but prevented the late increase. Late addition of CHX to cultures after stimulation with hr GM-CSF at 4 h resulted in decline of PGE2 synthesis from exogenous arachidonic acid. Treatment of PMNL with GM-CSF had direct effects on cyclooxygenase (COx). PMNL depleted from COx by acetyl salicylic acid (ASA) recovered to synthesize PGE2 following exposure to GM-CSF. Recovery from COx inhibition by ASA could be prevented by CHX.

Arachidonic Acid↗
PubMed1990

Effect of granulocyte-macrophage colony-stimulating factor on neutropenia and related morbidity induced by myelotoxic chemotherapy.

A phase Ib/II clinical study was undertaken to assess the efficacy of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) to attenuate neutropenia and associated morbidity caused by high-dose anticancer chemotherapy administered in the presence or absence of autologous bone marrow support. We treated 22 patients with various solid tumors and lymphoid neoplasias with a single daily subcutaneous dose of GM-CSF (250 micrograms/m2) 48 h after a second cycle of highly myelotoxic chemotherapy for a period of 10 days and compared intraindividually neutropenia-related clinical and laboratory variables with data obtained from the same patients having previously received a first neutropenia-inducing cycle of identical chemotherapy in the absence of GM-CSF. We show that GM-CSF is active in neutropenic patients by significantly increasing the neutrophil nadir, reducing the time of relevant neutropenia, and reducing the duration of the patient's hospital stay and necessity for parenteral antibiotics. No significant toxicity was encountered with subcutaneous GM-CSF treatment.

Agranulocytosis↗
PubMed1990

The role of colony-stimulating factors in acute leukemia.

This article summarises the effects of colony-stimulating factors and related molecules on leukemia blasts by focussing on autocrine and paracrine growth control. This information may lead to a better understanding of the pathobiology of this highly malignant disorder, and may have therapeutic implications.

Colony-Stimulating Factors↗
PubMed1990

Erythropoietin prevents chemotherapy-induced anemia: case report.

A thirty-seven year old male patient with heavily pretreated metastatic testicular carcinoma received escalating doses of recombinant human erythropoietin (EPO) before and throughout chemotherapy. Whereas previous chemotherapy regimens repeatedly caused anemic situations in this patient (hemoglobin (HB) 7.0 g/dl requiring multiple transfusions of red blood cells), EPO given as an i.v. bolus injection at escalating doses of 150 to 300 U/kg body weight (BW) twice/week, starting two weeks prior to the identical myelosuppressive treatment protocol, maintained HB at levels above 8.8 g/dl and thus obviated the need for erythrocyte transfusion. EPO was discontinued after 9 weeks of administration when the patient had achieved a hematocrit (HCT) of 41.1% and a HB of 12.7 g/dl. However, erythropoiesis continued to recover for the next 7 weeks reaching a HCT of 42.4% and a HB of 14.3 g/dl, although the next identical chemotherapy cycle had been given within this period. Along with the rise in HB, ferrokinetics changed significantly as measured by serum ferritin, which was reduced to one third at the end of EPO therapy after only 9 weeks (from 979 ng/ml to 320 ng/ml). No side effects due to EPO administration occurred. These data provide first evidence for efficacy of EPO in chemotherapy-induced anemia and may open new avenues for its clinical application.

Adult↗
PubMed1990

Animal models for the biological effects of continuous high cytokine levels.

Transgenic animals or animals engrafted with retrovirus-derived expression vectors provide models for studying the in vivo effects of high and continuous serum levels of cytokines. Studies employing these models in order to analyze the biological effects for granulocytes-macrophages colony-stimulating factors (CSFs), granulocytes of interleukin (IL-)2, IL-3, IL-6 and erythropoietin are reviewed. In all of these models, overexpression of the different cytokines achieved by use of these approaches resulted in syndromes that were related to nonneoplastic hyperplasia of the respective target cell population. In some but not all models, these syndromes were lethal, mostly due to hypercellularity. These models allow conclusions about the biological effects of very high and continuous levels of these substances as well as about their regulation in different tissues.

Animals↗
PubMed1990

Interferon alfa-2c in chronic myelogenous leukemia (CML): hematologic, cytogenetic and molecular-genetic response of patients with chronic phase CML previously resistant to therapy with interferon gamma.

Alpha- and gamma-interferons have been shown to actively suppress hematopoiesis in patients in the chronic phase of chronic myelogenous leukemia in vitro and in vivo. Since both interferons act through different receptors on their hematopoietic target cells, they are expected to be capable of independently inhibiting abnormal blood cell development in patients with chronic myelogenous leukemia. We have utilized recombinant human interferon alfa-2c to treat 11 patients with Philadelphia chromosome positive chronic myelogenous leukemia in chronic phase, who were resistant to previous interferon gamma therapy. Ten of the patients were evaluable for hematologic, cytogenetic and molecular-genetic response following interferon alfa-2c therapy for 6 to 30 months. In 5 patients, IFN alfa-2c treatment failed due to lack of hematologic response. A complete hematologic or partial hematologic response was achieved in the remaining 5 patients. Three of these experienced cytogenetic improvement with reappearence of 100% diploid hematopoietic cells and disappearence of c-abl/bcr rearrangement in one patient. In two patients interferon alfa-2c did not prevent transformation of the disease into an accelerated state or blast crisis, respectively. We conclude that recombinant human interferon alfa-2c may also control hematopoiesis in interferon-gamma resistant chronic myelogenous leukemia patients, although the long-term response will need to be elucidated in further studies.

