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Prognostic factors were obtained by retrospective analysis of data on 44 patients (34 men and ten women; average age 64 +/- 13 years) with a primary myelodysplastic syndrome. The most important factors for a poor prognosis were the presence of more than 5% blast cells in the bone marrow (P = 0.001), serum platelet count of less than 150,000/microliters (P = 0.05), serum white cell count less than 3000/microliters (not significant) and serum lactate dehydrogenase concentration greater than 240 U/l (P = 0.05). Protein electrophoresis revealed a polyclonal hypergammaglobulinaemia in 15 of 38 patients; in eight of 17 patients with partly normal curve pattern at protein electrophoresis, a monoclonal gammopathy was demonstrated (monoclonal gradient 3.5 g/dl) by immunoelectrophoresis or immunofixation. No prognostic significance could be established for these gammopathies.

A largely symptom-free swelling of the right submandibular lymph nodes developed in a 23-year-old woman with hyper-IgE syndrome who had suffered from recurrent staphylococcal abscesses since childhood. Histological examination of the lymph nodes revealed highly malignant non-Hodgkin lymphoma of centroblastic type. Extensive staging tests did not reveal any further tumour manifestations. Because granulocyte chemotaxis is abnormal in hyper-IgE syndrome and the patient also had an infection of an old lung cyst, treatment was restricted to local radiotherapy of the cervical lymph nodes. Since 12 months there has been no recurrence. There is probably no connection between the hyper-IgE syndrome and the development of a malignant non-Hodgkin lymphoma, judging by the results of immunological and immunoelectrophoretic findings.

To compare the cytokine profile with the degree and composition of cellular infiltration in rheumatoid arthritis (RA) and osteoarthritis (OA) synovium, synovial membranes from patients with RA (n = 14) and OA (n = 5) were examined, employing immunohistochemistry and competitive reverse-transcriptase polymerase chain reaction (RT-PCR), for interleukin (IL)-I beta, IL-2, IL-4, IL-5, IL-6, and IL-10, and tumour necrosis factor-alpha (TNF-alpha) gene expression. It was found that the strength of cytokine gene expression within the synovial membranes of patients with RA was not significantly correlated with the degree of synovial infiltration of T-cells, B-cells, or macrophages. No IL-2, IL-4, or IL-5 RNA was detected in the synovium of either RA or OA. Quantitative cytokine determination showed a similar pattern in RA and OA, although the two diseases differed in total synovial infiltration and the composition of infiltrating cellular elements. Thus the number of cell types known to produce certain cytokines does not appear to determine the strength of synovial cytokine expression measured by quantitative RT-PCR. Furthermore, the pattern of T-cell specific cytokines found in RA synovium does not accord with the concept of the TH0, TH1, and TH2.

The controlled clinical trial reported here is part of a multicenter clinical and basic research project, sponsored by the German Federal Minister of Science and Technology, directed by a standing commission of the president of the Max-Planck-Gesellschaft, and coordinated by the Max-Planck-Institut fur Biochemie, Munchen. Overall, 249 patients with rheumatoid arthritis (RA) were enrolled by 16 participating hospitals. In addition to NSAID treatment, patients were randomly given either interferon gamma (IFN-γ) or placebo. In the IFN-γ group, 107 patients were evaluated and in the control group, 116 patients were evaluated. The response rate after 3 months of treatment, according to joint pain indexes, was significantly higher in the IFN-γ group with an error probability of 1%. IFN-γ was able to reduce the quantity of corticosteroids administered. Compared with the control group, the IFN-γ group benefited considering all parameters measured. Most important side effects were transient fever and transient influenza-like symptoms; all other adverse events were comparable in both groups.

