[Direct and indirect costs of fractures due to osteoporosis in Austria]. / Direkte und indirekte Kosten von osteoporotisch bedingten Frakturen in Österreich.

OBJECTIVES: We examined the financial burden of osteoporosis in Austria. METHODS: We took both direct and indirect costs into consideration. Direct costs encompass medical costs such as expenses for pharmaceuticals, inpatient and outpatient medical care costs, as well as other medical services (e.g., occupational therapies). Non-medical direct costs include transportation costs and medical devices (e.g., wheel chairs or crutches). Indirect costs refer to costs of productivity losses due to absence of work. Moreover, we included costs for early retirement and opportunity costs of informal care provided by family members. While there exist similar studies for other countries, this is the first comprehensive study for Austria. For our analysis, we combined data of official statistics, expert estimates as well as unique patient surveys that are currently conducted in the course of an international osteoporotic fracture study in Austria. RESULTS: Our estimation of the total annual costs in the year 2008 imposed by osteoporosis in Austria is 707.4 million €. The largest fraction of this amount is incurred by acute hospital treatment. Another significant figure, accounting for 29% of total costs, is the opportunity cost of informal care. CONCLUSIONS: The financial burden of osteoporosis in Austria is substantial. Economic evaluations of preventive and therapeutic interventions for the specific context of Austria are needed to inform health policy decision makers.

Interleukin-1 is essential for systemic inflammatory bone loss.

OBJECTIVES: Chronic inflammation is a major risk factor for systemic bone loss leading to osteoporotic fracture and substantial morbidity and mortality. Inflammatory cytokines, particularly tumour necrosis factor (TNF) and interleukin-1 (IL1), are thought to play a key role in the pathogenesis of inflammation-induced bone loss, but their exact roles are yet to be determined. METHODS: To determine whether TNF directly triggers bone loss or requires IL1, human TNFalpha mice (hTNFtg) were crossed with mice lacking IL1alpha and IL1beta (IL1(-/-)hTNFtg). Systemic bone architecture was evaluated using CT scanning, static and dynamic bone histomorphometry and serum markers of bone metabolism. RESULTS: hTNFtg mice developed severe bone loss accompanied by a severe distortion of bone microarchitecture. Bone trabeculae were thinner and decreased in numbers, resulting in increased trabecular separation. Histomorphometric analyses revealed strongly increased bone resorption in hTNFtg mice compared with wild-type mice. In contrast, IL1(-/-)hTNFtg mice were fully protected from systemic bone loss despite still developing inflammation in their joints. Lack of IL1 completely reversed increased osteoclast formation and bone resorption in hTNFtg mice and the increased levels of RANKL in these mice. Structural parameters and osteoclast and osteoblast numbers were indistinguishable from wild-type mice. CONCLUSIONS: These data indicate that IL1 is essential for TNF-mediated bone loss. Despite TNF-mediated inflammatory arthritis, systemic bone is fully protected by the absence of IL1, which suggests that IL1 is an essential mediator of inflammatory osteopenia.

Selective p38MAPK isoform expression and activation in antineutrophil cytoplasmatic antibody-associated crescentic glomerulonephritis: role of p38MAPKalpha.

OBJECTIVE: Crescentic glomerulonephritis (crGN) is a frequent and life-threatening manifestation of antineutrophil cytoplasmatic antibody-associated vasculitis. Up-regulation of proinflammatory cytokines contributes to renal damage by activation of p38 mitogen-activated protein kinases (MAPKs). However, it is unclear which of the four p38MAPK isoforms are expressed, activated and hence of major importance in crGN. METHODS: Kidney biopsies of patients with antineutrophil cytoplasmatic antibody-positive crGN and control samples were investigated for the expression and phosphorylation of p38MAPK isoforms and downstream target kinase MAPKAP2 by immunohistochemistry. Expression and functional activation of p38MAPK isoforms by TNF was also assessed in a human podocyte cell line by reverse transcription-polymerase chain reaction, immunoblotting and kinase array. RESULTS: Strong expression of p38MAPKalpha, beta and gamma isoforms was found in glomerular podocytes and crescents. Infiltrating leucocytes showed predominant p38MAPKalpha expression. Activation of p38MAPK and its downstream mediator MAPKAP2 was found in crGN confined to glomerular podocytes, crescents and inflammatory infiltrates. Interestingly, corticosteroid treatment before kidney biopsy diminished p38MAPK activation in crGN. Activated p38MAPK co-localised with alpha, beta and gamma isoforms in podocytes and crescents, while leucocytes showed mainly p38MAPKalpha activation. In a human podocyte cell line mRNA and protein of all four p38MAPK isoforms was expressed but only p38MAPKalpha was activated upon challenge with TNF. CONCLUSIONS: This study shows selective p38MAPK isoform expression and activation in crGN. Podocytes and podocyte-induce crescent formation is the main source of p38MAPK activation in crGN. TNF is a potent and selective activator of the alpha-isoform in podocytes, which therefore appears as a main contributor to proinflammatory signalling in the glomerulum of crGN.

