Publications by authors named "Werner Kullich"

17 Publications

  • Page 1 of 1

Fatty Acid-Binding Protein 4 (FABP4) Is Associated with Cartilage Thickness in End-Stage Knee Osteoarthritis.

Cartilage 2021 Jul 5:19476035211011520. Epub 2021 Jul 5.

Department for Rehabilitation, Ludwig Boltzmann Institute for Arthritis and Rehabilitation, Gröbming, Austria.

Background: There is no single blood biomarker for the staging of knee osteoarthritis (KOA). The purpose of this study was to assess the relationship of obesity, serum biomarkers, the hip-knee-ankle angle (HKAA) with sonographic cartilage thickness.

Methods: We conducted a cross-sectional study of = 33 patients undergoing knee arthroplasty. Body mass index (BMI) was recorded, and patients were grouped based on BMI. Serum blood samples were collected, and the following biomarkers were measured using the ELISA technique (subgroup of = 23): oxidized low-density lipoprotein (oxLDL), soluble receptor for advanced glycation end-products (sRAGE), fatty acid-binding protein 4 (FABP4), membrane-bound phospholipase A2 (PLA2G2A). The HKAA was analyzed on full-length limb standing x-ray images. Cartilage thickness was assessed on ultrasound images. Multivariable regression analysis was performed to account for confounding.

Results: After adjusting for age, gender, and HKAA, obese patients had thicker medial femoral cartilage (β = 0.165, = 0.041). Furthermore, lateral cartilage thickness was negatively correlated with FABP4 level after adjusting for of age, gender, BMI, and HKAA (β = -0.006, = 0.001). Confirming previous studies, after adjustment, FABP4 level was associated with a higher BMI group (β = 42.99, < 0.001). None of the other markers (oxLDL, PLA2G2A, and sRAGE) was associated with BMI or cartilage thickness.

Discussion: Our results indicate that BMI has a weak, positive association with cartilage thickness in end-stage KOA patients. FABP4 levels were negatively associated with cartilage thickness. While our study is limited by a small sample size, these results further highlight the role of FABP4 as promising biomarkers of burden of disease in KOA.
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July 2021

Nuclear Magnetic Resonance Therapy Modulates the miRNA Profile in Human Primary OA Chondrocytes and Antagonizes Inflammation in Tc28/2a Cells.

Int J Mol Sci 2021 May 31;22(11). Epub 2021 May 31.

Division of Special Anaesthesia and Pain Medicine, Medical University of Vienna, 1090 Vienna, Austria.

Nuclear magnetic resonance therapy (NMRT) is discussed as a participant in repair processes regarding cartilage and as an influence in pain signaling. To substantiate the application of NMRT, the underlying mechanisms at the cellular level were studied. In this study microRNA (miR) was extracted from human primary healthy and osteoarthritis (OA) chondrocytes after NMR treatment and was sequenced by the Ion PI Hi-Q™ Sequencing 200 system. In addition, T/C-28a2 chondrocytes grown under hypoxic conditions were studied for IL-1β induced changes in expression on RNA and protein level. HDAC activity an NAD/NADH was measured by luminescence detection. In OA chondrocytes miR-106a, miR-27a, miR-34b, miR-365a and miR-424 were downregulated. This downregulation was reversed by NMRT. miR-365a-5p is known to directly target HDAC and NF-ĸB, and a decrease in HDAC activity by NMRT was detected. NAD/NADH was reduced by NMR treatment in OA chondrocytes. Under hypoxic conditions NMRT changed the expression profile of HIF1, HIF2, IGF2, MMP3, MMP13, and RUNX1. We conclude that NMRT changes the miR profile and modulates the HDAC and the NAD/NADH signaling in human chondrocytes. These findings underline once more that NMRT counteracts IL-1β induced changes by reducing catabolic effects, thereby decreasing inflammatory mechanisms under OA by changing NF-ĸB signaling.
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May 2021

General and Disease-Specific Health Indicator Changes Associated with Inpatient Rehabilitation.

J Am Med Dir Assoc 2020 12 28;21(12):2017.e10-2017.e27. Epub 2020 Jul 28.

Division of Physiology, Otto Loewi Research Center, Medical University of Graz, Graz, Austria; Human Research Institute, Weiz, Austria.

