Biomedical subjects

M Aringer

Publications and source records attributed to M Aringer.

At least 37 records · Page 2Linked to original sources

PubMed2000

Stat4 is expressed in activated peripheral blood monocytes, dendritic cells, and macrophages at sites of Th1-mediated inflammation.

Stat4 is a key transcription factor involved in promoting cell-mediated immunity, whose expression in mature cells has been reported to be restricted to T and NK cells. We demonstrate here, however, that Stat4 expression is not restricted to lymphoid cells. In their basal state, monocytes do not express Stat4. Upon activation, however, IFN-gamma- and LPS-treated monocytes and dendritic cells express high levels of Stat4. Monocyte-expressed Stat4 in humans is phosphorylated in response to IFN-alpha, but not IL-12. In contrast, the Th2 cytokines, IL-4 and IL-10, specifically down-regulate Stat4 expression in activated monocytes, while having little effect on Stat6 expression. Moreover, macrophages in synovial tissue obtained from patients with rheumatoid arthritis express Stat4 in vivo, suggesting a potential role in a prototypical Th1-mediated human disease. IFN-alpha-induced Stat4 activation in human monocytes represents a previously unrecognized signaling pathway at sites of Th1 inflammation.

Arthritis, Rheumatoid↗

PubMed2000

Successful treatment of high turnover osteoporosis in a patient with adrenocortical insufficiency.

We present a case of high-turnover osteoporosis associated with substituted adrenocortical insufficiency (Addison's disease) and its successful treatment with calcitonin and calcitriol. A 43-year-old man presented with markedly reduced bone mineral density (BMD) (lumbar spine BMD -3.46 SD below healthy young adults) after thirteen years of glucocorticoid substitution. Interestingly, his osteocalcin levels indicated an unusually high bone turnover and his alkaline phosphatase levels were also increased. Combination treatment with calcitriol and calcitonin was started. Re-evaluation after twelve months revealed a substantial increase in BMD (+6.8% for the lumbar spine, +15% for the left hip). Alkaline phosphatase levels had normalised and osteocalcin was nearly down to normal. In spite of a thorough evaluation, no other cause of osteoporosis was detected. We discuss these findings in view of the existing literature.

Addison Disease↗

PubMed2000

Inhibition of Th1 immune response by glucocorticoids: dexamethasone selectively inhibits IL-12-induced Stat4 phosphorylation in T lymphocytes.

Glucocorticoids are widely used in the therapy of inflammatory, autoimmune, and allergic diseases. As the end-effectors of the hypothalamic-pituitary-adrenal axis, endogenous glucocorticoids also play an important role in suppressing innate and cellular immune responses. Previous studies have indicated that glucocorticoids inhibit Th1 and enhance Th2 cytokine secretion. IL-12 promotes Th1 cell-mediated immunity, while IL-4 stimulates Th2 humoral-mediated immunity. Here, we examined the regulatory effect of glucocorticoids on key elements of IL-12 and IL-4 signaling. We first investigated the effect of dexamethasone on IL-12-inducible genes and showed that dexamethasone inhibited IL-12-induced IFN-gamma secretion and IFN regulatory factor-1 expression in both NK and T cells. This occurred even though the level of expression of IL-12 receptors and IL-12-induced Janus kinase phosphorylation remained unaltered. However, dexamethasone markedly inhibited IL-12-induced phosphorylation of Stat4 without altering its expression. This was specific, as IL-4-induced Stat6 phosphorylation was not affected, and mediated by the glucocorticoid receptor, as it was antagonized by the glucocorticoid receptor antagonist RU486. Moreover, transfection experiments showed that dexamethasone reduced responsiveness to IL-12 through the inhibition of Stat4-dependent IFN regulatory factor-1 promoter activity. We conclude that blocking IL-12-induced Stat4 phosphorylation, without altering IL-4-induced Stat6 phosphorylation, appears to be a new suppressive action of glucocorticoids on the Th1 cellular immune response and may help explain the glucocorticoid-induced shift toward the Th2 humoral immune response.

3T3 Cells↗

PubMed2000

Cytokine regulation of apoptosis and Bcl-2 expression in lymphocytes of patients with systemic lupus erythematosus.