Eotaxin-3 is involved in Churg-Strauss syndrome--a serum marker closely correlating with disease activity.

OBJECTIVE: Churg-Strauss Syndrome (CSS) is characterized by excessive eosinophil accumulation in peripheral blood and affected tissues with development of granulomatous vasculitic organ damage. The contribution of eosinophil-chemotactic cytokines (eotaxin family) to eosinophilia and disease activity in CSS is unknown. Thus, we compared serum levels of the eotaxin family members in CSS patients with healthy and disease controls. METHODS: Forty patients with CSS diagnosed according to ACR 1990 criteria, 30 healthy controls (HC) and 57 disease controls (28 asthma, 20 small vessel vasculitis, 9 hypereosinophilic syndrome) were studied. Clinical data were collected and serum levels of eotaxin-1, -2 and -3 were determined by ELISA. Further, immunohistochemistry was applied to identify eotaxin-3 expression in tissue biopsies from patients with CSS. RESULTS: In contrast to eotaxin-1 and -2, eotaxin-3 was highly elevated in serum samples of active CSS patients and correlated highly significantly with eosinophil counts, total immunoglobulin E (IgE) levels and acute-phase parameters. Moreover, eotaxin-3 was not elevated in other eosinophilic and vasculitic diseases. Immunohistochemical analysis revealed strong expression of eotaxin-3 in endothelial and inflammatory cells in affected tissues of active CSS patients. CONCLUSIONS: This study reveals the specific association of elevated eotaxin-3 expression with high disease activity and eosinophilia in CSS patients. Eotaxin-3 might thus be a pathogenic player, biomarker and potential therapeutic target in CSS.

Enhanced expression of heat shock protein 70 (hsp70) and heat shock factor 1 (HSF1) activation in rheumatoid arthritis synovial tissue. Differential regulation of hsp70 expression and hsf1 activation in synovial fibroblasts by proinflammatory cytokines, shear stress, and antiinflammatory drugs.

Heat shock proteins (hsp) have been repeatedly implicated to participate in the pathogenesis of rheumatoid arthritis (RA). Herein, we investigated the regulation of synovial hsp70 expression by analyzing the DNA-binding activity of heat shock transcription factor 1 (HSF1) as well as inducible hsp70 expression. Experiments were performed both on synovial tissue and on synovial fibroblast-like cells (SFC). Gel mobility shift analysis revealed increased HSF1 activation, and Western blotting and immunohistochemistry revealed increased hsp70 expression in RA synovial tissue, but not in synovial tissue derived from patients with osteoarthritis. Proinflammatory cytokines (TNF-alpha, IL-1alpha, IL-6), but not IFN-gamma or TGF-beta, induced activation of HSF1-DNA binding and hsp70 expression in cultivated SFC. Activation of HSF1 in SFC was accompanied by hyperphosphorylation and nuclear translocation of HSF1. Furthermore, shear stress also induced a complete heat shock response in cultivated synovial cells. In contrast, nonsteroidal antiinflammatory drugs triggered only an incomplete heat shock response, with HSF1 activation but not hsp70 induction, whereas steroids and immunosuppressive drugs did not affect the heat shock response at all. In summary, these data suggest that induction of hsp70 expression in rheumatoid synovial tissue is based on transcriptional activation of HSF1 due to the presence of proinflammatory cytokines (and possibly also shear stress).