Objectives: Rehabilitation plays a vital role in the mitigation and improvement of functional limitations associated with aging and chronic conditions. Moderating factors such as sex, age, the medical diagnosis, and rehabilitation timing for admission status, as well as the expected change related to inpatient rehabilitation, are examined to provide a valid basis for the routine assessment of the quality of medical outcomes.

Design: An observational study was carried out, placing a focus on general and disease-specific health measurements, to assess representative results of multidisciplinary inpatient rehabilitation. Aspects that were possibly confounding and introduced bias were controlled based on data from a quasi-experimental (waiting) control group.

Measures: Existing data or general health indicators were extracted from medical records. The indicators included blood pressure, resting heart rate, self-assessed health, and pain, as well as more disease-specific indicators of physical function and performance (eg, activities of daily living, walking tests, blood lipids). These are used to identify moderating factors related to health outcomes.

Setting And Participants: A standardized collection of routine data from 16,966 patients [61.5 ± 12.5 years; 7871 (46%) women, 9095 (54%) men] with different medical diagnoses before and after rehabilitation were summarized using a descriptive evaluation in terms of a content and factor analysis.

Results: Without rehabilitation, general health indicators did not improve independently and remained stable at best [odds ratio (OR) = 0.74], whereas disease-specific indicators improved noticeably after surgery (OR = 3.20). Inpatient rehabilitation was shown to reduce the risk factors associated with certain lifestyles, optimize organ function, and improve well-being in most patients (>70%; cutoff: z-difference >0.20), with a standardized mean difference (SMD) seen in overall medical quality outcome of -0.48 ± 0.37 [pre- vs post-rehabilitation: η = 0.622; d = -1.22; 95% confidence interval (95% CI) -1.24 to -1.19]. The baseline medical values obtained at the beginning of rehabilitation were influenced by indication, age, and sex (all P < .001); however, these factors have less significant effects on improvements in general health indicators (η < 0.01). According to the disease-specific results, the greatest improvements were found in older patients (SMD for patients >60 vs ≤60 years: 95% CI 0.08-0.11) and during the early rehabilitation stage (η = 0.063).

Conclusions And Implications: Compared with those who received no inpatient rehabilitation, patients who received rehabilitation showed greater improvements in 2 independent areas, general and disease-specific health measures, regardless of their diagnosis, age, and sex. Due to the study design and the use of a nonrandomized waiting group, causal conclusions must be drawn with caution. However, the comparability and stability of the presented results strongly support the validity of the observed improvements associated with inpatient rehabilitation.
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December 2020

Mechanical exposure and diacerein treatment modulates integrin-FAK-MAPKs mechanotransduction in human osteoarthritis chondrocytes.

Cell Signal 2019 04 21;56:23-30. Epub 2018 Dec 21.

Ludwig Boltzmann Department for Rehabilitation, Ludwig Boltzmann Cluster for Arthritis and Rehabilitation, Saalfelden, Austria; Department of Biophysics, Medical University Graz, Graz, Austria.

Background: Progression of osteoarthritis (OA) is characterized by an excessive production of matrix degrading enzymes and insufficient matrix repair. Despite of active research in this area, it is still unclear how the combination of mechanical exposure and drug therapy works. This study was done to explore the impact of the disease modifying OA drug (DMOAD) diacerein and moderate tensile strain on the anabolic metabolism and the integrin-FAK-MAPKs signal transduction cascade of OA and non-OA chondrocytes.

Methods: Cyclic tensile strain was applied in terms of three different intensities by the Flexcell tension system. Influence on catabolic parameters such as MMPs, ADAMTS, and IL-6 were assessed by qPCR. Changes in phosphorylation of FAK, STAT3 as well as MAP kinases were verified by western blot analysis. Intracellular calcium was measured fluorimetrically using fura-2.

Results: Tensile strain at moderate intensity (SM/SA profile) proved to be most efficient in terms of reducing production of matrix degrading enzyme and IL-6 expression. Treatment with diacerein by itself and diacerein in combination with SM/SA stimulation reduced phosphorylation of FAK and STAT3, which is more pronounced in OA cells. Pretreatment with diacerein for 7 days resulted in an increase in the sensitivity to Yoda1, the agonist for the mechanically activated ion channel Piezo1. However, in OA chondrocytes a significant reduction in Piezo1 expression was observed following treatment with diacerein.

