Biomedical subjects
Publications and source records attributed to L Bergmann.
Many different inhalative substances may cause allergic alveolitis (hypersensitivity pneumonitis). We report on a worker who developed lung fibrosis due to the sensitization to pearl oyster shell dust. High concentrations of IgG antibodies to proteins (conchagens) of the shell which appear to represent the relevant antigens were found in the patient's serum.
In our experimental study on 53 rabbits we compared the amount of corneal endothelial damage caused by radial keratotomy (RK) referred to (1) the number of incisions (4, 8, or 16), (2) the postoperative interval (0 h, 48 h) and (3) the direction of the incision [centripetal (cp), centrifugal (cf)]. The endothelial damage was quantified by means of the Janus green photometry technique. Morphological changes were evaluated by scanning electron microscopy (SEM). Depending on the group examined, we found endothelial damage extending over 3-7% of an analysed surface of 64 mm2. One perforation caused endothelial damage of up to 17% of the surface examined. Increasing the number of incisions from 4 to 8 or 16 resulted in a statistically significant increase in the amount of endothelial damage (4.2%, 5.1%, 5.8%; P less than 0.05). At 0 h it was significantly higher than after 48 h (5.5%, 4.6%; P less than 0.05). The direction of the incision had no statistically significant influence in our study (zp: 5.2%, zf: 4.9%). The morphological changes in the rabbit corneal endothelium examined directly after the RK procedure were ruptures in the cell membranes, loss of cells, and posterior corneal protrusions beneath the incisions. After 48 h, we found fewer damaged cells and no denuded Descemet's membranes, but larger polymorphy of the cells and a numerical increase in the microvilli of the cells surrounding the damaged cells. Our results support the crucial argument against RK: the alteration and destabilization of healthy corneal tissue up to the endothelium.
Biotinyl analogues of [Arg8]vasopressin were synthesized with the biotinyl moiety at position 4. This involved the substitution of 2, 4-diaminobutyric acid (Dab) for Gln4 in [1-deamino-Arg8]vasopressin to give the parent peptide des-[Dab4,Arg8]vasopressin. Two biotinyl analogues with different spacers between the side chain of Dab4 and the biotinyl residue were then prepared and characterized in detail. The analogues retained high binding affinities for the V2-receptor in both bovine kidney membranes and LLC-PK1 renal epithelial cells and for the V1-receptor in rat liver membranes. Both analogues were as potent as [Arg8] vasopressin in stimulating the cAMP-dependent protein kinase and the production of urokinase-type plasminogen activator in LLC-PK1 cells, with concentration dependence consistent with receptor binding affinities. Avidin or streptavidin did not appear to reduce receptor binding or biological activity of the biotinyl analogues. The use of the biotinylated vasopressin analogue des-[Dab-(biotinylamido)hexanoyl4, Arg8]vasopressin together with fluorescein-labeled streptavidin as a fluorescent probe for the V2-receptor in LLC-PK1 cells demonstrated the following: 1) Specific binding of the biotinyl analogue shown by quantitative single-cell fluorescence measurements using the technique of fluorescence microphotolysis; 2) the V2-receptor visualized by fluorescence microscopy; and 3) the expression of the V2-receptor detected by flow cytometry.
To reduce the risk of severe infections in splenectomized patients, new methods for splenic preservation or heterotopic autologous spleen implantation have been established. In the latter case, the immunological and functional benefits are still under discussion. In this study we compared immunological parameters in 16 splenectomized patients with and without heterotopic autologous spleen implantation with a nonsplenectomized control group. The total lymphocyte counts--T-cells, CD4+ -, as well as CD8+ - lymphocytes, CD16+ - and B-cells--were highly elevated in both groups, whereby the B-cells were relatively and absolutely higher in the implanted group than in the nonimplanted group. Splenectomized patients had a significantly reduced serum IgM level. The serum IgM of patients with splenic autotransplantation was not significantly lower than that of the controls. In contrast to the impaired in vitro immunoglobulin synthesis in the splenectomized group, the autotransplanted patients showed a normal PWM-induced IgG and IgM synthesis and an increased IgA production compared with the controls. The latter results support the findings of elevated serum IgA levels in this group. The mitogenic-induced proliferation with PHA, ConA, PWM, and OKT3 was not clearly different within the tested groups. The results may indicate a benefit of autologous spleen implantation in regard to the humoral immune response.
