The concentrations of markers of bone turnover in normal pregnancy and preeclampsia.

BACKGROUND: The purpose of our study was to investigate the concentrations of markers of bone turnover in normal pregnancy and preeclampsia. MATERIAL AND METHODS: Forty-five pregnant patients with preeclampsia, 78 healthy pregnant women (26 in first, 26 in the second, and 26 in third trimester of pregnancy), and 20 nonpregnant women were included in the study. Serum concentrations of osteoprotegrin (OPG), receptor activator of nuclear factor kappa B ligand (sRANKL), and the markers of bone turnover, osteocalcin and CrossLaps-degradation products of type I collagen, were determined using the ELISA method. Statistical analysis was performed using Mann-Whitney U-test. RESULTS: The concentrations of sRANKL and OPG were significantly higher in the second trimester of normal pregnancy when compared to the first and the third trimesters and to nonpregnant controls. The concentrations of osteocalcin were significantly higher in the first trimester of physiological pregnancy in comparison with nonpregnant women and with second and third trimesters of pregnancy. The concentrations of CrossLaps were significantly higher in the second trimester of normal pregnancy when compared to the first and third trimester. In preeclampsia, the sera concentrations of osteocalcin and CrossLaps were significantly higher when compared to the third trimester of normal pregnancy. CONCLUSION: The results suggest that the bone formation is increased in the first trimester, whereas the bone resorption is increased in the second trimester of normal pregnancy. Furthermore, the results suggest that the bone turnover is increased in patients with preeclampsia when compared to healthy normotensive pregnant women.

Predicting factors for severity of rheumatoid arthritis: a prospective multicenter cohort study of 172 patients over 3 years.

Rheumatoid arthritis may take an unfavourable course leading to rapid functional decline in a certain percentage of patients. Early identification of these patients is desirable. The aim of this study was to evaluate clinical and laboratory parameters for their value in the prediction of bad outcome. A total of 172 patients with early arthritis were followed for 3 years. Higher initial values for erythrocyte sedimentation rate, IgG and IgM rheumatoid factor, serum concentration of cartilage oligomeric matrix protein, Health Assessment Questionnaire score, Larsen score of feet, disease activity score, and swollen and tender joint count predicted worse outcome. An association with the presence of IgA rheumatoid factor or anti-cyclic-citrullinated peptide could not be established. We conclude that prognosis in an individual with rheumatoid arthritis depends on many factors. The determination of independent prognostic factors for progression of rheumatoid arthritis is a valuable tool in early arthritis to select patients for more aggressive therapy.

A short Larsen score is effective when evaluating radiographs in early rheumatoid arthritis.

PURPOSE: To compare the efficacy of the short Larsen score (LS 12) based on analysis of 12 areas with the original Larsen score (LS 40), which includes 40 areas for assessing radiographic changes in rheumatoid arthritis. MATERIAL AND METHODS: The radiographs of the hands, wrists, and feet of 122 patients with early rheumatoid arthritis were evaluated by two radiologists using both the LS 40 and LS 12 methods. Cross-sectional analysis of radiographs of 122 patients and longitudinal analysis in 68 patients were performed. RESULTS: There was no significant difference between the mean LS 40 and mean LS 12 in the cross-sectional study. LS 12 correlated strongly (r=0.93, P<0.01) with LS 40 at the baseline, and the rate of progression was similar in both methods (r=0.89, P<0.01) in the longitudinal study. CONCLUSION: The short Larsen score was as efficient as the original method.

Osteoprotegerin and the receptor activator of NF-kappa B ligand in the serum and synovial fluid. A comparison of patients with longstanding rheumatoid arthritis and osteoarthritis.