Conclusion: Our results demonstrated for the first time that diacerein intensively intervenes in the regulation of FAK and STAT3 and influences components considered relevant for the progression of OA, even in the presence of mechanical stimulation.
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April 2019

Nuclear magnetic resonance therapy (MBST) in the treatment of osteoporosis. Case report study.

Clin Cases Miner Bone Metab 2017 May-Aug;14(2):235-238. Epub 2017 Oct 25.

Ludwig Boltzmann Cluster for Arthritis and Rehabilitation, Department for Rehabilitation, Saalfelden, Austria.

Despite various pharmacological treatments, the problem of osteoporosis is not yet solved nor decreased. Drug's adverse event and fractures after long termed pharmacotherapy indicate a need for new treatment modalities. Nuclear magnetic resonance therapy could be a supplement to exercise and an alternative or supplement to pharmacotherapy. Number of clinical studies showed increase of BMD after nuclear magnetic resonance therapy and here presented case reports of eleven well-documented cases in which patients experienced severe trauma, having a huge hematoma around the hip but did not suffer any fracture, encourage this expectation. This case report study additionally presents case reports based on the follow-up of the incidence of fractures in a group of 450 patients (males n = 55, females n = 395) with a mean age of 68.4 years. All patients had been treated with MBST - therapeutic nuclear magnetic resonance, standard cycles of 10 days subsequently and followed during a five-year period. The data indicates that NMRT might reduce a risk of fractures in osteoporotic patients.
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October 2017

The therapeutic nuclear magnetic resonance changes the balance in intracellular calcium and reduces the interleukin-1β induced increase of NF-κB activity in chondrocytes.

Clin Exp Rheumatol 2018 Mar-Apr;36(2):294-301. Epub 2017 Nov 28.

Department of Special Anaesthesia and Pain Therapy, Medical University of Vienna, Austria.

Objectives: Osteoarthritis as the main chronic joint disease is characterised by the destruction of articular cartilage. Developing new, more effective and in particular non-invasive methods to achieve pain reduction of OA patients are of exceptional interest. Clinical observations demonstrated positive effects of therapeutically applied low nuclear magnetic resonance (NMRT) for the treatment of painful disorders of the musculoskeletal system. In this study the cellular mechanism of action of NMRT was examined on chondrocytes.

Methods: Cal-78 human chondrosarcoma cells were kept under inflammatory conditions by application of IL-1β. NMRT treated cells were tested for changes in histamine induced Ca2+ release by fura-2 calcium imaging. The effects of IL-1β and of NMRT treatment were further tested by determining intracellular ATP concentrations and the activity of MAP-kinases and NF-κB.

Results: NMRT influenced the intracellular calcium signalling by elevating the basal [Ca2+]i. The peak calcium concentration evoked by 10 μM histamine was increased by IL-1β and this increase was reversed under NMRT treatment. Screening of different kinase-activities revealed an apparent increase in activity of MAPK/ERK and MAPK/JNK in NMRT stimulated cells, p38 was downregulated. The IL-1β-induced decline in intracellular ATP and the elevated NF-κB activity was reversed under NMRT stimulation.

Conclusions: Under inflammatory conditions, NMRT influenced cellular functions by modulating cellular calcium influx and/or calcium release. Further, NMRT induced changes in MAPK activities such as down-regulation of NF-κB and increasing intracellular ATP might help to stabilise chondrocytes and delay cartilage damage due to OA.
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June 2018

Pharmacological treatment with diacerein combined with mechanical stimulation affects the expression of growth factors in human chondrocytes.

Biochem Biophys Rep 2017 Sep 1;11:154-160. Epub 2017 Jul 1.

Department of Orthopaedic Surgery, Medical University of Graz, Graz, Austria.

Background: Osteoarthritis (OA) as the main chronic joint disease arises from a disturbed balance between anabolic and catabolic processes leading to destructions of articular cartilage of the joints. While mechanical stress can be disastrous for the metabolism of chondrocytes, mechanical stimulation at the physiological level is known to improve cell function. The disease modifying OA drug (DMOAD) diacerein functions as a slowly-acting drug in OA by exhibiting anti-inflammatory, anti-catabolic, and pro-anabolic properties on cartilage. Combining these two treatment options revealed positive effects on OA-chondrocytes.

Methods: Cells were grown on flexible silicone membranes and mechanically stimulated by cyclic tensile loading. After seven days in the presence or absence of diacerein, inflammation markers and growth factors were analyzed using quantitative real-time PCR and enzyme linked immune assays. The influence of conditioned medium was tested on cell proliferation and cell migration.

