Objective
To evaluate the synovial membrane volume, determined by magnetic resonance imaging (MRI), as a marker of joint disease activity and a predictor of progressive joint destruction in ...rheumatoid arthritis (RA).
Methods
Twenty‐six patients with RA, randomized to receive disease‐modifying antirheumatic drug (DMARD) therapy alone (11 patients) or DMARDs in combination with oral prednisolone (15 patients), were followed up for 1 year with contrast‐enhanced MRI of the dominant wrist (months 0, 3, 6, and 12), conventional radiography (months 0 and 12), and clinical and biochemical examinations. Bone erosion (by MRI and radiography) and synovial membrane volumes (by MRI) were assessed.
Results
Significant synovial membrane volume reductions were observed after 3 and 6 months in the DMARD + prednisolone group, and after 6 and 12 months in the DMARD‐alone group (P < 0.01–0.02, by Wilcoxon‐Pratt analysis). The rate of erosive progression on MRI was highly correlated with baseline scores and, particularly, with area under the curve (AUC) values of synovial membrane volume (Spearman's σ = 0.69, P < 0.001), but not with baseline or AUC values of local or global clinical or biochemical parameters, or with prednisolone treatment. In none of 5 wrists with baseline volumes <5 cm3, but in 8 of 10 wrists with baseline volumes ≥10 cm3, erosive progression was found by MRI and/or radiography, indicating a predictive value of synovial membrane volumes. MRI was more sensitive than radiography for the detection of progressive bone destruction (22 versus 12 new bone erosions).
Conclusion
MRI‐determined synovial membrane volumes are closely related to the rate of progressive joint destruction. Quantitative MRI assessment of synovitis may prove valuable as a marker of joint disease activity and a predictor of progressive joint destruction in RA.
Objective
In a 5‐year followup study, we investigated the temporal relationship between development of wrist joint erosions as visualized by magnetic resonance imaging (MRI) versus conventional ...radiography (CR), in patients with rheumatoid arthritis. We also evaluated the risk of erosive progression on CR associated with the presence of MRI erosions.
Methods
In 10 patients with rheumatoid arthritis, MRI and CR of the dominant wrist were performed annually for 5 years. In each image set, each wrist bone (metacarpal bases, carpal bones, radius, and ulna) was assessed for the absence or presence of bone erosions.
Results
Nine bones showed radiographic erosions at baseline. Twenty‐seven new radiographic erosions developed during the 5‐year followup period. Of these 27 new erosions, 21 were detected 1–5 years earlier by MRI than by CR, 3 were simultaneously detected by both methods, 2 were detected 1–2 years later by MRI than by CR, and 1 erosion (radiographically detected at 5‐year followup) was not visualized with MRI. MRI detection of new radiographic erosions preceded CR detection by a median of 2 years. In bones with MRI erosions at baseline, the relative risk of radiographic erosions at 5‐year followup was 4.5 (95% confidence interval 95% CI 2.6–7.6), compared with bones without baseline MRI erosions. If bones with baseline radiographic erosions were excluded from the analysis, the relative risk was 4.1 (95% CI 2.2–7.5).
Conclusion
Most new radiographic bone erosions (78%) were visualized at least 1 year earlier by MRI than by CR. This illustrates that the information on joint destruction provided by CR is considerably delayed compared with that provided by MRI. A significantly increased risk of progression of radiographic erosion in bones with baseline MRI erosions was observed, demonstrating a prognostic value of MRI with respect to long‐term radiographic outcome.
Thrombus organization has been suggested to play a major role in late neointimal formation after coronary angioplasty. We sought to describe the time sequence of lesion formation after angioplasty in ...porcine coronary arteries and to quantify the relation between early thrombosis and late neointimal formation. Deep vessel wall injury was induced by conventional balloon angioplasty in the circumflex (CX) and right coronary (RCA) arteries and by retraction of a chain-encircled balloon in the left anterior descendent artery (LAD). Lesions were assessed by histomorphometry at days 0, 1, 4, 7, 14, 28, and 56 after angioplasty. A response-to-injury index (lesion area/injury length) was determined for each artery. Angioplasty led to rupture/removal of media. Thrombus was present at the exposed adventitia at days 0, 1, and 4. From day 7, neointima was observed on the luminal side of the arterial wall. All thrombus had disappeared at day 28, at which only neointima was observed. Histomorphometry revealed that lesion formation after angioplasty was a gradually increasing process from day 0 to day 28 with no further growth from day 28 to day 56. Maximal thrombus size (day 4, RCA: 0.07 ± 0.04 mm, CX: 0.23 ± 0.16 mm, LAD: 0.15 ± 0.11 mm) was significantly smaller than late neointimal formation (day 28, RCA: 0.68 ± 0.18 mm, CX: 0.63 ± 0.23 mm, LAD: 0.71 ± 0.18 mm) in all three arteries (
p < .03). Lesion formation after angioplasty is a gradually increasing process for 4 weeks. Maximal thrombus size is about four times smaller than late neointimal formation. Thus, thrombus organization plays no major role in late neointimal formation.