We examined OPG and soluble RANKL in the serum (sOPG, sRANKL) and synovial fluid (synOPG, synRANKL) in patients with rheumatoid arthritis (RA) and osteoarthritis (OA). OPG and RANKL were measured in 85 patients (44 with RA, 41 patients with OA) in serum and synovial fluid as well. For measuring of OPG and RANKL ELISA tests were used. The results of OPG and RANKL were compared with clinical and radiological scores. We found a negative correlation for OPG and RANKL in synovial fluids: not only for the whole group of patients (P < 0.003, r = -0.32), but also for the subgroups (RA: P < 0.04, r = -0.28, OA: P < 0.002, r = -0.54). SRANKL and synRANKL were positively correlated in the whole group (P < 0.01, r = 0.25) and in the OA group (P < 0.02, r = 0.35); the RA group was showing a trend (P < 0.063, r = 0.24), however. Serum OPG was lower in RA, synOPG higher in OA. The difference between the two patient groups was only significant for synOPG (P < 0.03, r = 0.056), but not for sOPG (P < 0.09, r = 0.19), sRANKL (P < 0.43, r = 0.85) or synRANKL (P < 0.11, r = 0.22). The synOPG:synRANKL ratio was significantly correlated with the Larsen score (P < 0.004, r = 0.38). Synovial OPG is significantly decreased in rheumatoid joints, whereby synovial RANKL is increased. Lower synOPG could reflect a lower protective effect on bone, thus leading to an earlier and more pronounced bone destruction in RA. However, the effect of different mediators for joint destruction in RA and OA seems not to be important to the pathophysiological changes in the joints. The upregulation of serum OPG might be the result of the inflammation; in contrast, an upregulation of RANKL could not be found in the serum of patients with RA and OA.

Serum levels of cartilage oligomeric matrix protein. A predicting factor and a valuable parameter for disease management in rheumatoid arthritis.

OBJECTIVE: To examine whether cartilage oligomeric matrix protein (COMP) correlates with inflammation and/or joint destruction of patients with rheumatoid arthritis (RA) and to test COMP as predicting factor for the outcome of patients with established RA. METHODS: Serum levels of COMP were measured in sera of 62 patients, suffering from RA according to the ACR criteria and treated in intervals in our department, over a period of 5 years. A commercially available sandwich--type ELISA-kit developed by AnaMar Medical AB, Sweden, was used. The results of serum COMP were compared with the Disease Activity Score (DAS), the Larsen Score, and clinical and laboratory parameters. RESULTS: We found a positive correlation between serum levels of COMP at baseline and deterioration of Larsen score even after 5 years (p < 0.007; r = 0.34). To confirm serum COMP as an independent predicting factor for patients with RA we looked at a subgroup of patients (n = 17) with elevated serum levels of COMP (mean 11,7 U/l) and low clinical prognostic factors. In this subgroup we also found a significant correlation with delta Larsen score (p < 0.01; r = 0.59) after 5 years. CONCLUSION: Serum levels of COMP is known to reflect increased cartilage turnover. The results indicate that serum COMP may be used as a prognostic marker of cartilage degradation in a patient group with established RA.

[Functional capacity and cartilage oligomeric protein (COMP) in serum of patients with maturity-onset polyarthritis]. / Funktionelle Kapazität und Cartilage Oligomeric Matrix Protein (COMP) im Serum bei Patienten mit Alterspolyarthritis.

OBJECTIVE: To compare late onset with adult onset rheumatoid arthritis. METHODS: Fifty-eight patients with late onset rheumatoid arthritis (LORA) were compared to 117 patients with adult onset rheumatoid arthritis (AORA) with respect to clinical and functional parameters. Furthermore, in 104 patients serum cartilage oligomeric matrix protein (COMP) was measured. Results were compared by means of ANOVA and possible influences of age, gender and clinical parameters were evaluated by Spearman rank correlation. RESULTS: Except a different distribution in gender (40% males in the LORA group) and a higher ESR, no differences could be found with respect to clinical parameters. However, a significantly higher HAQ score and significantly higher serum-COMP levels could be shown in the LORA group. HAQ scores correlated not only with disease activity parameters (C-reactive protein, disease activity score) but also with the age. Serum-COMP levels did show a correlation with the age as well, but not with disease activity. CONCLUSION: It is concluded that the higher serum-COMP levels in late onset rheumatoid arthritis could be due to concomitant osteoarthritic processes in larger joints, which are not symptomatic. The age dependence of the HAQ score is only weak, but may be the reason why patients with LORA show a worse functional capacity compared to patients with adult onset rheumatoid arthritis.

A prospective evaluation of the medical consultation system CADIAG-II/RHEUMA in a rheumatological outpatient clinic.