Recent clinical observations support the hypothesis that persistent parvovirus B19 is a triggering factor of rheumatoid arthritis (RA) in certain genetically predisposed individuals. If this hypothesis is correct, a number of RA patients may exhibit parvovirus B19 DNA in their synovial membranes. We tested the synovial tissue and peripheral blood leukocytes of 20 patients with RA, 24 patients with other arthritides or osteoarthritis (non-RA), and 34 healthy blood donors for the presence of parvovirus B19 DNA using specific DNA amplification by polymerase chain reaction (PCR). Using this technique, parvovirus B19 DNA was demonstrated in the synovial biopsies of 75% of patients with RA but in those of only 16.7% of patients with non-RA. In autologous peripheral blood mononuclear cells the percentage of PCR-positive patients was about 15% in both RA and non-RA groups and did not differ from that in healthy controls. When the PCR data were correlated with the presence of anti-parvovirus B19 IgG antibodies in serum and synovia all patients with parvovirus B19 DNA in peripheral blood alone or in both peripheral blood and synovial membrane were seropositive. In contrast, about 40% of patients with parvovirus B19 DNA restricted to the synovial membrane were seronegative. These data indicate a highly disease-related persistence of parvovirus B19 in the rheumatoid synovium.

Neo-synovial membranes, which formed after "primary" synovectomy in 21 patients with rheumatoid arthritis (RA), were studied at resynovectomy. The clinical, histomorphological, and immunohistological data were compared with data derived from "primary" synovial membranes from RA and osteoarthritis (OA) patients. The clinical data suggest a less active rheumatoid inflammatory response after synovectomy. Histomorphologicaly, the synovitis in resynovectomized neosynovial membranes of RA revealed no qualitative differences when compared with synovitis in the "primary" synovium. However, the degree of the inflammatory rection evaluated by the different parameters was found to be distinctly lower. The immunohistological data correlated with these findings.

The present prospective multicentre trial investigated whether topotecan, given at a starting dose of 1.25 mg.m(-2) with individual dose adjustment, can improve safety in patients with relapsed/refractory small cell lung cancer without loss of efficacy. Patients received topotecan intravenously on days 1-5, every 21 days, for up to six courses. In the absence of relevant haematotoxicities, topotecan was increased to 1.5 mg.m(-2) and reduced to 1.0 mg.m(-2) in case of severe haematotoxicities. Of 170 recruited patients, 73.2% had stage IV disease and 63.4% had platinum-containing pre-treatment. Patients received a total of 521 courses. In 72.6% of those courses, the dose remained at 1.25 mg.m(-2); in 9.1% it was reduced and in 18.3% it increased. Overall response rate was 14.1% including one complete response; 28.8% had stable disease. Median duration of response was 13.6 weeks and median survival was 23.4 weeks. Clinical benefit was obvious for sensitive as well as for refractory patients. Haematotoxicity of grade 3 or 4 was clearly lower compared with the standard dose of 1.5 mg.m(-2). In conclusion, topotecan at a dose of 1.25 mg.m(-2) appears to be as effective as the dose of 1.5 mg.m(-2), but with reduced toxicity. Since patients with recurrent small cell lung cancer have a poor prognosis, they benefit especially from good tolerability.

In spite of differences in etiology, RA and OA lead to astonishingly similar synovitic alterations. Fibroblastic transformation of the synovial membrane and an increase in monocytes constitute a rare but highly characteristic feature of RA. Monocytes synthesize factor (F) XIII, implying that FXIII (a and s) in synovial tissue might help to differentiate between RA and OA. Biopsies were obtained at open surgery from 98 unselected patients with the clinical diagnosis of RA (n = 54) or OA (n = 44). In a three-stage (ABC) immunoperoxidase technique, polyclonal antisera against factor XIIIa and factor XIIIs were investigated. Compared to OA sections. RA synovium showed more FXIIIa-positive cells-monocytes, fibrocytes, fibroblasts and synovial lining cells. In the subsynovial layer, band-like structure of FXIIIa-stained cells was observed in 27.8% of the RA patients, but in only one OA specimen. Higher proportions of FXIIIa-positive monocytes, macrophages, histiocytes and fibroblasts, as well as positive Langhans giant cells and vascular wall regions (except endothelial cells), were observed in RA. OA specimens revealed more intense FXIIIa labeling of these cells with a lower percentage of stained cells. Overall, labeling with FXIIIs antibody resulted in less intense staining. In conclusion, distinction between synovitis caused by RA and synovitis due to OA is possible, as the former show higher numbers of FXIIIa-positive cells, including monocytes, fibroblasts, fibrocytes and synovial lining cells. Further more, RA tissue is stained less intensely than OA tissue. There is evidence for continuous excretion of FXIII in the synovial membrane by the above-mentioned cell systems.