Results: Tensile strain and diacerein treatment reduced interleukin-6 (IL-6) expression, whereas cyclooxygenase-2 (COX2) expression was increased only by mechanical stimulation. The basic fibroblast growth factor (bFGF) was down regulated by the combined treatment modalities, whereas prostaglandin E2 (PGE2) synthesis was reduced only under OA conditions. The expression of platelet-derived growth factor (PDGF) and vascular endothelial growth factor A (VEGF-A) was down-regulated by both.

Conclusions: From our study we conclude that moderate mechanical stimulation appears beneficial for the fate of the cell and improves the pharmacological effect of diacerein based on cross-talks between different initiated pathways.

General Significance: Combining two different treatment options broadens the perspective to treat OA and improves chondrocytes metabolism.
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September 2017

Diacerein retards cell growth of chondrosarcoma cells at the G2/M cell cycle checkpoint via cyclin B1/CDK1 and CDK2 downregulation.

BMC Cancer 2015 Nov 10;15:891. Epub 2015 Nov 10.

Ludwig Boltzmann Institute for Rehabilitation of Internal Diseases, Ludwig Boltzmann Cluster for Rheumatology, Balneology and Rehabilitation, Saalfelden, Austria.

Background: Chondrosarcoma is characterized for its lack of response to conventional cytotoxic chemotherapy, propensity for developing lung metastases, and low rates of survival. Research within the field of development and expansion of new treatment options for unresectable or metastatic diseases is of particular priority. Diacerein, a symptomatic slow acting drug in osteoarthritis (SYSADOA), implicates a therapeutic benefit for the treatment of chondrosarcoma by an antitumor activity.

Methods: After treatment with diacerein the growth behaviour of the cells was analyzed with the xCELLigence system and MTS assay. Cell cycle was examined using flow cytometric analysis, RT-PCR, and western blot analysis of specific checkpoint regulators. The status for phosophorylation of mitogen-activated protein kinases (MAPKs) was analyzed with a proteome profiler assay. In addition, the possible impact of diacerein on apoptosis was investigated using cleaved caspase 3 and Annexin V/PI flow cytometric analysis.

Results: Diacerein decreased the cell viability and the cell proliferation in two different chondrosarcoma cell lines in a dose dependent manner. Flow cytometric analysis showed a classical G2/M arrest. mRNA and protein analysis revealed that diacerein induced a down-regulation of the cyclin B1-CDK1 complex and a reduction in CDK2 expression. Furthermore, diacerein treatment increased the phosphorylation of p38α and p38β MAPKs, and Akt1, Akt2, and Akt 3 in SW-1353, whereas in Cal-78 the opposite effect has been demonstrated. These observations accordingly to our cell cycle flow cytometric analysis and protein expression data may explain the G2/M phase arrest. In addition, no apoptotic induction after diacerein treatment, neither in the Cal-78 nor in the SW-1353 cell line was observed.

Conclusions: Our results demonstrate for the first time that the SYSADOA diacerein decreased the viability of human chondrosarcoma cells and induces G2/M cell cycle arrest by CDK1/cyclin B1 down-regulation.
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November 2015

Reduction of coronary risk factors immediately and 1 year after inpatient rehabilitation in a highly motivated patient cohort.

Wien Med Wochenschr 2015 Feb 9;165(3-4):71-8. Epub 2015 Jan 9.

Ludwig-Boltzmann-Institut für Rehabilitation Interner Erkrankungen, Thorerstrasse 26, 5760, Saalfelden, Austria,

Adherence to medical advice, driven by high patient motivation, could lead to a significant reduction in risk factors during cardiac rehabilitation.During a 1-year period, 9082 patients were admitted to six cardiac rehabilitation centres. A total of 1195 highly motivated subjects were selected based on their reliable completion of a survey regarding cardiac risk factors.Study subjects had lower risk factors at baseline compared with a contemporary Austrian database. At discharge from the rehabilitation programme subjects showed further reductions in median weight, low-density lipoprotein cholesterol, blood pressure and resting pulse rate (due to increased levels of daily exercise). Smoking also decreased. Most of these changes were still significant after 1 year.The risk factors in these highly motivated patients were low to begin with and were further reduced by an inpatient rehabilitation programme. The content and method of delivery of this programme seem to be effective. Efforts should focus on increasing motivation.
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February 2015

[Adipocytokines in rheumatoid arthritis and obesity].