To evaluate the performance of CADIAG-II/RHEUMA as consultant in the primary evaluation of patients visiting a rheumatological outpatient clinic, a CADIAG-II/RHEUMA consultation was done for 54 patients and the list of generated diagnostic hypotheses was compared to each clinical discharge diagnosis. For 26 of a total of 126 rheumatological discharge diagnoses, no matching CADIAG-II/RHEUMA diagnosis was available. 94% of all other discharge diagnoses were found in the list of CADIAG-II/RHEUMA hypotheses, 82% among the first third of the list of hypotheses and 48% among the first five hypotheses. We identified the following factors limiting the ability of CADIAG-II/RHEUMA to generate a comprehensive and correctly ranked list of diagnostic hypotheses: (1) a large percentage of patients with early stages of not clearly identified rheumatological conditions; (2) the limited number of CADIAG-II/RHEUMA diagnoses compared to the large number of known rheumatological conditions; (3) the fact that rheumatological diseases are rarely characterized by a single pathognomonic feature but are usually diagnosed by combinations of rather unspecific findings.

Intra-articular hyaluronic acid: duration of effect and results of repeated treatment cycles.

An open-label, multicenter study was designed to evaluate the effects of intra-articular (IA) hyaluronic acid in patients given a diagnosis of osteoarthritis of the knee. Patients (n = 108) received five weekly IA injections of hyaluronic acid 20 mg (Hyalgan) under sterile conditions, and were observed for up to 12 months after the last injection. Some patients received a second series of injections after 4 to 8 months. For the 59 patients who were observed for 12 months after the first treatment cycle, evaluation of pain according to a visual analog scale showed significant improvements lasting 12 months, with pain during load, pain at rest, and duration of walking ability compared with a baseline evaluation. Patients who required a second treatment cycle showed a further amelioration. Significant improvements were also seen in knee function and in global evaluations by both patient and investigators. Relief of symptoms of osteoarthritis of the knee was seen as early as 4 weeks after treatment in 68% of patients receiving IA hyaluronic acid. In 55% of these patients, relief was maintained until the end of the 12-month follow-up.

Inhibition of cytokine production and adhesion molecule expression by ibuprofen is without effect on transendothelial migration of monocytes.

The present study focusses on the effects of ibuprofen and its enantiomers on cytokine production by peripheral blood monocytes and endothelial cells as well as on the potential modulation of ADM-expression by human umbilical vein endothelial cells and the concomitant effects on monocyte transendothelial migration as measured by a cell migration assay system. This consists of an endothelial cell monolayer on a solid collagen substrate, i.e. an artificial vessel wall construct. We observed a significant inhibition by 100 microg/ml ibuprofen of VCAM-1 expression by endothelial cells while ELAM-1 and ICAM-1 expression was not influenced. However, we could not see any concomitant inhibitory effects on the spontaneous migration of monocytes after preincubating the endothelial cell monolayer with ibuprofen up to concentrations of 100 microg/ml and activating with suboptimal and optimal concentrations of TNF-alpha. Our monocyte transendothelial migration system reflects very sensitively endothelial cell-activation even by very low TNF-alpha concentrations. (S)- and (R)-ibuprofen were equal in their inhibitory/activating effects on cytokine production, with the exception of stronger IL-8 induction in endothelial cells by (R)-ibuprofen as compared to its chiral analogue.

[RHEUMexpert: a documentation and expert system for rheumatic diseases]. / RHEUMexpert: Ein Dokumentations- und Expertensystem für rheumatische Erkrankungen.

A computer assisted documentation of signs and findings in rheumatic diseases is described. This documentation was developed by the Austrian Society for Rheumatology and thought to be a minimal standard for the use by general practitioners. In addition, a knowledge-based basic differential diagnosis support was developed, which differentiates between major groups of rheumatic diseases as inflammatory spine diseases, mechanical or metabolic reasons for spine disorders, inflammatory joint diseases, degenerative or metabolic joint diseases, soft tissue diseases. This presentation describes the results of an evaluation of 75 typical case histories and a second study where 252 case histories were documented retrospectively in this new system. The results of the first showed a pretty good discrimination between the described groups of different diagnoses (sensitivity between 71 and 100 percent for all groups with the exception of metabolic joint diseases, specificity between 75 and 94 percent). The second--retrospective--documentation and diagnostic support showed much weaker results (sensitivity for major groups 74-76 percent). The reasons for the different outcomes are discussed: On the one hand, signs and symptoms from case reports could not be transferred completely in the new documentation, as some findings retrospectively could not be defined sharp enough. On the other hand the study showed, that the sensitivity of well defined disorders as inflammatory joint diseases (exp. rheumatoid arthritis) reaches almost 100 percent, whereas it is as low as 50 percent in some other diseases (e.g. gout) whose characteristic findings and symptoms are suppressed by treatment (drug medication) in many cases. The results show that computer based documentation of rheumatic diseases facilitates the systematized and standardised documentation of patient data. However, a few modifications of the knowledge base as well as the knowledge representation formalisms are necessary to achieve a better performance in differential diagnostic support.