Both faulty regulation of apoptosis and the inappropriate expression of several interleukins have been considered important defects of lymphocytes in the human autoimmune disease systemic lupus erythematosus (SLE). We therefore tested the in vitro effect of recombinant interleukin (IL-)-2, 4, 7, and 15 on peripheral blood mononuclear cells from patients with SLE and from healthy volunteers. Intracellular Bcl-2 and Bax expression was measured by fluorocytometry and the rate of apoptosis was determined by the TUNEL technique and propidium iodide staining. IL-2, IL-4, IL-7 and IL-15 led to a significant increase in Bcl-2 and a reduction in cell death rates, which was even more pronounced in SLE. Bax levels remained unchanged. Interestingly, the high ex vivo Bcl-2 content of lymphocytes from some SLE patients was maintained after growth factor withdrawal. Anti-apoptotic cytokine signaling may significantly influence the deregulation of cell death in SLE lymphocytes.

Adolescent↗

PubMed2000

Derangement of apoptosis-related lymphocyte homeostasis in systemic sclerosis.

OBJECTIVES: Both increased and decreased apoptosis may be involved in generating autoimmunity. This study addressed the question of whether apoptosis and apoptosis-regulating proteins are altered in systemic sclerosis (SSc). Patients and methods. Peripheral lymphocytes of 39 SSc patients and 47 healthy control persons were studied for apoptosis, Bcl-2 and Bax levels, expression of Fas (CD95) and activation markers (CD25, HLA-DR) as determined by fluorocytometry. Serum Fas and Fas ligand were measured by ELISA. RESULTS: SSc lymphocytes (mainly CD4(+)) expressed increased amounts of Bcl-2, while Bax was not elevated. Apoptosis rates of SSc lymphocytes were increased in unsupplemented medium, but returned to normal in the presence of autologous plasma. SSc patients had increased percentages of activated and CD95(+) lymphocytes and elevated soluble Fas and soluble FasL levels in serum. Activating anti-CD95 antibodies further increased the apoptosis rate. CONCLUSIONS: Increased in vitro apoptosis, elevated lymphocytic Bcl-2 content and the increased number of Fas-positive T cells are not specific for peripheral blood from SSc patients, but indicate deregulation of lymphocyte homeostasis in this disease.

Adult↗

PubMed1999

Ultrasound therapy for calcific tendinitis of the shoulder.

BACKGROUND AND METHODS: Although ultrasound therapy is used to treat calcific tendinitis of the shoulder, its efficacy has not been rigorously evaluated. We conducted a randomized, double-blind comparison of ultrasonography and sham insonation in patients with symptomatic calcific tendinitis verified by radiography. Patients were assigned to receive 24 15-minute sessions of either pulsed ultrasound (frequency, 0.89 MHz; intensity, 2.5 W per square centimeter; pulsed mode, 1:4) or an indistinguishable sham treatment to the area over the calcification. The first 15 treatments were given daily (five times per week), and the remainder were given three times a week for three weeks. Randomization was conducted according to shoulders rather than patients, so a patient with bilateral tendinitis might receive either or both therapies. RESULTS: We enrolled 63 consecutive patients (70 shoulders). Fifty-four patients (61 shoulders) completed the study. There were 32 shoulders in the ultrasound-treatment group and 29 in the sham-treatment group. After six weeks of treatment, calcium deposits had resolved in six shoulders (19 percent) in the ultrasound-treatment group and decreased by at least 50 percent in nine shoulders (28 percent), as compared with respective values of zero and three (10 percent) in the sham-treatment group (P=0.003). At the nine-month follow-up visit, calcium deposits had resolved in 13 shoulders (42 percent) in the ultrasound-treatment group and improved in 7 shoulders (23 percent), as compared with respective values of 2 (8 percent) and 3 (12 percent) in the sham-treatment group (P=0.002). At the end of treatment, patients who had received ultrasound treatment had greater decreases in pain and greater improvements in the quality of life than those who had received sham treatment; at nine months, the differences between the groups were no longer significant. CONCLUSIONS: In patients with symptomatic calcific tendinitis of the shoulder, ultrasound treatment helps resolve calcifications and is associated with short-term clinical improvement.

Calcinosis↗

PubMed1999

Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes.