Wien Med Wochenschr 2010 Aug;160(15-16):391-8

Ludwig Boltzmann Cluster für Rheumatologie, Balneologie und Rehabilitation, Ludwig Boltzmann Institut für Rehabilitation interner Erkrankungen, Saalfelden, Austria.

In obese rheumatoid arthritis (RA) patients inflammatory mechanisms and cardiovascular secondary disorders are possibly related to changed expression of adipocytokines. Various adipocytokines and inflammatory parameters were examined in 112 patients (23.2% men; 76.8% women) suffering from RA: leptin, adiponectin, visfatin, sCD40 L, CRP, and ESR. Average BMI was 27.6 (+/-5.6). Leptin and BMI as well as visfatin and BMI correlated positively, BMI and adiponectin, however, showed a negative correlation. Significant differences between normal-weight and obese RA patients were found in both leptin and adiponectin measurements. Visfatin showed a positive correlation with CRP; sCD40 ligand which is a marker for increased T-cell activity correlated with CRP and ESR. Patients with low adiponectin levels (<10 microg/ml) more often suffered from cardiovascular diseases (28.6%) than those with enhanced adiponectin (14.3%). Increased pro-inflammatory leptin and decreased anti-inflammatory adiponectin in obese RA patients can be associated with RA activity and enhanced cardiovascular risk.
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August 2010

Cardiac rehabilitation in Austria: long term health-related quality of life outcomes.

Health Qual Life Outcomes 2009 Dec 8;7:99. Epub 2009 Dec 8.

Medical University Innsbruck, Department of Medical Psychology, Innsbruck, Austria.

Background: The goal of cardiac rehabilitation programs is not only to prolong life but also to improve physical functioning, symptoms, well-being, and health-related quality of life (HRQL). The aim of this study was to document the long-term effect of a 1-month inpatient cardiac rehabilitation intervention on HRQL in Austria.

Methods: Patients (N = 487, 64.7% male, age 60.9 +/- 12.5 SD years) after myocardial infarction, with or without percutaneous interventions, coronary artery bypass grafting or valve surgery underwent inpatient cardiac rehabilitation and were included in this long-term observational study (two years follow-up). HRQL was measured with both the MacNew Heart Disease Quality of Life Instrument [MacNew] and EuroQoL-5D [EQ-5D].

Results: All MacNew scale scores improved significantly (p < 0.001) and exceeded the minimal important difference (0.5 MacNew points) by the end of rehabilitation. Although all MacNew scale scores deteriorated significantly over the two year follow-up period (p < .001), all MacNew scale scores still remained significantly higher than the pre-rehabilitation values. The mean improvement after two years in the MacNew social scale exceeded the minimal important difference while MacNew scale scores greater than the minimal important difference were reported by 40-49% of the patients.Two years after rehabilitation the mean improvement in the EQ-5D Visual Analogue Scale score was not significant with no significant change in the proportion of patients reporting problems at this time.

Conclusion: These findings provide a first indication that two years following inpatient cardiac rehabilitation in Austria, the long-term improvements in HRQL are statistically significant and clinically relevant for almost 50% of the patients. Future controlled randomized trials comparing different cardiac rehabilitation programs are needed.
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December 2009

Short-term patient-reported outcomes after different exercise-based cardiac rehabilitation programmes.

Eur J Cardiovasc Prev Rehabil 2007 Jun;14(3):441-7

Department of Interventional Cardiology, Academic Hospital, Austria.

Background: An objective of exercise-based cardiac rehabilitation is improvement in patient-reported outcomes such as health-related quality of life as well as anxiety and depressive symptoms. There are no direct comparisons of the effectiveness of inpatient and outpatient exercise-based cardiac rehabilitation programmes on patient-reported outcomes.

Methods: In this non-randomized study we collected patient-reported outcomes data with the MacNew Heart Disease health-related quality of life questionnaire and the Hospital Anxiety and Depression Scale at baseline, 1 month and again 3 months after admission to exercise-based cardiac rehabilitation in a cohort of 216 consecutive patients enrolled either in a 4-week inpatient exercise-based cardiac rehabilitation (n=62) or a 3-month outpatient exercise-based cardiac rehabilitation (n=87) and in a usual care group (n=67) to document the natural course in patient-reported outcome variables without exercise-based cardiac rehabilitation.