The mechanism(s) by which CTL induce target cell lysis have not been clearly elucidated. Perforin and the cytotoxic cell proteinases (granzymes) contained within the granules of CTL and NK, have been ...implicated, but abundant evidence for the existence of alternate lytic pathways has accumulated. In this report we characterize the mechanism of killing used by two cytolytic hybridomas (PMM-1 and MD90) that express neither perforin nor the granzymes. These characteristics are compared with results obtained by using a representative Ag-dependent, granule-containing T cell clone in cytolysis assays. The major differences were that the granule-negative hybridomas could lyse a variety of target cells in the presence of cyclosporin and the absence of calcium. All the effectors could kill in the presence of protein synthesis inhibitors (cycloheximide and emetine) and induced DNA fragmentation in the target cells. The cytolytic hybridomas had to be stimulated to be cytolytic and this activation required the presence of calcium, was dependent on protein synthesis, and inhibited by the addition of cyclosporin. Although TNF was shown not be involved, the sensitivity of the target cells to lysis by the granule-negative killers correlated with the level of expression of Fas Ag. With the use of L1210 and an L1210 cell line transfected with Fas cDNA we demonstrated that these MD90 and PMM-1 kill the latter much more effectively and that this increase was effectively inhibited with anti-Fas Ab. Furthermore the lack of sensitivity to cyclosporin, cycloheximide, emetine, and EGTA was confirmed with these targets. We conclude that these two cytolytic hybridomas use the Fas lytic pathway to induce lysis in target cells.
In order to describe velocity profiles and the size of deterministic and non-deterministic velocity disturbances at arterial stenoses, symmetrical and asymmetrical stenoses with intended area ...reductions of 50% ('moderate') and 85% ('severe') were applied on the abdominal aorta in six pigs. Blood velocities were registered by hot-film anemometry in 21 measuring points distributed across the vessel cross-sectional area in one pre-stenotic and three post-stenotic positions. Signal analysis included ensemble averaging, the high-pass filtering technique, and three-dimensional visualization. None of the stenoses affected the pre-stenotic velocity field. Downstream moderate stenoses flow separation and vortex formation were present. Moderate asymmetric stenoses induced turbulence in the post-stenotic velocity field. Immediately downstream of severe stenoses a prominent post-stenotic jet was present. Farther downstream, a multitude of coherent vortices and turbulence dominated the flow field. The transverse distribution of turbulence intensity paralleled with the peak systolic velocity profile, whereas transverse profiles of the relative turbulence intensity (turbulence intensity/mean velocity) revealed peak values in flow field locations with high velocity gradients. Velocity parameters for symmetric and asymmetric severe stenoses were highly comparable. However, the exact degree of stenosis was significantly higher for symmetrical (85%) than for asymmetrical (76%) stenoses. Therefore, recalling that stenosis severity strongly influences the development of velocity disturbances, this indicates that asymmetry of a stenosis is a predictor for blood velocity disturbances.