17Beta-estradiol antagonizes effects of 1alpha,25-dihydroxyvitamin D3 on interleukin-6 production and osteoclast-like cell formation in mouse bone marrow primary cultures.

In mouse bone marrow primary cultures, the formation of osteoclast-like, i.e. tartrate-resistant acid phosphatase (TRAP)- and calcitonin receptor-positive multinucleated cells (MNC), when induced by 1alpha,25-dihydroxyvitamin D3 (1alpha,25(OH)2D3), can be suppressed by 17beta-estradiol (17beta-E2), whereas 17alpha-E2 is without any effect. 17beta-E2, above 10(-11) M, significantly reduced 1alpha,25(OH)2D3-mediated TRAP+ MNC formation in cultured bone marrow cells from both female and male mice. The estrogen at 10(-8) M suppressed the peak response to the vitamin D sterol by 50%. 17beta-E2 significantly suppressed basal and 1alpha,25(OH)2D3-stimulated cellular production of interleukin (IL)-6. IL-6 alone, although bone marrow cells in hormone-free culture produced appreciable amounts of the cytokine, did not induce any TRAP+ MNC. Therefore, the changes in IL-6 production induced by the hormones could not be the sole determinant for the extent of TRAP+ MNC formation. However, the stimulatory effect of 1alpha,25(OH)2D3 on osteoclastogenesis nevertheless can be significantly reduced by a neutralizing monoclonal anti-IL-6 antibody. In the presence of 10(-8) M 17beta-E2, the anti-IL-6 monoclonal antibody does not achieve any further suppression of 1alpha,25(OH)2D3-related osteoclast-like cell formation. Our data suggest that induction of osteoclastogenesis by 1alpha,25(OH)2D3 is partially dependent on IL-6 signaling and can be modulated by 17beta-E2 through interference with IL-6 receptor activation, in addition to inhibition of IL-6 production by marrow stromal cells.

Interaction of triiodothyronine with 1alpha,25-dihydroxyvitamin D3 on interleukin-6-dependent osteoclast-like cell formation in mouse bone marrow cell cultures.

In mouse bone marrow cultures, the formation of osteoclast-like, that is, tartrate-resistant acid phosphatase-positive (TRAP+) and calcitonin (CT) receptor-positive multinucleated cells (MNCs), induced by 10(-10) to 10(-8) mol/L 1alpha,25-dihydroxyvitamin D3 [1alpha,25(OH)2D3], could be augmented by triiodothyronine (T3), which alone had no effect on osteoclast-like cell formation. The permissive effect of T3 increased the response to 1alpha,25(OH)2D3 by approximately one order of magnitude. Linear concentration dependence was observed between 10(-11) and 10(-8) mol/L T3. Importantly, inhibition of prostaglandin synthesis by indomethacin significantly impeded osteoclast-like cell formation by 1alpha,25(OH)2D3 and abrogated the effect of T3 thereon. Basal interleukin-6 (IL-6) production by cultured marrow cells was significantly stimulated by 1alpha,25(OH)2D3. However, even at an exceedingly high concentration of 20 ng/mL, IL-6 was ineffective in inducing osteoclast-like cell formation. Therefore, any hormonally induced rise in IL-6 release from bone marrow cells could not account for the observed changes in TRAP+ MNC numbers. Nevertheless, the stimulatory effect of 1alpha,25(OH)2D3 on osteoclastogenesis was partially dependent on IL-6 because it could be significantly blocked by a neutralizing monoclonal anti-IL-6 antibody, and to the same extent by a monoclonal anti-IL-6 receptor antibody. Unimpaired signaling through the IL-6/IL-6R system is also a prerequisite for the auxiliary effect of T3 on induction of osteoclast-like cells by 1alpha,25(OH)2D3. Our data provide evidence that 1alpha,25(OH)2D3 induces osteoclast-like cell formation, at least in part, in an IL-6-dependent mode of action, which is also subject to modulation by T3. The mechanism of interaction of the two hormones apparently involves joint stimulation of prostaglandin synthesis.