[Comparison between early and late inpatient rehabilitation measures after implantation of total hip endoprostheses]. / Vergleich zwischen frühen und späten stationären Rehabilitationsmassnahmen nach Implantation von Hüfttotalendoprothesen.

This study was aimed at answering the question of whether a four-week inpatient early rehabilitation programme, i.e. within the first two months following total hip replacement surgery, will have a favourable impact as compared to later-onset inpatient rehabilitation measures; a total of 219 patients was studied: 137 were admitted during the first two months post-op (group A), 45 within three to four months post op (group B), and 37 patients were admitted at a later date (group C). Assessments were carried out for pain, walking performance and self-help status (scores) as well as for mobility, gait patterns, walking aids, walking speed, and disablement. In group A patients, significant improvement was achieved for all of these parameters: at the end of the rehabilitation programme (2.4 months post-op) these patients already were more mobile than group B patients at the time of admission (3.3 months post-op). In group B, improvements were found for several parameters. At a later time, the natural healing process had brought about so good a baseline situation in the group C patients that no further improvement was possible. The 162 patients treated successfully, i.e. where score reductions occurred, had been admitted significantly (p = 0.0001) earlier (2.9 months post-op) than the remaining 57 patients (5.7 months post-op). Some 14 months after programme participation, follow-up examinations were possible for 90 patients of group A, and for 27 patients from groups B and C. Further significant improvements had occurred in group A patients only, notably relative to muscle strength and reduction of walking aids. It is concluded from our data that inpatient early rehabilitation will achieve the greatest effect and will substantially reduce the recovery phase with its mobility limitations and daily living handicaps.

Modulation of nitric oxide synthase activity by ibuprofen.

Inhibition of NO synthesis represents a new therapeutical approach in the treatment of inflammation. Clinical use of NOS inhibitors will necessitate the design of drugs selective for iNOS, because inhibition of constitutive endothelial NOS may cause adverse cardiovascular side effects. This study examines the effect of ibuprofen and its stereoeisomeric components on the activation of iNOS and cNOS as well as on the NO production by human umbilical vein endothelial cells. At therapeutic concentrations Ibuprofen activated iNOS and inhibited NOS. In endothelial cell culture experiments activation of NO production was seen especially at supratherapeutic ibuprofen concentrations. Both stereoisomeric components of ibuprofen showed comparable effects. This drug can therefore not be used for the selective inhibition of iNOS.

Development and evaluation of fuzzy criteria for the diagnosis of rheumatoid arthritis.

In 1987, the American Rheumatism Association issued a set of criteria for the classification of rheumatoid arthritis (RA) to provide a uniform definition of RA patients. Fuzzy set theory and fuzzy logic were used to transform this set of criteria into a diagnostic tool that offers diagnoses at different levels of confidence: a definite level, which was consistent with the original criteria definition, as well as several possible and superdefinite levels. Two fuzzy models and a reference model which provided results at a definite level only were applied to 292 clinical cases from a hospital for rheumatic diseases. At the definite level, all models yielded a sensitivity rate of 72.6% and a specificity rate of 87.0%. Sensitivity and specificity rates at the possible levels ranged from 73.3% to 85.6% and from 83.6% to 87.0%. At the superdefinite levels, sensitivity rates ranged from 39.0% to 63.7% and specificity rates from 90.4% to 95.2%. Fuzzy techniques were helpful to add flexibility to preexisting diagnostic criteria in order to obtain diagnoses at the desired level of confidence.

Intracellular distribution of ibuprofen within monocytes.