Adult↗
PubMed1990

Induction of monocytic differentiation and modulation of the expression of c-fos, c-fms and c-myc protooncogenes in human monoblasts by cytokines and phorbolester.

Growing evidence suggests that proto-oncogenes regulate central aspects of cellular physiology such as cell proliferation and differentiation. The proto-oncogenes c-fos, c-fms and c-myc are thought to be involved in these processes. In this study the human myelomonoblast line THP-1 has been used to study monocytic differentiation in response to various cytokines and the phorbolester TPA. After treatment of THP-1 cells with Tumor Necrosis Factor (TNF)-alpha, Interleukin (IL-6) and TPA the cells became adherent, lost their division potential and expressed new surface structures associated with monocytic differentiation. The expression of c-fos and c-fms transcripts was rapidly induced within 45 min by these agents and declined to undectable levels within 24 h. Exposure of THP-1 to TNF-alpha, IL-6 and TPA was associated with a rapid downregulation of c-myc expression, that returned to starting levels within 36 h. However, treatment of THP-1 with other cytokines including Granulocyte (G)-, Macrophage (M)-, Granulocyte/Macrophage (GM)-Colony Stimulating Factor (CSF), Interleukin (IL)-3 and Interleukin (IL)-4 failed to result in monocytic differentiation. These data suggest that changes in c-fms, c-myc and c-fos expression may be related to induction of monocytic differentiation and that their appearance or downregulation can be induced by certain cytokines.

Antigens, CD↗
PubMed1990

Effect of granulocyte-macrophage colony-stimulating factor on neutropenia and related morbidity induced by myelotoxic chemotherapy.

PURPOSE: A phase Ib/II clinical study was undertaken to assess the efficacy of recombinant human (rh) granulocyte-macrophage colony-stimulating (GM-CSF) factor in attenuating neutropenia and associated morbidity caused by high-dose anticancer chemotherapy administered in the presence or absence of autologous bone marrow support. PATIENTS AND METHODS: Twenty-two patients with various solid tumors and lymphoid neoplasias were treated with a single daily subcutaneous dose of rh GM-CSF (250 micrograms/m2) 48 hours after receiving a second cycle of highly myelotoxic chemotherapy for a period of 10 days. Within-subject comparisons on neutropenia-related clinical and laboratory variables were made with data obtained from the same patients after they received the first neutropenia-inducing cycle of identical chemotherapy in the absence of GM-CSF. RESULTS: GM-CSF was active in neutropenic patients because it significantly increased the neutrophilic nadir, reduced the time of relevant neutropenia, and reduced the duration of a patient's hospital stay and the necessity for parenteral antibiotics. No significant toxicity was encountered with subcutaneous GM-CSF treatment. CONCLUSION: Although GM-CSF was shown to significantly reduce chemotherapy-associated morbidity in patients receiving myelotoxic cancer chemotherapy, additional studies are needed to assess whether the use of GM-CSF in anticancer chemotherapy will allow an increase in the dosage level, leading to improved response rates and survival among cancer patients.

Adolescent↗
PubMed1990

Circannual oscillations of function compared with morphometric changes in the thyroid gland of the Wistar-rat.

To investigate biological rhythms of the thyroid gland circannual oscillations of thyroxine (T4), triiodothyronine (T3), and thyrotropin (TSH) were compared in serum samples of untreated young male Wistar-rats with the circannual changes of thyroid weights and with the relative proportion of colloid, epithelium, and interstitium of the thyroids. Animals were kept under standard environmental conditions, however, lighting conditions simulated the natural day-night changes. Thyroid weights, T4, T3, and TSH showed a statistically significant circannual rhythm with maxima in winter and spring and minima in summer and autumn. The same circannual patterns were observed in the proportion of epithelium and interstitium of the thyroids, while the colloid exhibited an inverse circannual pattern. These data were verified by biomathematical methods, like locally adjusted functional approximation, analysis of variance, and Spearman rank correlation. Our results represent an example for the concordance between functional and morphometrical changes in the course of circannual oscillations. Furthermore, these data confirm our earlier results describing higher T4-levels in the winter time (short-day) and lower serum titers in the summer time (long-day).

Animals↗
PubMed1990

[Pregnancy outcome with intensified insulin therapy in manifest diabetes].

In 1981, the intensified insulin therapy for achievement of euglycaemia in pregnant diabetics was introduced at the University Department of Obstetrics and Gynaecology in Cologne. This study compares the results of 112 pregnancies in women with overt diabetes monitored before (1971-1980) or after (1981-1988) changing the therapeutic regimen. In the period from 1981 to 1988, the proportion of euglycaemic patients (preconceptionally 19%, before delivery 79%) was clearly higher than from 1971 to 1980 (n = 42; 7% and 9%, respectively). The tight blood glucose control resulted in a doubling of hypoglycaemic episodes during pregnancy. The proportion of preterm deliveries was reduced from 47% to 24%. The rate of caesarean sections was nearly constant (1971-1980: 38%, 1981-1988: 34%). The marked success of therapy was the decrease of perinatal mortality from 20.9% to 2.9%. The perinatal morbidity also diminished, as shown by the decreasing rates (30-90%) of foetopathy, macrosomy, respiratory distress syndrome, birth trauma, hypoglycaemia, hypocalcaemia and polycythaemia. The malformation rate, however, remained high (1971-1980 = 7%, 1981-1988 = 11%). The results demonstrate the necessity of a strict blood glucose control during pregnancy, beginning before the time of conception.

Adult↗