Color Doppler ultrasonography of hand and finger arteries to differentiate primary from secondary forms of Raynaud's phenomenon.

OBJECTIVE: Modern ultrasound (US) equipment allows rheumatologists to directly visualize hand and finger arteries. How does US aid in diagnosis of Raynaud's phenomenon (RP)? METHODS: Color Doppler US of the proper and common palmar digital, radial, and ulnar arteries and the superficial palmar arch of both hands was performed in 135 consecutive patients who presented with suspected RP. RESULTS: US was pathologic in 63% of patients with secondary RP, in 6% with primary RP, and in none with pseudo-RP (p < 0.0001). We found 3 types of vascular pathology: Type 1 showed narrowing or chronic occlusion of some proper digital arteries; Type 2 was characterized by the same finding in all proper digital arteries; and Type 3 involved acute occlusions. Type 1 was found in 3 of 53 patients with primary RP and in 19 patients with secondary RP including 5 of 9 patients with anti-centromere positive systemic sclerosis (SSc); Type 2 occurred in 16 patients with SSc, MCTD, and dermatomyositis; and Type 3 was found in 8 patients with antiphospholipid antibody syndrome, thromboangiitis obliterans, vibration trauma, or vasculitis. The ulnar arteries were more commonly affected than the radial arteries. The 2nd radial, 3rd radial, 4th ulnar, and 5th ulnar proper palmar digital arteries were most commonly involved. CONCLUSION: Aiding in differentiating primary versus secondary RP, severe versus less severe disease, and acute versus chronic vascular occlusion, digital artery US depicts the same anatomical structures as angiography, but it is cheaper, faster, and noninvasive.

Ultrasonography of salivary glands -- a highly specific imaging procedure for diagnosis of Sjögren's syndrome.

OBJECTIVE: To verify ultrasonographic criteria for examination of the major salivary glands in diagnosis of primary and secondary Sjögren's syndrome (SS). METHODS: Three hundred sixteen consecutive patients with rheumatic diseases were selected according to the European Consensus Study Group diagnostic criteria for SS. Fifty-seven had primary SS, 33 had secondary SS, 78 had Sicca symptoms, and 148 patients served as asymptomatic controls. This cohort was analyzed for size and parenchymal echogenicity of the major salivary glands by ultrasonography. RESULTS: Evident parenchymal inhomogenicity in 2 or more major salivary glands was detected by ultrasonography in patients with primary and secondary SS with a sensitivity of 63.1% and 63.6%, respectively. The specificity of this imaging approach in our cohort was 98.7%. The volume of submandibular glands was reduced in patients with primary and secondary SS by about 30% compared to patients with sicca symptoms and asymptomatic controls. In receiver-operating characteristic (ROC) curve analysis, the detection of reduced volumes of both submandibular glands in patients with primary and secondary SS had a specificity of 93% and a sensitivity of 48% at the cutoff point of 3.0 ml. Of note, the volume of the parotid glands did not differ between the groups of patients. In patients with primary SS, parenchymal inhomogenicity of the salivary glands was strongly associated with positivity for anti-Ro and/or anti-La antibodies. CONCLUSION: Ultrasonographic detection of parenchymal inhomogenicity of the major salivary glands and observation of reduced volume of the submandibular glands resulted in high specificities for diagnosis of primary and secondary SS. The data indicate that ultrasonography of major salivary glands is a noninvasive imaging procedure with high diagnostic value for the diagnosis of primary and secondary SS.

Interface membrane fibroblasts around aseptically loosened endoprostheses express MMP-13.

The objective of this article was to assess whether matrix metalloproteinase-13 (MMP-13) is produced by cells of the peri-implant interface tissues and to further characterize these cells. Tissue specimens were collected from the bone-prosthesis interface at the time of revision surgery of clinically loosened hip and knee arthroplasties (n = 27). Synovial tissues from osteoarthritic patients and young patients with mild joint deformity were used as controls (n = 6). Tissue samples were fixed in 4% PFA, decalcified with EDTA, and embedded in paraffin. Sections (4 microm) were stained with hematoxylin/eosin and for the osteoclastic marker enzyme tartrate resistant acid phosphatase. Monocytes/macrophages were characterized with a monoclonal antibody against CD68 and mRNAs encoding MMP-13 and alpha(1) collagen I (COL1A1) were detected by in situ hybridization. Cells expressing transcripts encoding MMP-13 were found in 70% of the interface tissues. These cells colocalized with a cell population expressing COL1A1 mRNA, and were fibroblastic in appearance. MMP-13 expressing cells were found in the close vicinity of osteoclasts and multinuclear giant cells. No signals for transcripts encoding MMP-13 were detected in multinuclear giant cells or in osteoclasts. Control tissues were negative for transcripts encoding MMP-13 mRNA. Fibroblasts of the interface from aseptically loosened endoprostheses selectively express MMP-13. By the expression and the release of MMP-13, these fibroblastic cells may contribute to the local degradation of the extracellular matrix and to bone resorption.