We investigated 86 synovial membranes from patients suffering either from rheumatoid arthritis (RA) or osteoarthritis (OA). Iron deposits in the synovial membrane were stained by the Prussian blue reaction, and the amount of stained iron was quantitatively assessed by microscope photometry. We found a statistically significant increase in iron deposits in the synovial membrane of RA patients when compared to OA patients. The amount of iron deposits correlated with the histological subtype of synovitis, those presenting with more exudative and proliferative features showing greater amounts of iron deposits. We also observed an inverse correlation between the haemoglobin concentration and erythrocytes in the serum and the amount of iron in the synovial membrane. From our data we concluded that iron deposits in the synovial membrane can contribute by several mechanisms, including activation of oxygen radicals, to the chronic inflammatory reaction in RA synovitis.

We report the occurrence of bilateral sacroiliitis in 2 cases of biopsy-proven sarcoidosis. Tuberculosis was excluded by tuberculin testing and bronchoalveolar lavage in both cases. In the literature, 5 cases of sacroiliitis and sarcoidosis have thus far been described, but in all tuberculosis was not excluded (tuberculin testing was not performed or revealed a positive test result). In 1 of these cases tuberculosis was even simultaneously suspected to be present. In all previous cases, antituberculous or other antimicrobial agents were given. Previously reported cases of sacroiliitis in sarcoidosis are briefly reviewed, and possible relations between seronegative spondylarthropathies, slow bacterial infections, sarcoidosis and other granulomatous diseases are discussed.

The case of a 30-year-old man with primary systemic amyloidosis is reported. Three months prior to admission the patient developed fever, night sweats, dyspnea, and bilateral ankle swelling. Recurrent left-sided pleural effusion led to further investigation when massive proteinuria with free monoclonal lambda chains in the urine became evident. Abdominal subcutaneous fat aspiration and renal biopsy confirmed the diagnosis of amyloidosis. Bone marrow biopsy and bone scan did not reveal multiple myeloma. Echocardiography showed a sparkling texture of the interventricular septum. Pulsed-wave Doppler recording of the left ventricular inflow profile showed the pattern of advanced cardiac amyloidosis consistent with markedly impaired diastolic heart function. Electrocardiogram-gated magnetic resonance imaging was carried out for noninvasive evaluation of cardiac function. The patient was started on repeated courses of melphalan, prednisone, and colchicine therapy. Despite increasing deterioration of renal function the therapy was tolerated quite well, and the patient is still alive 10 months after initial diagnosis. Although very rare in this age, primary systemic amyloidosis should be considered as a cause of pleural effusion, proteinuria, and congestive heart failure and should lead to further investigation.

In a study aimed at correlating cytokine levels in synovial fluid with the pathology of rheumatoid arthritis (RA), tumour necrosis factor alpha, interleukin 1 beta and interferon gamma were immunoassayed in 27 patients with RA, 16 patients with other arthritides, 23 with osteoarthritis, 13 patients with trauma, and 18 patients at necropsy without inflammatory disease and not known to have had joint disease (median 27 hours after death). The results for interleukin 1 beta clearly show higher cytokine levels in patients with RA and other arthritides than in patients with osteoarthritis, trauma, or the patients at necropsy. Interferon gamma levels in patients with osteoarthritis and the patients at necropsy, however, were significantly greater than in patients with RA, and tumour necrosis factor alpha levels were also greater in the patients at necropsy compared with patients with RA. This study also correlated histomorphological patterns of synovitis and indicators of local inflammatory activity with synovial fluid cytokine levels, showing, for example, a positive association of interleukin 1 beta titre and a negative association of interferon gamma titre with ulcerogranulomatous synovitis (itself associated with RA). Taken together, these results extend and strengthen data suggesting a possible part played by increased synovial fluid levels of interleukin 1 beta in joint destruction in RA, but provide no evidence for increases in levels of tumour necrosis factor alpha or interferon gamma affecting the disease pathology.

