Inhibition of leukotriene B4-induced CD11B/CD18 (Mac-1) expression by BIIL 284, a new long acting LTB4 receptor antagonist, in patients with rheumatoid arthritis.

BACKGROUND: Leukotriene B4 (LTB(4)) has a key role in the pathophysiology of rheumatoid arthritis (RA). OBJECTIVE: To investigate the inhibition of ex vivo LTB(4)-induced Mac-1 (CD11b/CD18) expression in leucocytes of patients with RA by the new oral LTB(4) receptor antagonist BIIL 284. METHODS: The pharmacokinetics and inhibition of LTB(4)-induced Mac-1 expression of BIIL 284 were characterised in 26 adult patients with RA who were treated with BIIL 284 25 mg, 150 mg, or placebo given once a day for 14 days according to a double blind, randomised, parallel group design. RESULTS: T(max) of BIIL 315 in plasma (main metabolite and active principle of BIIL 284 in plasma) was achieved about four hours after drug administration, and C(max,ss) and AUC(0-6h,ss) increased in proportion to the dosage. 100% inhibition of LTB(4)-induced MAC-1 expression was reached after two hours (150 mg) or four hours (25 mg), showing a statistically significant difference in comparison with placebo (p<0.005). A longlasting dynamic effect was seen consistently even when plasma concentrations declined to very low values 24 hours after administration. Secondary clinical efficacy end points remained unchanged probably owing to the short duration of treatment. Adverse events (AEs) were reported in 12 patients during the study. No serious AEs or laboratory AEs were seen. CONCLUSIONS: Both the 25 mg and 150 mg doses of BIIL 284 safely and effectively inhibit Mac-1 expression on neutrophils; thus longer treatment with BIIL 284 may result in clinical benefit for patients with RA.

[Laboratory diagnosis of osteoporosis]. / Labordiagnostik der Osteoporose.

Bone is biologically a highly active tissue whose cells are embedded in a complex network of systemically acting hormones and local mediators. The mechanisms of action involved are as yet only partially understood. With the increase in life expectancy and the resultant change of the population's age structure, diseases of the musculoskeletal system and bones have increased in importance. Thus, research is directed to a greater extent toward bone metabolism and the most frequent bone disease, osteoporosis. Until a few decades ago, the diagnosis of a bone disease was based principally on clinical and radiological methods. Laboratory methods only included the measurement of total alkaline phosphatase activity and calcium and phosphate balance. The development and introduction of new biochemical markers of bone metabolism in recent years led to a considerable increase in available laboratory methods. To evaluate the activity of osteoblastic synthesis, alkaline phosphatase and other bone-forming markers with higher tissue specificity such as bone alkaline phosphatase, osteocalcin, and several collagen propeptides are used. Bone degradation (calcium and hydroxyproline were the only markers until several years ago) can now be detected quickly and reliably with many new serological and urinary markers. Pyridinium derivatives and telopeptides as products of the metabolic activity of osteoclasts have been proved efficacious in diagnosis and therapy control.

Laminin fragment P1 in the sera of patients with pulmonary sarcoidosis.

Laminin is a noncollagenous component of the extracellular matrix in the alveolar wall and may play a role in the development of fibrotic lung disease. Serum levels of laminin fragment P1 as well as procollagen III peptide were determined in 28 patients with pulmonary sarcoidosis and 10 healthy controls using specific radioimmunoassays. The patients' results were compared with the clinical appearance, lung function values (vital capacity, total lung capacity, FEV1, transfer coefficient (KCO), and alveolar-arterial oxygen difference during exercise) and serum concentrations of angiotensin converting enzyme and soluble interleukin 2 receptor. Laminin levels in patients were significantly higher than in controls but always remained within normal limits. Although there was a tendency towards higher values in patients with active disease and with radiographic involvement, no significant correlation was found between laminin concentration and clinical, functional or biochemical data. In contrast, procollagen III N-terminal peptide concentrations were elevated in 19 of 28 patients and showed a weak but significant inverse correlation with parameters of restriction with significantly higher values in patients with active disease. In conclusion, serum levels of laminin fragment P1 are not elevated in pulmonary sarcoidosis and do not correlate with other parameters of the disease. Yet serum levels of procollagen III N-terminal peptide were associated with the degree of parenchymal involvement as expressed by functional disturbance and with active disease.