Hard-thermal-loop resummed pressure of a degenerate quark-gluon plasma

We compute the pressure of a finite-density quark-gluon plasma at zero temperature to leading order in hard-thermal-loop perturbation theory, which includes the fermionic excitations and Landau damping. The result is compared with the weak-coupling expansion for finite positive chemical potential &mgr; through order alpha(2)(s) and with a quasiparticle model with a mass depending on &mgr;.

Ticlopidine induced prolonged leucopenia in a patient with immunocytoma and chronic hepatitis C.

Ticlopidine is increasingly used in the secondary prophylaxis in patients with arterial occlusive diseases. Neutropenia is a well known side effect of this drug. We report a case of a 73 year old woman who was admitted because of severe prolonged ticlopidine induced leucopenia. The past medical history included an immunocytoma of the IgM-kappa type diagnosed seven years ago with less than 10% infiltration of the bone marrow and a chronic hepatitis C. On admission the white cell count was 1000/microL. Ticlopidine was stopped. The white cell count did not increase within one week, thus filgastrim was applied on two consecutive days. The leucocyte count promptly increased to 6000/microL but consecutively dropped within the next fortnight again to levels below 500/microL forcing daily filgastrim application for another 9 days. Four months after the initiation of the therapy with filgastrim the patient had a white cell count of 4300/microL. We therefore conclude that in patients with a history of potentially bone marrow suppressing diseases the use of ticlopidine has to be carefully weighed against possible myelosuppressive effects.

Density fluctuations in the presence of spinodal instabilities.

Density fluctuations resulting from spinodal decomposition in a nonequilibrium first-order chiral phase transition are explored. We show that such instabilities generate divergent fluctuations of conserved charges along the isothermal spinodal lines appearing in the coexistence region. Thus, divergent density fluctuations could be a signal not only for the critical end point but also for the first-order phase transition expected in strongly interacting matter. We also compute the mean-field critical exponent at the spinodal lines. Our analysis is performed in the mean-field approximation to the Nambu-Jona-Lasinio model formulated at finite temperature and density. However, our main conclusions are expected to be generic and model independent.

[Pathogenesis of osteoporosis in rheumatoid arthritis]. / Pathogenese der Osteoporose bei chronischer Polyarthritis.

Osteoporosis is a major clinical problem in rheumatoid arthritis. Patients with rheumatoid arthritis frequently not only present with juxta articular osteopenia and bone erosions but also with generalized axial and appendicular osteoporosis at sites distant from inflamed joints. The pathogenesis of bone loss in rheumatoid arthritis is multifactorial; disease activity certainly is a major determinant of bone mass. Further pathogenetic factors include effects of anti-inflammatory therapies (in particular glucocorticoids), reduced mobility, estrogen and/or androgen deficiency. Recently, receptor activator of nuclear factor kappa B ligand (RANKL) and osteoprotegerin (OPG), a decoy receptor for receptor activator of nuclear factor kappa B ligand, were identified as central regulators of osteoclast recruitment and activation. Osteoprotegerin and receptor activator of nuclear factor kappa B ligand production is modulated by several cytokines, growth factors and hormones. In rheumatoid synovium both fibroblasts and activated T cells express receptor activator of nuclear factor kappa B ligand and thereby promote osteoclast recruitment and activation. Thus, osteoprotegerin and receptor activator of nuclear factor kappa B ligand appear to represent important molecular links between the immune system and bone metabolism in rheumatoid arthritis.

Comparative study on the effect of calcium channel blockers on basal and parathyroid hormone-induced bone resorption in vitro.

A number of clinical and experimental studies suggest that the effects of calcium channel blockers are not limited to the cardiovascular system but might also involve skeletal calcium metabolism due to the presence of L-type calcium channels in osteoblastic cells. We therefore investigated the influence of calcium channel blockers of the dihydropyridine type (nifedipine, amlodipine) as well as of the phenylalkylamine type (verapamil, gallopamil) on basal and parathyroid hormone-induced bone resorption utilizing organ-cultured neonatal mouse calvaria. Only at 10(-4) M, amlodipine, verapamil and gallopamil reduced basal and parathyroid hormone-induced resorption In contrast, nifedipine, between 10(-5)-10(-4) M, exhibited a dose-dependent inhibitory effect on parathyroid hormone-related bone resorption by up to 50%. When calvariae were cultured for 48 hr in the presence of inhibitory concentrations of the calcium channel blockers and then stimulated with parathyroid hormone, only parietal bones pretreated with nifedipine remained completely responsive to the bone resorbing action of the hormone.