Results: Although MacNew health-related quality of life scores improved more with inpatient than outpatient exercise-based cardiac rehabilitation by month 1, the improvement was still significant in both groups at month 3 and also in the usual care group when compared to baseline. The health-related quality of life scores in the inpatient group, however, decreased between month 1 and 3 whereas they continued to improve in the outpatient group. The significant reduction in both anxiety and depressive symptoms in both exercise-based cardiac rehabilitation groups by month 1 was maintained at month 3 only with outpatient exercise-based cardiac rehabilitation. No significant changes over the 3 months were observed in the usual care group.

Conclusion: Significant improvements of 1-month patient-reported outcomes are achieved in patients attending inpatient as well as outpatient exercise-based cardiac rehabilitation when compared with no exercise-based cardiac rehabilitation. In contrast to inpatient exercise-based cardiac rehabilitation, however, outpatient exercise-based cardiac rehabilitation leads to a further improvement of patient-reported outcomes. These results suggest that, if patients have to be admitted for inpatient exercise-based cardiac rehabilitation, this programme should be followed by an outpatient exercise-based cardiac rehabilitation to further improve and stabilize these patient-reported outcome variables.
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June 2007

Cardiac rehabilitation in Austria: short term quality of life improvements in patients with heart disease.

Wien Klin Wochenschr 2006 Dec;118(23-24):744-53

Medizin Universität Innsbruck, Univ.-Klinik für Medizinische Psychologie und Psychotherapie, Innsbruck, Osterreich.

Background: The goal of cardiac rehabilitation programs is not only to prolong life, but also to improve physical functioning, symptoms, wellbeing and health-related quality of life (HRQL). The aim of the study was to document short-term outcomes of cardiac rehabilitation programs in Austria.

Methods: Consecutive patients (N = 487, 64.7% male, age 60.9 +/- 12.5 SD years) after myocardial infarction (MI), with or without percutaneous interventions (PCI), coronary artery bypass grafting (CABG) or heart valve surgery (HVS), referred to the six inpatient rehabilitation centers of the Austrian PVA insurance company, were included in the study. Exercise capacity, risk factors and HRQL (MacNew Heart Disease Quality of Life Instrument [MacNew] and EuroQoL-5D [EQ-5D]) were measured at the beginning and end of the 4-week inpatient cardiac rehabilitation program.

Results: Global HRQL (MacNew) improved significantly over time in all patients combined (+0.75 +/- 0.88 SD, T = -16.99, df = 394, p < .001) and exceeded the minimal important difference. Patients with CABG, HVS or MI without PCI showed the greatest improvements in global HRQL after cardiac rehabilitation (p < .02). Blood pressure, cholesterol, triglyceride, body mass index, waist circumference improved significantly (all p < .001).

Conclusion: These findings provide evidence that the improvements in HRQL and risk factors following cardiac rehabilitation in Austria are clinically important. HRQL should become a standard outcome parameter in cardiac rehabilitation.
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December 2006

Between adaptive and innate immunity: TLR4-mediated perforin production by CD28null T-helper cells in ankylosing spondylitis.

Arthritis Res Ther 2005 18;7(6):R1412-20. Epub 2005 Oct 18.

Department of Internal Medicine, Innsbruck Medical University, Austria.

CD3+CD4+CD28null and CD3+CD8+CD28null T cells are enriched in patients with immune-mediated diseases compared with healthy controls. This study shows that CD4+CD28null T cells express Toll-like receptors recognizing bacterial lipopolysaccharides in ankylosing spondylitis, psoriatic arthritis and rheumatoid arthritis. In ankylosing spondylitis, TLR4 (23.1 +/- 21.9%) and, to a smaller extent, TLR2 (4.1 +/- 5.8%) were expressed on CD4+CD28null T cells, whereas expression was negligible on CD4+CD28+ and CD8+ T cells. CD4+CD28null T cells produced perforin upon stimulation with lipopolysaccharide, and this effect was enhanced by autologous serum or recombinant soluble CD14. Perforin production could be prevented with blocking antibodies directed against CD14 or TLR4. Incubation of peripheral blood mononuclear cells with tumour necrosis factor alpha led to an upregulation of TLR4 and TLR2 on CD4+CD28null T cells in vitro, and treatment of patients with antibodies specifically directed against tumour necrosis factor alpha resulted in decreased expression of TLR4 and TLR2 on CD4+CD28null T cells in vivo. We describe here a new pathway for direct activation of cytotoxic CD4+ T cells by components of infectious pathogens. This finding supports the hypothesis that CD4+CD28null T cells represent an immunological link between the innate immune system and the adaptive immune system.
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January 2006

Stabilized autologous fibrin-chondrocyte constructs for cartilage repair in vivo.