Autonomic cardiac control in animal models of cardiovascular diseases. I. Methods of variability analysis.

Analysis of heart rate variability (HRV) and blood pressure variability (BPV) and baroreceptor sensitivity (BRS) has become a proven tool in clinical cardiovascular diagnostics and risk stratification. In the present work, traditional and new methodological approaches for analysis of HRV, BPV, and BRS data are summarized. HRV, BPV, and BRS parameters were obtained from animal studies designed to study pathogenetic mechanisms of distinct cardiovascular diseases. Different non-linear approaches for HRV and BPV analysis are presented here, in particular measures of complexity based on symbolic dynamics. The dual sequence method (DSM) was employed for BRS analysis. In comparison to the classical measure of BRS using the average slope [ms/mm Hg], DSM offers additional information about the time-variant coupling between BPV and HRV. Since cardiovascular regulation shares common features among different species, data on HRV and BPV, as well as BRS, in animal models might be useful for understanding the pathogenetic mechanisms of cardiovascular diseases in humans and in the development of new diagnostic approaches.

Autonomic cardiac control in animal models of cardiovascular diseases II. Variability analysis in transgenic rats with alpha-tropomyosin mutations Asp175Asn and Glu180Gly.

Animal models of cardiovascular diseases allow to investigate relevant pathogenetic mechanisms in detail. In the present study, the mutations Asp175Asn and Glu180Gly in alpha-tropomyosin (TPM1), known cause familiar hypertrophic cardiomyopathy (FHC) were studied for changes in hemodynamic parameters and spontaneous baroreflex regulation in transgenic rats in comparison to transgenic and non-transgenic controls by telemetry. Heart rate variability (HRV) and blood pressure variability (BPV) were analyzed using time- and frequency domain, as well as non-linear measures. The dual sequence method was used for the estimation of the baroreflex regulation. In transgenic rats harboring mutated TPM1, changes in HRV were detected during exercise, but not at rest. Both mutations, Asp175Asn and Glu180Gly, caused increased low frequency power. In addition, in animals with mutation Asp175Asn a reduced total HRV was observed. BPV did not show any differences between all transgenic animal lines. During exercise, a strong increase in the number of bradycardic and tachycardic fluctuations accompanied with decreased baroreflex sensitivity (BRS) was detected in animals with either TPM1 mutation, Asp175Asn or Glu180Gly. These data suggest, that the analysis of cardiac autonomic control, particularly of baroreflex regulation, represents a powerful non-invasive approach to investigate the effects of subtle changes in sarcomeric architecture on cardiac physiology in vivo. In case of mutations Asp175Asn or Glu180Gly in TPM1, early detection of alterations in autonomic cardiac control could help to prevent sudden cardiac death in affected persons.

The expression of collagenase 3 (MMP-13) mRNA in the synovial tissue is associated with histopathologic type II synovitis in rheumatoid arthritis.

The histopathologic analysis of the synovial tissue is important to distinguish rheumatoid arthritis (RA) from other forms of synovitis and to provide information about prognosis and therapeutic strategies at early stages of the disease. In this context, the present study was performed to investigate the correlation between immunohistopathological and morphological features of synovitis and the expression of collagenase 3 (MMP-13) known to contribute significantly to cartilage degradation in RA. In the histopathologic scoring system used in this study, type I synovitis is characterized by B lymphocyte infiltration and an intact lining, and is only mild destructive to cartilage and bone. Type II shows marked diffuse infiltrations of macrophages and T lymphocytes, an ulcerated lining, fibrin exudation, and invasive growth into cartilage and bone tissue. Investigating 36 patients with RA, 21 patients (58%) were positive for the expression of collagenase 3 mRNA in the synovial tissue. Among these patients, 19 showed a histopathologic type II synovitis and only 2 patients had undifferentiated synovitis. In contrast, synovial tissue samples from patients without collagenase 3 mRNA expression were characterized in 6 cases by type I, in 5 cases by type II and in 4 cases by undifferentiated synovitis. The analysis of the clinical data revealed that RA patients with a histopathologic type II synovitis and synovial tissue collagenase 3 mRNA expression had elevated levels of systemic markers of inflammation and received stronger therapies. The data suggest, that collagenase 3 expression and the histopathologic type II synovitis are associated with a severe and destructive course of RA.