Autosomal dominant periodic fever syndromes are characterized by unexplained episodes of fever and severe localized inflammation. In seven affected families, we found six different missense mutations of the 55 kDa tumor necrosis factor receptor (TNFR1), five of which disrupt conserved extracellular disulfide bonds. Soluble plasma TNFR1 levels in patients were approximately half normal. Leukocytes bearing a C52F mutation showed increased membrane TNFR1 and reduced receptor cleavage following stimulation. We propose that the autoinflammatory phenotype results from impaired downregulation of membrane TNFR1 and diminished shedding of potentially antagonistic soluble receptor. TNFR1-associated periodic syndromes (TRAPS) establish an important class of mutations in TNF receptors. Detailed analysis of one such mutation suggests impaired cytokine receptor clearance as a novel mechanism of disease.

Amino Acid Sequence↗

PubMed1999

Janus kinases and their role in growth and disease.

Janus kinases (JAK) play a crucial role in the initial steps of cytokine signaling. Each of the four members (JAK1, JAK2, JAK3, TYK2) of this non-receptor tyrosine kinase family is indispensable for the effects of distinct cytokines. Moreover, recent reports have added to our knowledge on their highly specific functions: JAK3 knockout mice and JAK3 deficient patients cannot signal through the interleukin-2,4,7,9, or 15 receptors and suffer from severe combined immunodeficiency (SCID). JAK1 and JAK2 knockout mice do not survive, their cells again showing distinct patterns of cytokine signaling deficits. At the other end of the spectrum, JAK fusion proteins have been shown to play a role in leukemias. In addition, a new class of JAK-specific inhibitors was described by several groups, the CIS/SOCS/Jab family. This review on the rapidly growing field focuses on JAK function and regulation, and on their emerging role in development and human disease.

Animals↗

PubMed1999

Expression of adhesion molecules on synovial fluid and peripheral blood monocytes in patients with inflammatory joint disease and osteoarthritis.

OBJECTIVE: To determine the presence of adhesion molecules on monocytes/macrophages (Mphi) from peripheral blood (PB) and synovial fluid (SF) in patients with osteoarthritis (OA) and inflammatory joint diseases (rheumatoid (RA) and reactive arthritis (ReA)) in order to improve our understanding of the possible mechanisms underlying the inflammatory process. METHODS: Whole blood and SF cells were stained with monoclonal antibodies against CD11a (LFA-1), CD15 s (sialyl-Lewis X), CD44, CD54, VLA-4, and HLA-DR counterstained with anti-CD14 antibodies as a Mphi marker for dual fluorescence analysis by flowcytometry. RESULTS: On PB-Mphi, CD15s was markedly increased in both RA as well as ReA compared with OA. Furthermore, in the PB LFA-1, CD44, and HLA-DR showed a higher surface density on Mphi in ReA than in OA. Comparison between SF and PB showed significantly higher CD44 and CD54 expression on SF-Mphi. These molecules play an important part in lymphocyte-Mphi interaction. CONCLUSION: In PB from patients with inflammatory joint diseases, Mphi are activated, allowing recruitment into the synovial compartment. These disorders, in contrast with OA seem to be "systemic" in nature. Within the SF, different adhesion molecules are expressed on CD14(+) Mphi as compared with PB.

Adult↗

PubMed1998

Severe infections in plasmapheresis-treated systemic lupus erythematosus.

OBJECTIVE: To assess the risk of infection in patients with systemic lupus erythematosus (SLE) treated with plasmapheresis in addition to intravenous (I.V.) pulse cyclophosphamide (CYC). METHODS: We searched the records of all our SLE patients for those who had undergone plasmapheresis plus I.V. CYC treatment (n = 9). Consecutive patients with similarly high SLE activity who underwent I.V. CYC therapy but not plasmapheresis were included as controls (n = 12). We evaluated both groups for severe infections, outcome, and confounding clinical variables. RESULTS: Seven of 9 plasmapheresis-treated patients had serious bacterial or viral infections, including 3 cases of cytomegalovirus infections. Among the 12 patients treated with I.V. CYC alone, only 2 had severe infections (P < 0.01). Three patients in the plasmapheresis group and none in the control group died of infections. Treatment efficacy, however, was similar for both groups. CONCLUSION: Among SLE patients treated with plasmapheresis and I.V. CYC, life-threatening bacterial and viral infections and mortality occur more frequently than among patients with similarly active SLE treated with I.V. CYC alone.

Adult↗

PubMed1998

High turnover bone disease following lung transplantation.