Ann Plast Surg 2003 Nov;51(5):493-8

Department of ENT, Head and Neck Surgery, General Hospital, Wels, Austria.

Stabilization of fibrin-chondrocyte constructs with fibrinolytical inhibitors has been shown to be a feasible method for the reconstruction of cartilage in vitro. In this study, the method was tested in vivo. Autologous cultures were used to form stabilized fibrin-chondrocyte constructs that were injected into auricular cartilage defects of rabbits. Stabilization was achieved by high doses of fibrinolytic inhibitors. Samples were prepared for magnetic resonance imaging, histology, and immunohistochemistry after 1, 2, 4, and 6 months. Defects of the contralateral ear, which were treated with stabilized fibrin without cells, were used for controlled comparisons. In all cell-fibrin samples, cartilage-like tissue was present. Immunohistochemistry revealed the presence of collagen II. This finding was similar for all observations. In the control samples, only minor new cartilage could be detected at the cut edges. The reconstruction of cartilage in vivo by injecting fibrin-chondrocyte constructs, stabilized with inhibitors of fibrinolysis, is thus possible.
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November 2003

[Calcification marker matrix G1a protein in patients with hyperlipidemia].

Wien Med Wochenschr 2003 ;153(15-16):360-4

Ludwig Boltzmann Institut für Rehabilitation interner Erkrankungen, Thorerstrasse 26, 5760 Saalfelden.

At the site of atherosclerotic plaque formation, proliferating vascular muscle cells express Matrix-Gla-protein (MGP) which depends on vitamin K and plays a regulatory role in tissue calcification. Measurements of MGP in serum showed significantly higher values in 66 patients with hyperlipidemia compared to healthy controls. MGP correlated with cholesterol, triglyceride, and low-density lipoprotein, but not with the adhesion molecule GMP-140. The evaluation of the patients' life and nutritional habits showed that nearly exclusively the patients who regularly consume fruit had low MGP values. Smokers had high MGP levels, three times higher than non-smokers. A decrease in MGP levels could be shown already three weeks after inpatient rehabilitation comprising therapeutic exercise and change in nutrition.
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January 2004

[Effects of the chemokine MIP-1alpha on anemia and inflammation in rheumatoid arthritis].

Z Rheumatol 2002 Oct;61(5):568-76

Ludwig Boltzmann Institut für Rehabilitation interner Erkrankungen Thorerstrasse 26 5760 Saalfelden, Austria.

Macrophage inflammatory protein-1alpha (MIP-1alpha) is an interesting chemokine because in addition to its variety proinflammatory activities including chemotaxis and immunomodulation, it is a potent inhibitor of hematopoetic stem cell proliferation. Inhibition of erythroid progenitor cells due to MIP-1alpha or other cytokines can play a role in the pathogenesis of anemia which is one of the most common extra-articular features of active rheumatoid arthritis (RA). In 84 patients with RA, serological and immunological parameters were assessed to detect inflammatory mechanisms and anemia in relation to the serum concentrations of MIP-1alpha. All patients fulfilled the ACR criteria for the diagnosis of a definite or classic RA. We used a quantitative enzyme immuno assay for the detection of MIP-1alpha as well as for the measurement of the acute phase protein serum amyloid A (SAA), the erythropoiesis inducer erythropoietin (EPO) and the transferrin receptor (TfR). The immune activation marker neopterin was measured radioimmunologically. Half of the patients with RA were anemic with hemoglobin values below 12 g/dl. MIP-1alpha was found to be elevated significantly in serum of patients with active rheumatoid arthritis and in patients with anemia. Most of the anemic patients with markedly elevated acute phase reactions had an anemia with chronic diseases and not a functional iron deficiency alone. TfR correlated with EPO. The results show that enhanced expression of MIP-1alpha is indicative of systemic inflammation in RA. Moreover, besides the regulation of inflammatory processes, this chemokine may influence the pathogenesis of anemia in RA patients.
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October 2002