In vivo and in vitro humoral and cell-mediated immunological defects have been described in untreated patients with Hodgkin's disease (HD). The cellular basis of the recently described in vitro reduction of mitogen-induced immunoglobulin synthesis has not been elucidated so far. In this study, we attempted to dissect T and B lymphocyte function in untreated HD patients. Mitogen-induced in vitro immunoglobulin synthesis was assessed in the presence of pokeweed mitogen, the mitogenic anti-CD3 monoclonal antibody OKT3 and the relatively T-cell-independent B cell mitogen Nocardia opaca delipidated mitogen (NDCM). Mitogen-induced Ig synthesis by HD peripheral blood mononuclear cells was significantly reduced compared to that in control peripheral blood mononuclear cells. In coculture assays, T cells of HD patients exerted an adequate helper function to control B cells. However, normal donor T cells did not restore Ig synthesis by B cells of HD patients. Finally, B cells of HD patients were unresponsive to NDCM, which is able to induce Ig synthesis in control B cells even in the absence of T cells. These data provide evidence for an intrinsic functional B lymphocyte defect in HD patients, and suggest that increased activation of suppressor HD T lymphocytes may not play a significant role in the suppression of in vitro Ig synthesis.
In vitro, the combination of interleukin-2 (Il-2) with interferon-alpha (IFN-alpha) seems to act synergistically on the generation of lymphokine activated killer (LAK) cells. Due to this fact two clinical trials with the combination of Il-2 and IFN-alpha were initiated in malignant melanoma (MM) and renal cell cancer (RCC). Patients with disseminated MM were treated by a sequential application of 10 x 10(6) U/m2 rIFN-alpha 2b s.c. on days 1-7 followed by continuous intravenous infusion of 3 x 10(6) U/m2 rIl-2 on days 8-13 and 15-20. After a pause of 4 weeks the cycle was repeated. In advanced or disseminated RCC, the patients were treated with a daily alternating scheme of 10 x 10(6) U/m2 rIFN-alpha and rIl-2 as 1 h infusion 1 x /day for 14 days. The rIl-2 escalates intra- and interindividually beginning with a dose of 3 x 10(6) U/m2. The cycles were repeated after a pause of 3 and 4 weeks, respectively. The preliminary results show that the schedules are practicable and that the toxicity of the combination of rIl-2 and IFN-alpha does not accumulate. Within the MM group 3/11 evaluable patients achieved partial remission and 2/11 stable disease. In the RCC-group 2/5 evaluable patients achieved partial remission and 2/5 had stable disease so far.
The induction and activation of autologous cytotoxic cells (lymphokine activated killer cells = LAK) by interleukin-2 (Il-2) is an interesting new approach in cancer treatment. So far, Il-2 alone or in combination with the transfer of in vitro activated LAK (adoptive immunotherapy = AI) was shown to be effective predominantly in renal cell cancer and malignant melanoma with a response rate of 20-35%. The results in colorectal tumors are disappointing. Clinical experiences with Il-2 in other tumor entities are limited and/or mostly lack sufficient responses. To improve therapeutic results and to reduce the serious side effects, present trials focus on combinations of Il-2 with other cytokines, predominantly interferon-alpha (IFN-alpha), or chemotherapy. So far, the combination of Il-2 + IFN-alpha seems to be at least as effective as Il-2 + AI in renal cell cancer. Combinations of chemotherapy and Il-2, especially in gastrointestinal tumors, have not been shown to exceed the moderate results of chemotherapy alone so far. Trials with highly activated or specific cytotoxic cells as tumor-infiltrating lymphocytes (TILs) or adherent-LAK-cells are still more experimental. The value of IL-2 for elimination of minimal residual disease in acute leukemias after autologous bone marrow transplantation or as consolidation of complete response will have to be defined. The present paper reviews clinical studies with Il-2 in malignancies and its significance for therapeutic approaches.