Recipients of lung transplants are at very high risk for significant bone loss. Nevertheless, data on bone disease after lung transplantation are still limited. We, therefore, retrospectively evaluated the data of 33 patients surviving at least 1 year after lung transplantation (LTx) who were seen in our outpatient clinic for osteologic evaluation. Results of clinical evaluations, radiographs, and dual-energy X-ray absorptiometry (DXA) were related to each other, to clinical variables, and to serum levels of osteocalcin, parathyroid hormone (PTH), and 25-hydroxyvitamin D: 14 of 33 patients (42%) had vertebral fractures, 9 of whom were diagnosed within 2 years after transplantation. Bone mineral density values (DXA) were markedly decreased and predictive of compression fractures. 25-Hydroxyvitamin D levels were low in 13 patients (39%) and PTH was elevated in 7 (21%). Despite corticosteroids and low 25-hydroxyvitamin D, serum osteocalcin was elevated in 12 patients (36%). This was only partially explained by hyperparathyroidism, low sex hormones, and impaired renal function, and may partly be caused by cyclosporin A. We thus conclude that severe symptomatic bone disease is common in lung transplant recipients and due to a complex situation including high turnover bone loss and hypovitaminosis D. DXA can be used to estimate fracture risk for individual patients.

Absorptiometry, Photon↗

PubMed1998

Improvement of physical fitness and muscle strength in polymyositis/dermatomyositis patients by a training programme.

In the present investigation, the benefit of physical training in patients with inflammatory myopathy was studied. In this prospective, randomized, controlled study, 14 patients with polymyositis (PM) or dermatomyositis (DM) were investigated. The training, consisting of bicycle exercise and step aerobics, took place over a 6 week period. Baseline and endpoint measurements included an 'activities of daily living' (ADL) score, peak isometric torque (PIT) generated by muscle groups in the lower extremities, peak oxygen consumption (VO2max), and creatine phosphokinase (CPK) levels. There was no significant rise in disease activity in the training group in comparison to the controls. The ADL score for the treatment group, in comparison to the control group, improved (P < 0.02), PIT rose (P < 0.05) and there was a statistically significant increase in oxygen uptake relative to body weight (P < 0.05). No rise in inflammatory activity, but significant improvement in muscle strength, oxygen uptake and well-being, were found in patients with inflammatory myopathy as a result of physical training. Besides medication, a physical training programme consisting mainly of concentric muscle contractions should therefore be an integral part of therapy, particularly in view of the cardiopulmonary risk of these patients.

Adult↗

PubMed1997

Photopheresis treatment enhances CD95 (fas) expression in circulating lymphocytes of patients with systemic sclerosis and induces apoptosis.

We investigated the effects of photopheresis in systemic sclerosis by analysing its influence on lymphocytes with regard to apoptosis and expression of bcl-2 and fas. Peripheral blood lymphocytes isolated immediately before and 24 h after photopheresis were investigated for apoptosis, bcl-2 and fas expression by fluorocytometry, and compared to controls. In addition, leucocytes from systemic sclerosis patients taken directly from the photopheresis system were tested for apoptosis after 24 h in culture. fas expression was similar in controls and patients with systemic sclerosis just before photopheresis, but increased 24 h after photopheresis, mainly due to an increase of CD4+CD95+ cells. bcl-2 was overexpressed in scleroderma peripheral lymphocytes, but not influenced by photopheresis. As compared to healthy controls, the percentage of apoptotic cells 24 h after photopheresis was high in cultured lymphocytes, but not ex vivo. The significant increase in fas on peripheral lymphocytes observed in this study may be a major operative mechanism of photopheresis in addition to (and possibly related to) the induction of apoptosis.

Adult↗

PubMed1996

[MR imaging in gout].

The appearance of gouty tophus in magnetic resonance imaging (MRI) is characteristic. On T1- and T2-weighted SE images, the signal intensity of tophaceous lesions is similar to that of muscles. According to the histology, T2-weighted SE images demonstrate extremely hyperintense signals, which reflect the high protein content in the amorphous center of the tophus. The microscopic urate crystals deposited there have no MRI signal and are of no further diagnostic impact. Vascularized granulation tissue surrounding the tophus center enhance after intervenous application of contrast agents (Gadolinium). The inflamed tophus is associated with local edema, causing high signal intensity. MRI is superior to plain radiography for early detection of intraosseous tophi. Involvement of anatomical structures such as ligaments and tendons can be evaluated sufficiently. For peripheral joints, axial slice orientation is most helpful.