[Abdominal variant of benign symmetrical Launois-Bensaude lipomatosis]. / Abdominelle Variante einer benignen symmetrischen Lipomatose Launois-Bensaude.

We report on a patient with an abdominal type of benign symmetrical Launois-Bensaude lipomatosis. New aspects of the pathogenesis of abnormal distribution of the fatty tissue are also discussed.

[Immune status of pregnant patients especially in possible premature labor]. / Untersuchung zur Immunitätslage Schwangerer insbesondere beim Vorliegen einer Frühgeburtsymptomatik.

In this study it could be shown that pregnant women having a normal course of pregnancy had significantly higher levels of T-lymphocytes and T-helper cells compared with non-pregnant women. Also other parameters belonging to cellular immune defence showed a similar--in the sense of an improved immune function--trend (even though this was not statistically significant). In pregnant women with symptoms of threatened prematurity significantly lower levels for lymphocytes. T-lymphocytes and T-helper cells were measured than in women who had a normal course of pregnancy. The ratio was also clearly reduced--in those cases where later preterm labour did actually occur it was particularly low at 1.1. In the group of pregnant women with premature labor the number of those who found the situation "very stressful" amounted to 65% and in the group whose course of pregnancy was normal, the percentage was 26%. The results of this study point to the fact that in pregnant women with premature labor the immune function is often impaired and it can be assumed that this provides favourable conditions for ascending infections which then cause a higher risk of prematurity. Further studies should be made concerning the causal connections which we have postulated between physical and psychological overstrains and impairment of the immune function.

Specification and quantitation of circulating immune complexes in the serum of patients with active pulmonary sarcoidosis.

BACKGROUND: Circulating immune complexes can be elevated in serum samples of patients with sarcoidosis and are associated with disease activity, but their diagnostic significance is not understood. METHODS: The different classes of circulating immune complexes containing immunoglobulin A, G, or M, and the content of complement in circulating immune complexes (polyethylene glycol precipitation) as well as levels of complement binding circulating immune complexes (complement binding assay) were determined in 19 patients with active, untreated pulmonary sarcoidosis. The results were compared with other parameters in the serum (soluble interleukin 2 receptor, angiotensin converting enzyme, immunoglobulin A, G, and M) and the bronchoalveolar lavage fluid (lymphocytes, helper cells, suppressor cells, activated T cells), and with radiological stage and functional parameters (FEV1, vital capacity, total lung capacity, transfer coefficient (KCO), and the alveolar-arterial oxygen difference during exercise). RESULTS: In all patients circulating immune complexes could be detected by polyethylene glycol precipitation and were similar to control subjects. The content of C1q in circulating immune complexes was higher than in controls, yet in all but one of the cases was still within normal limits. In contrast, elevated levels of complement binding circulating immune complexes were found in 67% of the patients. No correlation was seen between circulating immune complexes and any of the other parameters in the serum, bronchoalveolar lavage fluid, or lung function values. No differences were found between radiological type I and II presentations of sarcoidosis. CONCLUSIONS: The complement binding assay showed a much higher sensitivity for the detection of circulating immune complexes in active pulmonary sarcoidosis than the polyethylene glycol precipitation method. As there was no correlation between levels of circulating immune complexes and other parameters of the disease they are probably not useful for the assessment of disease activity.

Immunohistochemical studies with skin mast cells.