The clinical use of interleukin-2 (IL-2) for generation and activation of cytotoxic lymphocytes lymphokine-activated killer cells (LAK) has principally demonstrated that tumors can be restricted by modulation of the immune system. However, innovative approaches are required to improve the therapeutic results. In this connection, combinations of IL-2 with other cytokines may be of interest to increase the numbers and cytotoxic activity of LAK. On the other hand, IL-2 itself mediates immune reactions and secretion of various cytokines. Therefore, we investigated the effect of interferon-alpha (IFN-alpha), IFN-gamma and tumor necrosis factor (TNF-alpha) on the induction of LAK activity by IL-2, and the induction of IFN-gamma and TNF-alpha by IL-2. LAK activity could not be enhanced by IFN-gamma and TNF-alpha, but was enhanced by IFN-alpha. This may in part be due to the fact that IL-2 itself induces high amounts of TNF-alpha and IFN-gamma. Besides the effect of IFN-alpha on LAK activity, an increased susceptibility of tumor cells for LAK in vitro could be achieved by preincubation of tumor cells with IFN-alpha. This mechanism seems not to be related to an increased expression of MHC class I and II antigens.
In a phase I/II study, 11 patients with myelodysplastic syndromes (MDS) and severe transfusion-dependent cytopenia were treated with recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) to investigate the effects of rhGM-CSF on normal hematopoiesis and leukemic cells. The treatment schedule included dose escalation from 15 micrograms/m2 to 150 micrograms/m2 administered by continuous intravenous (IV) infusion for seven to 14 days and was repeated after a two-week treatment-free interval. The blood leukocyte counts increased dose dependently by 130% to 1,800% in ten patients; a rise of monocytes and eosinophils occurred in seven and six patients, respectively. No sustained increase in reticulocytes or platelets was observed. Lymphocyte counts increased in all patients affecting both T-helper and T-suppressor cells; however, the lymphocytes were not activated as analyzed by the expression of the interleukin-2 receptor. In four of the patients, all with greater than 14% blast cells in the bone marrow, the percentage of bone marrow blast cells increased during treatment with rhGM-CSF. Cytogenetic data indicated induction of both proliferation and differentiation of the leukemic clones by rhGM-CSF. Toxic side effects were minor with slight fever, phlebitis at the infusion site, and bone pain in the minority of patients. In conclusion, rhGM-CSF effectively stimulates hematopoiesis in vivo in patients with myelodysplastic syndromes. However, as the leukemic cell population can be stimulated in patients with a higher initial blast cell count, the combination of rhGM-CSF with other differentiation-inducing or cytotoxic agents has to be considered.
The prognosis of malignant melanoma (MM) depends on the level of invasion, vertical tumour size, location of the primary, clinical stage, and sex. Whereas MMs are potentially curable in the early stage of disease, the therapeutic possibilities are very limited in advanced and disseminated MM. Most chemotherapeutic agents lack sufficient activity in MM especially with regard to survival. Dacarbazine (DTIC) is the most effective drug in MM with response rates of 20-25% followed by other drugs such as melphalan with 15-20%, hydroxyurea and platin derivates. Multidrug regimens were not shown to be more effective than DTIC alone. Radiotherapy may be relevant in local treatment of metastases. With regard to the poor prognosis and limited therapeutic approaches in advanced and disseminated MM, new strategies are required. In this context immunotherapeutic strategies with biological response modifiers are of interest for adjuvant or palliative approaches. Earlier trials with Bacillus Calmette-Guerin (BCG) +/- DTIC as adjuvant or palliative treatment revealed no effect of BCG on the prognosis. Alpha-interferon (alpha-IFN) was shown to induce remissions in about 15% and gamma-IFN in about 10% of patients. A very interesting new approach is the induction and/or activation of autologous cytotoxic cells by systemic administration of recombinant interleukin-2 (rIL-2) with response rates of 20-25% and the in vivo propagation and transfer of so-called tumour infiltrating lymphocytes. Further trials combining rIL-2 with other cytokines, chemotherapy, tumour vaccination or monoclonals against melanoma cells are required.
Case reports on 4 women operated on for suspected tumour. The diagnosis of sarcoidosis was confirmed histologically. The difficulties associated with the differential diagnosis are discussed and, the need for morphological clarification is emphasized.
We compared the endothelial damage to freshly excised pig corneas (n = 156) as a result of contact with IOLs made of PMMA, silicone and polyhema. The contact time was 15 s, 1 min and 30 min. The endothelial damage was quantified with the Janus green vital staining photometric technique. Morphological changes were evaluated by scanning electron microscopy. The most damage was caused by PMMA (7.6%; 10.2%; 19.7%), followed by silicone (4.8%; 6.8%; 10.2%) and polyhema (4.6%; 5.9%; 8.3%). The degree of endothelial damage was statistically significant (P less than 0.01) in comparison with the control groups without any relationship to lens material or contact time. There was no significant difference between the damage caused by silicone and polyhema, but there was a significant difference between PMMA and silicone or polyhema.