The pharmacodynamics of i.v. and subcutaneous (s.c.) tinzaparin sodium compared with heparin in healthy volunteers were studied. A randomized, open-label, five-treatment, five-period-crossover study ...with a Latin square design was performed in 30 healthy men to estimate tinzaparin pharmacodynamics (anti-Xa and anti-IIa activities) after single-dose i.v. and s.c. administration, to evaluate absolute bioavailability, to determine the effect of a preservative (benzyl alcohol), to evaluate the dose-activity relationship, and to compare tinzaparin with unfractionated heparin. Treatments were (1) heparin 5,000 units s.c., (2) tinzaparin 4,500 anti-Xa IU without preservative s.c., (3) tinzaparin 4,500 anti-Xa IU without preservative i.v., (4) tinzaparin 12,250 anti-Xa IU with preservative s.c., and (5) tinzaparin 4,500 anti-Xa IU with preservative s.c. Blood samples for the measurement of anti-Xa and anti-IIa activities were drawn over 24 hours. Anti-Xa and anti-IIa activities were determined by chromogenic methods; data were analyzed by using a noncompartmental approach. The clearance of tinzaparin based on anti-Xa activity ranged from 1.14 to 2.04 L/hr. The volume of distribution was 3.1-5.0 L, suggesting that the molecular entities responsible for anti-Xa and anti-IIa activities are confined to the intravascular space. Mean peak anti-Xa activity occurred three to four hours after s.c. injection, independent of the dose. The mean half-life of anti-Xa activity after s.c. injection ranged from 3.41 to 4.13 hours and was independent of the dose. The mean absolute bioavailability of s.c. tinzaparin was 86.7%. Intersubject pharmacodynamic variability was low for tinzaparin compared with heparin. Benzyl alcohol did not affect tinzaparin pharmacodynamics. A clear dose-activity relationship was seen for the two fixed doses of tinzaparin (12,250 and 4,500 IU). Single doses of tinzaparin were safe and well tolerated after administration by either route. The anti-Xa profile of tinzaparin supports the pharmacodynamic superiority of low-molecular-weight heparins over standard i.v. heparin administration. This pharmacodynamic study in healthy volunteers indicates that s.c. tinzaparin sodium was well absorbed; the presence of a preservative, benzyl alcohol, did not affect the activity of tinzaparin; and tinzaparin activity is dose-related.
The covalent structures of two, novel, neutrophile, leucocyte-derived, strongly basic proteins of porcine and human origin have been determined by microsequencing in combination with time-of-flight ...plasma desorption mass spectrometry. The porcine protein primary structure of 219 amino acid residues was shown to contain 6 cysteine residues, 2 putative carbohydrate sites and 14% basic residues. The human protein contained 221 amino acid residues of which 8 were cysteine, 4 putative carbohydrate sites and 12% basic. A 47% direct sequence similarity to human neutrophile elastase was found, but due to mutations of two of the three amino acids in the catalytic triad, proteolytic activity is absent. Modelling and alignment studies unveil a close relationship of both proteins to the serine protease family, the greatest similarity being to those serine proteases present in granules from peripheral blood cells. Both proteins have been shown to be chemotactically active for monocytes and fibroblasts in vitro.
Since detailed knowledge about velocity fields downstream of heart valve prostheses obtained from in vitro studies has not been followed up by similar detailed studies in vivo a pig model for acute ...velocity field studies downstream of aortic valve prostheses was established. Two mechanical and two bioprosthetic valves were studied and a dynamic three dimensional visualisation of velocity fields one diameter downstream performed under different haemodynamic conditions in a total of 22 pigs. The Ionescu-Shiley pericardial valve had velocity fields very similar to the normal native porcine aortic valve. The Edwards-Carpentier porcine valve caused a jet type flow, and the valve design of the St Jude Medical and Björk-Shiley Monostrut valves was reflected in the velocity profile. Normalised (mean(SEM systolic Reynolds normal stresses in the total cross sectional area were: native porcine 15(1.5) Nm-2; St Jude Medical 24(3.4) Nm-2; Björk-Shiley Monostrut 25(1.6) Nm-2; Edwards-Carpentier Supra-annular 51(6.6) Nm-2; Ionescu-Shiley Pericardial 19(2.0) Nm-2. Reynolds normal stresses were higher in areas of rapidly changing or constantly high velocity gradients.
Since data on velocity fields in the ascending aorta downstream of normal aortic valves in pigs have not yet been obtained velocity profiles were visualised using a hot film anemometer needle probe ...before and after total cardiopulmonary bypass and cold cardioplegic arrest. Furthermore, measurements were made during increased heart rate and cardiac output. A dynamic three dimensional visualisation of velocity fields showed a skewed clockwise rotating velocity profile, developing from peak systole and continuing throughout the systolic deceleration phase. This pattern was consistent regardless of the haemodynamic state. Heart rate was increased to 180 beats.min-1 and cardiac output by a maximum of 91%. It is concluded that the pig model is valuable for haemodynamic studies in the ascending aorta before and after cold cardioplegic arrest and that the velocity profiles found in this study are important basic data for velocity field studies downstream of artificial heart valves implanted in the aortic position.
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