Using different histochemical and immunohistochemical methods we demonstrate that isolated skin mast cells used for different pharmacological and biochemical studies exhibit the same staining pattern compared to skin mast cells in situ. Surface structures and enzyme content of the cells appear not to be influenced by the isolation technique. We also observed no differences in the staining pattern of mast cells in neurofibroma, a cutaneous disorder characterized by an increase of mast cell numbers.

[Vascular risk factors of sudden deafness and its incidence in the normal population. A retrospective study]. / Vaskuläre Risikofaktoren beim Hörsturz und ihre Häufigkeit in der Normalbevölkerung. Eine retrospektive Studie.

We report the frequency of the vascular risk factors (overweight, hypertension, hypercholesterinaemia, hypertriglyceridaemia, hyperuricaemia, hyperglycaemia and smoking) in patients with sudden hearing loss. Analysis of 264 cases shows that only hyperuricaemia and hyperglycaemia are found more often in patients suffering from sudden deafness than in the normal population. There was a negative correlation between hearing improvement and the number of risk factors. Also the number of risk factors increased proportionally to the age of the patients. The patient's age and late treatment were the only unfavourable prognostic factors for hearing improvement.

[Immunologic tumor diagnosis]. / Immunologische Tumordiagnostik.

Tumour markers are substances stemming either from the tumour cell itself or the production of which is stimulated by the malignant growth. They are released into body fluids where they can be detected quantitatively with the aid of sensitive immunological methods. In addition to oncofetal antigens they include hormones, enzymes, isoenzymes as well as special proteins. The determination of markers by aid of monoclonal antibodies has led to an additional improvement in tumour diagnostics. Tumour markers are indubitably valuable preoperatively as prognostic parameters, and postoperatively for the follow-up and after-care. However, the tumour-associated substances so far in use are unsuitable for the early recognition of malignant processes.

[Functional disorders of the immune system]. / Funktionsstörungen des Immunsystems (II).

In common with other organ systems in the body the immune system demonstrates functional disturbances which may lead to numerous immunological disorders with grave consequences for the health of the patient. Whenever the complex network of regulation and counter-regulation mechanisms within the defence system is impaired, by hereditary or acquired defects, immunological defect syndromes occur. One of the disorders that has been the object of intensive discussion in this context over the past few years is the acquired immune deficiency syndrome AIDS, a dangerous viral infection that mostly affects the T4 cells, whose helper and inductor function is absolutely essential for successful immunological defence. Furthermore, functional impairment of the antibody-producing plasma cells leads to the heterogeneous group of gammopathies which are characterized by an uncontrolled and excessive proliferation of structurally uniform antibody molecules in the blood. Overreactions of the immune system which wrongly attack endogenous tissue are accredited with causing the so-called auto-immune diseases. The clinical pictures within this group are exceptionally varied, and depend both on the self-antigen that the attack is aimed at as well as the erroneously triggered effector function that is affected. Whenever the immune system reacts disproportionately strongly against otherwise harmless foreign antigens, allergic clinical picture emerge.

[Organization and function of the immune system (I)]. / Aufbau und Funktion des Immunsystems (I).

An immune reaction is a complex process. Nonspecific resistance is always induced besides specific humoral and cellular defense reactions. After binding to an antigen (antigen-antibody reaction) antibodies can activate complement. If the entire complement cascade occurs, for example at the surface of cells (bacteria), this leads to complement-induced lysis and to destruction of the antigen. Complement cleavage products which are formed during the activation of complement have biological activities. They can attract granulocytes, macrophages and lymphocytes chemotactically or induce and accelerate processes of phagocytosis. In consequence of the activation of T-lymphocytes sensitized T-cells are formed. T-helper-cells intensify both the humoral cellular immune response mediated by B-cells and the cellular immune response mediated by cytotoxic T-cells. They effect this by secretion of substances resembling hormones, the so-called lymphokines. Cytotoxic T-cells (killer cells) can kill their target cells directly. Immune reactions are regulated in multifarious ways. T-suppressor-cells slow down the immune reactions of B- and T-cells. The close interaction of the T-helper and T-suppressor-cells designated as "regulatory T-cells" ensures the functional equilibrium within the immune system.