Manifestation of rheumatoid arthritis in a patient with hereditary haemochromatosis.

Articular symptoms are frequent manifestations of hereditary haemochromatosis. The clinical signs of the arthropathy of haemochromatosis are not specific and difficult to identify in case of co-incidence of haemochromatosis with Heberden's and Bouchard's osteoarthritis or rheumatoid arthritis (RA). Here the manifestation of RA in a patient is reported who was successfully treated for haemochromatosis. Six months after terminating phlebotomy, the patient presented again suffering from impressive swelling of all MCP joints, showing strong synovitis in ultrasound, and from morning stiffness longer than 1 h. ESR, CRP, IgM rheumatoid factor, and anti-cyclic citrullinated peptide antibodies were markedly elevated. Based on these findings the diagnosis of RA was made. Therefore, the high prevalence of RA and haemochromatosis in the general population underlines the usefulness of a screening for HFE gene mutations in RA patients with an atypical course of the disease as well as in patients with undifferentiated arthritis.

alpha-Tropomyosin mutations Asp(175)Asn and Glu(180)Gly affect cardiac function in transgenic rats in different ways.

To study the mechanisms by which missense mutations in alpha-tropomyosin cause familial hypertrophic cardiomyopathy, we generated transgenic rats overexpressing alpha-tropomyosin with one of two disease-causing mutations, Asp(175)Asn or Glu(180)Gly, and analyzed phenotypic changes at molecular, morphological, and physiological levels. The transgenic proteins were stably integrated into the sarcomere, as shown by immunohistochemistry using a human-specific anti-alpha-tropomyosin antibody, ARG1. In transgenic rats with either alpha-tropomyosin mutation, molecular markers of cardiac hypertrophy were induced. Ca(2+) sensitivity of cardiac skinned-fiber preparations from animals with mutation Asp(175)Asn, but not Glu(180)Gly, was decreased. Furthermore, elevated frequency and amplitude of spontaneous Ca(2+) waves were detected only in cardiomyocytes from animals with mutation Asp(175)Asn, suggesting an increase in intracellular Ca(2+) concentration compensating for the reduced Ca(2+) sensitivity of isometric force generation. Accordingly, in Langendorff-perfused heart preparations, myocardial contraction and relaxation were accelerated in animals with mutation Asp(175)Asn. The results allow us to propose a hypothesis of the pathogenetic changes caused by alpha-tropomyosin mutation Asp(175)Asn in familial hypertrophic cardiomyopathy on the basis of changes in Ca(2+) handling as a sensitive mechanism to compensate for alterations in sarcomeric structure.

Stimulation of collagenase 3 expression in synovial fibroblasts of patients with rheumatoid arthritis by contact with a three-dimensional collagen matrix or with normal cartilage when coimplanted in NOD/SCID mice.

OBJECTIVE: To study the expression of collagenase 3 (matrix metalloproteinase 13 [MMP-13]) and collagenase 1 (MMP-1) in synovial fibroblasts from patients with rheumatoid arthritis (RA) when cultured within 3-dimensional collagen gels or coimplanted with normal cartilage in immunodeficient NOD/SCID mice. METHODS: Messenger RNA (mRNA) and protein expression of collagenase 3 and collagenase 1 were characterized in synovial and skin fibroblasts by Northern blot and Western blot analysis. The mRNA expression of both collagenases in cell-cartilage implants in NOD/SCID mice was investigated by in situ hybridization in combination with immunohistochemistry of human fibroblasts. RESULTS: Synovial fibroblasts coimplanted with normal cartilage in NOD/SCID mice deeply invaded adjacent cartilage tissue. In this in vivo system of cartilage destruction, collagenase 3 mRNA was induced in synovial fibroblasts at sites of cartilage erosion, while the expression of collagenase 1 mRNA could not be detected. Culture of synovial fibroblasts within 3-dimensional collagen gels was associated with a marked increase in collagenase 3 mRNA expression and proenzyme production. This stimulatory effect was 1 order of magnitude higher in comparison with a 2-4-fold increase upon treatment with interleukin-1beta or tumor necrosis factor a. In contrast, mRNA expression and proenzyme production of collagenase 1 were increased strongly, and to a similar extent, either by contact with 3-dimensional collagen or by proinflammatory cytokines. CONCLUSION: The expression of collagenase 3, in contrast to that of collagenase 1, is preferentially stimulated in synovial fibroblasts by 3-dimensional collagen rather than by proinflammatory cytokines. The induction of collagenase 3 by cell-matrix interactions represents a potential mechanism contributing to the invasive phenotype of synovial fibroblasts at sites of synovial invasion into cartilage in RA.