The interaction of ibuprofen (CAS 15687-27-1) with muscle proteins was investigated in vitro and binding to actin was found to be more marked than to other muscle proteins. Actin polymerization, however, was not influenced by this interaction. The kinetics of ibuprofen internalization by human monocytes/macrophages from peripheral blood at 37 degrees C and its partitioning to different cellular compartments was studied and compared to the actin content of these subcellular fractions. The bulk of cell-bound ibuprofen (89.7%) was found in the cell debris fraction (1,000 g sediment), 7.3% were recovered in the 10,000 g sediment, only 0.5% in the 100,000 g sediment and 2.5% in the cytosolic fraction. The distribution of F-actin to the different subcellular fractions was verified by fluorescence analysis using NBD-phallacidin. Four times more F-actin was found in the 1,000 g sediment than in the 10,000 g fraction, while the microsomal fraction contained only 8% of total F-actin. In the cytosol, significant amounts of soluble actin were detected. These data indicate that ibuprofen could theoretically interact with actin in all the cellular subfractions to which it is distributed after internalization.

[Effect of inpatient rehabilitation measures on patients with total hip endoprostheses--evaluation 15 months after operation]. / Effekt von stationären Rehabilitationsmassnahmen bei Patienten mit Hüfttotalendoprothesen--Beurteilung 15 Monate nach der Operation.

159 patients were examined approximately 15 months after hip arthroplasty. 116 of these patients have had at that time point a postoperative 4 week hospital stay for rehabilitation. A score that considered pain at motion and at rest, maximal walking capacity and activity of daily living was used for evaluation. The preoperative conditions did not differ between patients that had their postoperative hospital stay for rehabilitation (n = 116) and those that did not (n = 43). The results at the time of examination were regarded as excellent (group 1; score 3) in 64 (40.3%) patients, as good (group 2; score 4) in 56 (35.2%) patients and as poor (group 3; score > or = 5) in 39 (24.5%) patients. The amount of patients with a hospital stay for rehabilitation was significantly (p = 0.025) higher in the patient groups with excellent or good results in comparison with the patients with poor postoperative outcome. The most excellent results were obtained in patients who had their rehabilitation within the first two months after surgery (p = 0.008). Apart from the above mentioned score the following-additionally assessed-parameters differed significantly between the 3 groups: hip mobility; pain elicited by pressure on the operated joint; pain in the contralateral hip or knee joints; consumption of analgetics; walking time for 15 meters; degree of handicap as assessed by the patient or the occupational therapist or the physician; coping with household activities (for females only). We conclude that a poor result of hip arthroplasty may be due not only to degenerative joint disease of the lower limbs but also (or in combination) to the lack of a postoperative hospital stay for rehabilitation.

[New approaches to computer-assisted diagnosis of rheumatologic diseases]. / Neue Ansätze zur computerassistierten Diagnose rheumatologischer Erkrankungen.

UNLABELLED: Since the 1960s, several knowledge-based systems for computer-assisted diagnosis in radiology have been developed. The great majority of these tools has been implemented as off-line systems. This requires interaction with the system solely for the purpose of consultation and therefore interrupts the radiologist's work flow. This and inadequate man-machine interfaces may have inhibited the routine clinical use of such systems. The goal of this paper is to describe the current research toward the development of the on-line expert system Cadiag-4/Rheuma-Radio. The underlying fundamentals of the system design, including client/server architecture, communication interfaces, and fuzzy set theory and fuzzy logic as methods for knowledge representation and interference, are presented. METHODS: In radiology today, computers are routinely used to acquire radiological images in hospital and radiology information systems (HIS/RIS) and picture archiving and communication systems (PACS). In our approach, we make use of pre-existent sources of information to build an expert system that minimizes the interaction between radiologists and the computer. To handle uncertainty and vagueness of medical knowledge, fuzzy set theory and fuzzy logic are used. Given data of a specific case, a deductive inference procedure combines the observed radiological signs, establishes confirmed and excluded diagnoses as well as diagnostic hypotheses, and provides explanations for these conclusions. Furthermore, proposals for confirmation or exclusion of diagnostic hypotheses are offered. RESULTS: For evaluation purposes, an early prototype of Cadiag-4/Rheuma-Radio was tested on radiological disorders of the hip joint related to rheumatological diseases. Twenty radiological cases were used as test cases, reaching a diagnostic accuracy of about 80%. CONCLUSION: The first results are acceptable and encourage further work to cover the whole area of rheumatologically relevant radiological signs and diagnoses. Furthermore, research into the development of user-oriented data acquisition tools will be carried out.