A sensitive and specific method to monitor suppression of cytomegalovirus (CMV) replication is essential in patients treated with ganciclovir after allogeneic bone-marrow transplantation. In this study, antiviral therapy of eighteen episodes of symptomatic CMV infection in 15 such patients were followed up clinically and by virus culture and polymerase chain reaction (PCR). Clinical improvement, culture, and PCR were assessed for their ability to predict the efficacy of ganciclovir therapy in each patient. In eleven successfully treated episodes of CMV disease (disappearance of symptoms and improvement in biochemical variables) clinical improvement was associated with an effective suppression of virus replication as shown by negative culture and PCR assays of blood and urine specimens obtained after antiviral therapy. 1 patient who did not improve clinically when receiving antiviral therapy remained both culture positive and PCR positive for CMV. 6 patients with early relapse of CMV disease or who died after an initial clinical improvement were PCR positive but culture negative after termination of therapy. Demonstration of CMV in blood and urine by PCR after stopping antiviral therapy (even when culture is negative) points to incomplete suppression of virus replication. The findings show that PCR is a better predictor of the efficacy of antiviral therapy than are culture or clinical assessment.

Interleukin-1 beta, interleukin-2, tumour necrosis factor alpha, and the interferons, alfa and gamma, were measured concurrently in synovial fluid samples from 68 patients with rheumatic diseases. Mean interleukin-1 beta concentrations (130.3 (SD 22) pg/ml) were higher in synovial fluids from patients with rheumatoid arthritis (RA) than in those from patients with osteoarthritis (27.8(4.5)pg/ml), while measurements in synovial fluids from patients with seronegative spondarthritis were intermediate (72.7 (32) pg/ml). Interleukin-2 and tumour necrosis factor alpha concentrations were lower in the inflammatory arthropathies (RA: 4.5 (0.6) U/ml, 0.39 (0.04) ng/ml; seronegative spondarthritis: 3.1 (0.3) U/ml, 0.33 (0.03) ng/ml respectively) than those in patients with osteoarthritis (5.2 (0.6) U/ml; 0.05 (0.04) ng/ml). Interleukin-2 and tumour necrosis factor alpha concentrations correlated in all groups (r = 0.7), as did the interferons alfa and gamma (r = 0.7). There was no relation between interleukin-1 beta and either interleukin-2 or tumour necrosis factor alpha, or between the interferons and any other cytokine. Several distinct cytokine patterns were noted. Synovial fluids from two non-arthritic subjects were also examined: interleukin-1 beta concentrations were low, but concentrations of the other cytokines were higher than those seen in most arthritic fluids.

An in vitro lymphocyte-mediated cytotoxicity assay using [3H]proline-labeled target cells is described. The assay, modified from an original procedure of Bean et al., assesses the release of [3-H]proline by filtering the total culture fluid containing both trypsinized tumor cells and effector cells. Filtration is performed with a semiautomatic harvesting device using low suction pressure and large-diameter glass filters. Pretreatment of filters with whole serum diminishes adsorption of cell-free radioactive material considerably and thus increases the sensitivity of the assay. Nearly 100% of the radioactivity could be recovered with this harvesting device. The technique allowed the detection of cytolytic activities of lymphocytes after 6 h of incubation. Lymphocytes from patients with primary malignant melanoma showed a significantly higher cytolytic reactivity (P less than 0.001) than normal donors' lymphocytes against three different melanoma cell lines. In a series of parallel experiments on 36 patients and 18 normal donors, this modification of the [3H]proline test was compared with three different assays: the conventional microcytotoxicity test of Takasugi and Klein, the original [3H]proline microcytotoxicity test of Bean et al., and the viability count of tumor cells.

In connective tissue diseases, the differentiation of disease-related hematological aberrations from drug-induced cytotoxic or allergic blood-cell dyscrasias is often difficult. In this paper we report on the positive identification of an indoprofen-induced severe pancytopenia in a multi-drug-treated patient with active systemic lupus erythematosus by use of a drug-specific lymphocyte transformation test.