Kinetic equation for gluons in the background gauge of QCD.

We derive the quantum kinetic equation for a pure gluon plasma, applying the background field and closed-time-path method. The derivation is more general and transparent than earlier works. A term in the equation is found which, as in the classical case, corresponds to the color charge precession for partons moving in the gauge field.

Overpopulation of Omega; in pp collisions: a way to distinguish statistical hadronization from string dynamics.

The Omega/Omega ratio originating from string decays is predicted to be larger than unity in proton-proton interactions at SPS energies ( E(lab) = 160 GeV). The antiomega dominance increases with decreasing beam energy. This surprising behavior is caused by the combinatorics of quark-antiquark production in small and low-mass strings. Since this behavior is not found in a statistical description of hadron production in proton-proton collisions, it may serve as a key observable to probe the hadronization mechanism in such collisions.

Kinetic equation with exact charge conservation.

A kinetic master equation for multiplicity distributions is formulated for charged particles which are created or destroyed only in pairs due to the conservation of their Abelian charge. It allows one to study time evolution of the multiplicity distributions in a relativistic many-body system with arbitrary average particle multiplicities. It is shown to reproduce the equilibrium results for both canonical (rare particles) and grand canonical (abundant particles) systems. For canonical systems, the equilibrium multiplicity is much lower and the relaxation time is much shorter than the naive extrapolation from grand canonical results. Implications for chemical equilibration in heavy-ion collisions are also discussed.

Growth inhibitory effects on human colon adenocarcinoma-derived Caco-2 cells and calcemic potential of 1 alpha,25-dihydroxyvitamin D3 analogs: structure-function relationships.

A panel of synthetic analogs of 1 alpha,25-dihydroxyvitamin D3 [1 alpha,25(OH)2D3] bearing one or multiple structural modifications at functionally or metabolically sensitive positions of the molecule, i.e., C-1, 16, 23, 26 and 27, were tested for their growth inhibitory and prodifferentiating potency in human colon adenocarcinoma-derived Caco-2 cells. With respect to the peak response elicited at 10(-8) M, 1 alpha,25-dihydroxy-16-ene-vitamin D3, 1 alpha,25-dihydroxy-23-yne-vitamin D3 and 1 alpha,25-dihydroxy-16,23Z-diene-vitamin D3 suppressed [3H]thymidine incorporation in confluent Caco-2 cells less than 1 alpha,25(OH)2D3. 1 alpha,25-dihydroxy-16,23e-diene-vitamin D3 was at least equipotent to the parent compound, whereas 1 alpha,25-dihydroxy-16-ene-23-yne-vitamin D3 and most conspicuously 1 alpha,25-dihydroxy-26,27-hexafluoro-16-ene-23-yne- vitamin D3 reduced growth of Caco-2 cells to significantly (P < .05) lower levels than 1 alpha,25(OH)2D3. The same rank order was obtained for the ability of the vitamin D compounds to induce activity of the differentiation marker enzyme, alkaline phosphatase, in quiescent Caco-2 cells. Whereas the effect of the synthetic analogs on calcium uptake by cultured embryonic chick duodenum in general was less pronounced than that of 1 alpha,25(OH)2D3, the two most potent antimitogenic compounds, 1 alpha,25-dihydroxy-16-ene-23-yne-vitamin D3 and 1 alpha,25-dihydroxy-26,27-hexafluoro-16-ene-23-yne-vitamin D3, elicited calcium mobilization from cultured neonatal mouse calvaria at a 10-fold lower concentration than the parent compound.(ABSTRACT TRUNCATED AT 250 WORDS)

Activation, differential localization, and regulation of the stress-activated protein kinases, extracellular signal-regulated kinase, c-JUN N-terminal kinase, and p38 mitogen-activated protein kinase, in synovial tissue and cells in rheumatoid arthritis.