For palliative therapy during the chronic phase of CML busulfan has proved to be the drug of choice. During the past years hydroxyurea and also interferon-alpha have gained increasing significance since they might prolong the duration of the chronic phase. In a multicenter study it is being determined, whether the use of hydroxyurea or of interferon-alpha instead of busulfan prolongs the duration of the chronic phase of Philadelphia positive CML. Additional goals are the examination of whether the types of disease evolution and the terminal phases differ between the treatment groups, and the prospective recognition of prognostic criteria for the duration of the chronic phase of CML. By December 31, 1987, 326 CML-patients had been randomized, 150 for busulfan, 150 for hydroxyurea and 26 for interferon-alpha. The average age is 50 years. 59 patients reached the end of the chronic phase, 55 died. The mean observation time of all patients is 1.34 years. At present no significant difference in survival is recognizable between the busulfan and hydroxyurea groups. Fewer adverse effects have been observed in the hydroxyurea group. Philadelphia chromosome negative patients show a higher average age and tend to have lower white blood cell and platelet counts. The number of patients having received interferon-alpha is still too small to allow evaluation. This report intends to document organization and progress of this study which to our knowledge is, at present, the largest ongoing prospective multicenter study on the therapy of CML.
Initial combination drug regimen containing cisplatin in patients with stage III and IV head and neck cancer produced a high percentage of clinical response. This trial was initiated to assess the role of multimodality treatment (chemotherapy plus radiotherapy) versus chemotherapy alone. Ninety-six patients entered into this study; 80 patients were evaluable at time of analysis (Table I). Patients were randomized between chemotherapy and radiotherapy (group I) and chemotherapy alone (group II). The chemotherapy administered consisted of cisplatin, bleomycin and methotrexate and was given in 2 cycles over 35 days. Local radiotherapy followed. In group II 3 cycles of chemotherapy were given without radiotherapy. The overall tumour response after chemotherapy rose up to 75 per cent. After radiotherapy in group II the response rate sank to 59 per cent. In both regimes the remission duration was very short. Patients receiving only two cycles of chemotherapy do not have a statistically shorter survival than patients, who were treated by chemotherapy plus radiotherapy, or by a 3rd cycle of chemotherapy.
For palliative therapy during the chronic phase of CML busulfan has proved to be the drug of choice. During the past years hydroxyurea and also interferon-alpha have gained increasing significance since they might prolong the duration of the chronic phase. In a multicenter study it is being determined, whether the use of hydroxyurea or of interferon-alpha instead of busulfan prolongs the duration of the chronic phase of Philadelphia-positive CML. Additional goals are the examination, whether the types of disease evolution and the terminal phases differ between the treatment groups, and the prospective recognition of prognostic criteria for the duration of the chronic phase of CML. By November 26, 1987, 321 CML-patients had been randomized, 147 for busulfan, 149 for hydroxyurea and 25 for interferon-alpha. The average age is about 50 years. 59 patients reached the end of the chronic phase, 55 died. The mean observation time of all patients is 1.34 years. At present no significant difference in survival is recognizable between the busulfan and hydroxyurea groups. Fewer adverse effects have been observed in the hydroxyurea group. Philadelphia chromosome-negative patients show a higher average age and tend to have lower white blood cell and platelet counts. The number of patients having received interferon-alpha is still too small to allow evaluation. This report intends to document organization and progress of this study which to our knowledge is, at present, the largest ongoing prospective multicenter study on the therapy of CML.
The design of a prospective phase-II study on the treatment of Kaposi's sarcoma (KS) in patients with HIV infection is described. In this study the toxicity and antineoplastic activity of high-dose alpha-interferon (20 x 10(6) U/m2 s.c. daily) will be investigated in patients with advanced and progressive KS. Patients with progressing KS during IFN treatment or with relapsing KS after IFN will be treated with vinblastine (4 mg/m2 i.v., days 1, 8, and 15) and bleomycin (15 mg i.v., days 1 + 8). The study was only recently activated; results are so far not available.
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Investigations of diseases due to professional exposure, especially the development of malignant tumors, are of increasing interest. In the present case the development of a bronchogenic carcinoma on the base of sidero-fibrosis in a 46-year-old man (E-welder) is described. Several aspects of the problem are discussed.