[Liberalized diabetic diet for type I diabetics under intensive insulin injection therapy. Follow-up observations for over 2 years]. / Liberalisierte Diabetesdiät bei Typ-I-Diabetikern unter intensivierter Insulin-Injektionsbehandlung. Verlaufsbeobachtung über 2 Jahre.

The dietary habits and metabolic status of 14 selected ambulant type-1 diabetics, who were previously treated with conventional insulin therapy, were investigated over a period of 2 years under intensified insulin injection therapy. In this, multiple doses of regular insulin in combination with intermediate-acting insulin were injected daily and the regular metabolic controls as well as adjustment of the insulin dosage were undertaken by the patients themselves. Whereas conventional insulin therapy made exclusive use of intermediate-acting insulin, 41% of the daily dose in the intensified insulin injection therapy was regular insulin. The total daily insulin dose of 51 +/- 12 U/d was therefore not significantly different from that in the conventional insulin therapy (49 +/- 10 U/d). During the intensified insulin injection therapy the usual diabetic diet was relaxed in several aspects: neither the daily intake of fat, protein and calories, nor substitution in the diet using exchange lists was specified. Despite this liberalization HbA1c values decreased significantly from 9.3 +/- 1.2% to 7.8 +/- 0.7% (P less than 0.05) and blood lipids remained in the normal range. The results of this retrospective investigation lead to the conclusion that despite some measure of diet liberalization, selected, trained, type-1 diabetics of normal body weight and without primary dyslipoproteinaemia can attain good metabolic control under intensified insulin injection therapy.

[Inflammatory diseases of the vessels. Clinical aspects, immunopathology, characteristic features of therapy (author's transl)]. / Entzündliche Gefässerkrankungen. Klinik, Immunpathologie, Grundzüge der Therapie.

Arterial obstructive diseases become manifest principally in the great peripheral vessels, visceral symptoms are rare. In the overwhelming majority of inflammatory vascular processes changes in the small arteries are impressive, visceral symptoms are common, in many cases the rule, peripheral occlusive syndromes are exceptions, although possible, and then prognostically especially serious in the individual case. The diagnosis of such vascular processes can be extraordinarily difficult if there is systemic spread because of the great variety of symptoms, and in the individual case may be almost impossible. Principles of classification should contribute to the facilitation of necessary clinical differentiation and lead to the proper therapeutic indication of the fundamental process. But they should also serve for the understanding of those inflammatory vascular diseases whose special position is based on the new scientific knowledge of immunopathology.

[Clinical, light- and electron-microscopic investigations on the effect of 5-ethyl-2-deoxyuridine (EDU) in herpes simplex keratitis in rabbits (author's transl)]. / Klinische, licht- und elektronenmikroskopische Untersuchungen über den Einfluss von 5 Athyl-2-Desoxyuridin (ADU) auf die Herpes-simplex-Keratitis beim Kaninchen

Morphologic changes in rabbit cornea accompanying herpes simplex keratitis especially under the treatment of ethyldeoxyuridine (EDU) are summarized in regard to clinical aspects, light microscopy and electron microscopy. Untreated eyes show virus-dependent characteristic changes of the cell structure: peripheral migration of the cell chromatin, swelling of the nucleus, and disappearance of the nucleolus are persistent. In the nucleus as well as in the cytoplasm mature and immature virus particles are visible which demonstrate the normal virus-replication course. In the EDU treated cornea these particular changes are observed only in the primary stage. After prolonged treatment in the nucleus of the infected cells there are only immature virus particles with optically empty center. This can be evaluated as a sign of inhibition of the normal replication. No virus formation was detected in the cytoplasm. After 7 day treatment of EDU, the corneal epithelium is almost of normal structural appearance. Accordingly, the present results on the rabbit seem to correlate well with the reported therapeutic antiherpetic studies in the human cornea.