Synovial membranes of patients with osteoarthritis--a disease with unaltered immunoregulation--and rheumatoid arthritis were immunostained for the different immunoglobulin isotypes using the PAP-method and a two-layer alkaline phosphatase technique. Randomly selected plasma cells with positive immunostaining were measured by plug photometry. The average extinction of the single plasma cell is considered to be indicative of the immunoglobulin synthesis of the measured plasma cell and the isotype under study. When we compared both disease entities, patients with rheumatoid arthritis were characterized (i) by higher average extinction values for all Ig-isotypes except IgG (ii) by a higher rate of high producer plasma cells. From this data, we conclude that immunophotometry is a new in vivo method for discriminating two types of synovitis (i) one without increased Ig-synthesis at the single cell level and (ii) a second one with increased Ig-synthesis.

Lysozyme-producing cells were analysed by enzyme histochemistry in paraffin sections of synovial tissue of 60 patients with rheumatoid arthritis (RA) and 20 patients with osteoarthritis (OA). For lysozyme detection three enzyme histochemical systems - peroxidase-anti-peroxidase, alkaline phosphatase and biotin-avidin - were used in parallel experiments. Lysozyme was found to be produced by polymorphonuclear cells, mononuclear phagocytes and part of synovial lining cells. All types of lysozyme-producing cells were increased in RA compared with OA. Subgrouping of RA synovitis according to histomorphological criteria allowed the demonstration of an inverse relationship between the number of lysozyme-producing cells and the grade of proliferation of fibroblasts, called mesenchymoid transformation by Fassbender [19]. The different methods of lysozyme detection differed in specificity and sensitivity. The immunoenzymatic staining of lysozyme allows specific and quantitative evaluation of phagocytizing cells in RA and OA.

Die Expression der sauren Phosphatasen sind das starkste zytochemische Merkmal lymphoider Zellinien. In einigen Zellen erscheint die saure Phosphatase zytochemisch resistent gegen Tartrat.

THYMUS-DERIVED (T) lymphocytes from animals immunised with syngeneic or allogeneic tumour cells are well known to kill specifically target cells in vitro1. The as yet unidentified antigen recognition structure on T lymphocytes is not deemed to be a conventional type of immunoglobulin. In contrast to this kind of cell-mediated cytolysis another cellular killing mechanism has been described, called antibody-dependent cell-mediated cytolysis (ADCC), in which cells bearing the Fc receptor (FcR) cooperate with humoral antibody in the cytolytic action2,3. The nature of the main lymphoid effector cells (K cells) involved in the latter system is still ill-defined. They are supposed not to be T lymphocytes. Recently however, Lamon et al. reported on mouse thymocytes which were able to lyse MSV-induced tumour cells using IgM antibodies4. In this report we present evidence that human lymphocytes bearing the T marker in collaboration with homologous or autologous antibodies can efficiently kill tumour cells in vitro.

The 3H-proline release test was used to measure spontaneous cytolytic activity of lymphocytes (CMC) from 94 melanoma patients after resection of the primary tumor. This assay showing a remarkable sensitivity and reproducibility allowed the detection of a certain disease-related pattern defined as preferential lysis of tumor cells when patients with mammary carcinoma and bladder tumor were tested simultaneously against corresponding tumor cells.

Connective tissue diseases and rheumatoid arthritis (RA) are characterized by polyclonal B-cell hyperreactivity associated with an oligoclonal, disease-related pattern of autoantibody production. The underlying defects in immune regulations may be found either in the peripheral blood or locally at sites of lymphocyte/plasma cell infiltration. Our interest has focused on the local microenvironment of the inflammed joint as the main site for RA. The dynamic changes in histopathology-cellular infiltration and fibroblast proliferation- characteristic of RA-synovitis require separate analysis of the different states of the disease. In contrast to the morphological approach, a functional analysis of joint inflammation requires isolating the infiltrating cells. In this study, we report first on the distribution of mononuclear and polymorphonuclear (PMN) phagocytes in paraffin sections of different stages of RA-synovitis. Second, infiltrating lymphocytes were isolated from RA-synovium and the cellular eluates analysed for T-cell subpopulations.