Adult↗

PubMed1995

Destructive lymphadenopathy and T-lymphocyte activation in adult-onset Still's disease.

Recurrent arthritis, fever and lymphadenopathy are symptoms of adult onset of Still's disease (AOSD). Differential diagnosis requires the exclusion of infections or malignant lymphomas. We report on a case of AOSD showing destructive lymphadenopathy, immunophenotyping of peripheral blood leucocytes revealed strong activation of T-lymphocytes. Bone marrow biopsy also showed an increase of lymphopoietic cells to 23%. Analysis of peripheral blood lymphocytes (PBL) after remission showed no remaining signs of activation. Analysis of lymphocyte activation by flow cytometry correlated with disease activity.

Adult↗

PubMed1995

[AV-block II and arthritis as manifestations of Lyme borreliosis].

A 23-year old patient suffered from transient oligoarthritis and second degree AV block. The diagnosis of stage II systemic Lyme borreliosis was supported by a history of tick bites and the detection of both IgG and IgM borrelia antibodies in the patient's serum. The ECG-findings (bradyarrhythmia and AV block II) were detected several weeks after the onset of arthritis, whilst the patient reported no cardiac symptoms. Treatment was started with ceftriaxone and then continued with doxycycline because of an allergic reaction to the first antibiotic.

Adult↗

PubMed1995

Differential expression of the protooncogene bcl-2 in normal and osteoarthritic human articular cartilage.

OBJECTIVE: To investigate the expression of bcl-2 in healthy and osteoarthritic articular cartilage at the transcriptional level and at the protein level. METHODS: bcl-2 mRNA was detected by reverse transcriptase/polymerase chain reaction. The expression of bcl-2 protein was studied using flow cytometry analysis with a monoclonal antibody against intracellular bcl-2 and by immunohistochemistry. RESULTS: mRNA for bcl-2 was detectable in chondrocytes of both healthy and osteoarthritic cartilage. bcl-2 protein was present in the chondrocytes of the middle layer of cartilage by immunohistochemical staining. In osteoarthritis (OA), chondrocytes adjacent to cartilage defects expressed a particularly high signal intensity. Flow cytometry analysis demonstrated the presence of bcl-2 protein in virtually all chondrocytes. CONCLUSION: Our results show that bcl-2 is expressed in healthy adult and osteoarthritic human cartilage. The increased staining of chondrocytes adjacent to osteoarthritic defects indicates a differential regulation of programmed cell death during the degenerative process in OA.

Adult↗

PubMed1994

High levels of bcl-2 protein in circulating T lymphocytes, but not B lymphocytes, of patients with systemic lupus erythematosus.

OBJECTIVE: Defective regulation of programmed cell death (apoptosis) may play a role in the development of autoimmune diseases, and the proto-oncogene bcl-2 is involved in the control of apoptosis in immunocompetent cells. We therefore wished to investigate the expression of bcl-2 in the peripheral lymphocytes of patients with systemic lupus erythematosus (SLE), a prototypical autoimmune disease. METHODS: Levels of bcl-2 expression in the lymphocytes of patients with SLE and, for comparison, in the lymphocytes of healthy controls and patients with rheumatoid arthritis (RA), systemic bacterial infections, and chronic B cell lymphocytic leukemia were studied by 2-color cytofluorography and RNA analysis. RESULTS: In SLE patients, a significant proportion of T cells expressed increased amounts of bcl-2 protein. By fluorescence-activated cell sorter analysis, bcl-2--enriched lymphocytes were found in the CD45RO+ as well as in the CD45RO-, and also in the CD4+ and CD8+, lymphocyte subpopulations. Mononuclear cells of patients with SLE showed increased amounts of bcl-2 messenger RNA. An increased percentage of strongly bcl-2 positive peripheral T lymphocytes was found in patients with bacterial infections, but not in those with RA. CONCLUSION: Although the occurrence of circulating T lymphocytes with abnormally high bcl-2 expression is not specific for SLE, it is evidence for a dysregulation of lymphocytic programmed cell death in this autoimmune disease.

Adolescent↗