OBJECTIVE: To investigate whether stress- and mitogen-activated protein kinases (SAPK/MAPK), such as extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 MAPK, are significantly activated in rheumatoid arthritis (RA) synovial tissue compared with their activation in degenerative joint disease; to assess the localization of SAPK/MAPK activation in rheumatoid synovial tissue; and to search for the factors leading to stress kinase activation in human synovial cells. METHODS: Immunoblotting and immunohistology by antibodies specific for the activated forms of SAPK/MAPK were performed on synovial tissue samples from patients with RA and osteoarthritis (OA). In addition, untreated and cytokine-treated human synovial cells were assessed for SAPK/MAPK activation and downstream signaling by various techniques. RESULTS: ERK, JNK, and p38 MAPK activation were almost exclusively found in synovial tissue from RA, but not OA, patients. ERK activation was localized around synovial microvessels, JNK activation was localized around and within mononuclear cell infiltrates, and p38 MAPK activation was observed in the synovial lining layer and in synovial endothelial cells. Tumor necrosis factor alpha, interleukin-1 (IL-1), and IL-6 were the major inducers of ERK, JNK, and p38 MAPK activation in cultured human synovial cells. CONCLUSION: Signaling through SAPK/MAPK pathways is a typical feature of chronic synovitis in RA, but not in degenerative joint disease. SAPK/MAPK signaling is found at distinct sites in the synovial tissue, is induced by proinflammatory cytokines, and could lead to the design of highly targeted therapies.

Correlation of placental isoferritin with birth weight and time point of first contractions.

In a prospective study, the correlation between serum levels of placental isoferritin (PLF) and outcome of pregnancy was determined in 56 pregnant women. Women with contractions before the 36th week of pregnancy showed significantly lower PLF values compared with women with later contractions (p < 0.01). Furthermore, a strong correlation of PLF levels with birth weight was observed. In 11 (79%) cases with a birth weight < 2,500 g (group A), PLF values were < 10 U/ml whereas only 14% (6 of 42) of women with babies with a birth weight > 2,500 g (group B) revealed PLF levels < 10 U/ml. Because it has been shown previously that PLF has immunosuppressive properties, the secretion of PLF by the placenta could be responsible for the inhibition of the immunoreactivity of the maternal lymphocytes against the embryo. The strong correlation of low PLF values with preterm contractions and/or low birth weight recommends the determination of this protein as a marker for monitoring women with high risk pregnancies.

Tumor necrosis factor alpha promotes the expression of stem cell factor in synovial fibroblasts and their capacity to induce mast cell chemotaxis.

OBJECTIVE: To investigate the expression of the stroma cell product stem cell factor (SCF) in synovial fibroblasts (SFB) in patients with rheumatoid arthritis (RA) and osteoarthritis (OA), and to analyze the capacity of SFB to induce mast cell (MC) chemotaxis. METHODS: Synovial tissue was obtained from 29 patients with RA and 25 patients with OA. Tissue was dispersed by enzymatic digestion using collagenase. SFB were grown in serial passage and exposed to tumor necrosis factor alpha (TNFalpha) or control medium. Expression of SCF in cultured SFB was analyzed by reverse transcription-polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA), and immunostaining. The ability of SFB (supernatants) to induce MC migration was analyzed using a double-chamber chemotaxis assay and the human mast cell line HMC-1. In situ expression of SCF in synovial tissue from patients with RA (n = 6) and OA (n = 6) was examined by double immunohistochemistry using antibodies against SCF and the fibroblast-specific antibody AS02. RESULTS: In both RA and OA, cultured SFB were found to express SCF messenger RNA, as assessed by RT-PCR. In addition, the SCF protein was detectable in cell lysates and supernatants of SFB by ELISA. Incubation of SFB with TNFalpha resulted in an increased expression and release of SCF. Recombinant human SCF (rHuSCF) and SFB supernatants induced significant migration of HMC-1 cells above control levels. In addition, exposure of SFB to TNFalpha led to an increased migration of HMC-1, and a blocking anti-SCF antibody inhibited the rHuSCF- and SFB-induced migration of HMC-1. In situ double immunostaining revealed expression of SCF in AS02-positive SFB in the synovium of patients with RA. CONCLUSION: Our results show that SFB (in RA and OA) express SCF and induce MC chemotaxis. Furthermore, TNFalpha was found to augment SCF expression in SFB. It is hypothesized that these cellular interactions play an important role in MC accumulation and related events in RA.