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author:("kettinen, Y T")
1.  Novel biological strategies for treatment of wear particle-induced periprosthetic osteolysis of orthopaedic implants for joint replacement 
Wear particles and by-products from joint replacements and other orthopaedic implants may result in a local chronic inflammatory and foreign body reaction. This may lead to persistent synovitis resulting in joint pain and swelling, periprosthetic osteolysis, implant loosening and pathologic fracture. Strategies to modulate the adverse effects of wear debris may improve the function and longevity of joint replacements and other orthopaedic implants, potentially delaying or avoiding complex revision surgical procedures. Three novel biological strategies to mitigate the chronic inflammatory reaction to orthopaedic wear particles are reported. These include (i) interference with systemic macrophage trafficking to the local implant site, (ii) modulation of macrophages from an M1 (pro-inflammatory) to an M2 (anti-inflammatory, pro-tissue healing) phenotype in the periprosthetic tissues, and (iii) local inhibition of the transcription factor nuclear factor kappa B (NF-κB) by delivery of an NF-κB decoy oligodeoxynucleotide, thereby interfering with the production of pro-inflammatory mediators. These three approaches have been shown to be viable strategies for mitigating the undesirable effects of wear particles in preclinical studies. Targeted local delivery of specific biologics may potentially extend the lifetime of orthopaedic implants.
doi:10.1098/rsif.2013.0962
PMCID: PMC3928932  PMID: 24478281
wear particles; orthopaedic implants; inflammation; cell trafficking; macrophage polarization; NF-κB
2.  No evidence of long-term benefits of arthroscopic acromioplasty in the treatment of shoulder impingement syndrome 
Bone & Joint Research  2013;2(7):132-139.
Objectives
To report the five-year results of a randomised controlled trial examining the effectiveness of arthroscopic acromioplasty in the treatment of stage II shoulder impingement syndrome.
Methods
A total of 140 patients were randomly divided into two groups: 1) supervised exercise programme (n = 70, exercise group); and 2) arthroscopic acromioplasty followed by a similar exercise programme (n = 70, combined treatment group).
Results
The main outcome measure was self-reported pain as measured on a visual analogue scale. At the five-year assessment a total of 109 patients were examined (52 in the exercise group and 57 in the combined treatment group). There was a significant decrease in mean self-reported pain on the VAS between baseline and the five-year follow-up in both the exercise group (from 6.5 (1 to 10) to 2.2 (0 to 8); p < 0.001) and the combined treatment group (from 6.4 (2 to 10) to 1.9 (0 to 8); p < 0.001). The same trend was seen in the secondary outcome measures (disability, working ability, pain at night, Shoulder Disability Questionnaire and reported painful days). An intention-to-treat analysis showed statistically significant improvements in both groups at five years compared with baseline. Further, improvement continued between the two- and five-year timepoints. No statistically significant differences were found in the patient-centred primary and secondary parameters between the two treatment groups.
Conclusions
Differences in the patient-centred primary and secondary parameters between the two treatment groups were not statistically significant, suggesting that acromioplasty is not cost-effective. Structured exercise treatment seems to be the treatment of choice for shoulder impingement syndrome.
doi:10.1302/2046-3758.27.2000163
PMCID: PMC3728648  PMID: 23836479
Shoulder impingement; Syndrome; Operation; Physiotherapy; Arthroscopic; Acromioplasty
4.  Macrophages overloaded with tissue debris in Wegener's granulomatosis 
Annals of the Rheumatic Diseases  2005;64(8):1229-1232.
Methods: Immunohistochemical staining of lung, nasopharynx, and skin for macrophage markers related to scavenging (macrophage scavenger receptor MARCO, collagenase-1 and gelatinase-B), formation of multinuclear foreign body giant cells (ADAM 9/meltrin-γ and ADAM 12/meltrin-α), and cell debris derived from neutrophils, endothelial cells and mast cells (specific granule protein 28 (SGP28), von Willebrand factor (vWF) and mast cell tryptase, respectively). TechMate staining robot and biotin-streptavidin protocol were used.
Results: Some macrophages were activated and expressed collagenase-1 and gelatinase-B. Approximately 5% of macrophages expressed scavenger receptor, whereas 20–30% were meltrin positive. Interstitial and granuloma associated macrophages and giant cells contained partly undigested, immunoreactive SGP28-, vWF- and tryptase-positive cell rests and collagenous matrix. Lymphocytic follicles with germinal centres were found in the same areas.
Conclusion: In WG tissue lesions macrophage and giant cells seem to be overwhelmed by the bulk to be scavenged. Despite cellular activation and continuing maturation to professional scavenger receptor (MARCO) and meltrin positive multinuclear giant cells combined with an organisation into granulomas, macrophages still contain partially undigested cell and tissue rests. This necrotic and damaged self may be the driving force for the formation of giant cell ("foreign body") granulomas. This, together with the local formation of secondary lymphatic follicles (with germinal centres), indicates active local antigen processing and presentation.
doi:10.1136/ard.2004.027029
PMCID: PMC1755591  PMID: 16014685
5.  Spacer prostheses in two-stage revision of infected knee arthroplasty 
International Orthopaedics  2006;30(4):257-261.
At present, no consensus exists on the best spacer alternative for the management of two-stage exchange arthroplasty of infected knee arthroplasties. In this retrospective study, patient records of 24 patients, who had undergone two-stage revisions in which resterilised prosthetic components were used as spacers, were reviewed. The outcome was compared to that of operations performed during the same period (1993–2003) using cement spacers (n=10). With an average follow-up of 32 months, control of infection was achieved in 26 cases (76%), with good or excellent clinical outcome in 19 cases (56%). Treatment failed and resulted in amputation at the level of the thigh before reimplantation in one case. Three patients did not undergo reimplantation. In four cases (12%) infection relapsed. The reinfection rate did not differ between the two spacer groups. Patients treated with resterilised components had a superior range of motion during the period between the two stages. Operative time was shorter and there was less blood loss in the reimplantation arthroplasty when a prosthetic spacer was used. We consider resterilised prosthetic components a safe and effective alternative to cement spacers in the management of infected knee arthroplasties.
doi:10.1007/s00264-006-0102-2
PMCID: PMC2532134  PMID: 16565839
6.  Salivary gland scintigraphy in Sjögren's syndrome and patients with sicca symptoms but without Sjögren's syndrome: the psychological profiles and predictors for salivary gland dysfunction 
Annals of the Rheumatic Diseases  2003;62(10):964-968.
Objective: To characterise the psychological profiles of Sjögren's syndrome (SS) and patients with sicca symptoms but without SS; to find predictors for salivary gland function; to evaluate salivary scintigraphy as a method to differentiate between SS and patients with sicca symptoms but without SS.
Patients and methods: Psychological tests (Medical Outcomes Study Short Form General Health Survey (SF-36), Jenkins Activity Survey, Toronto Alexithymia Scale, and Maastricht Questionnaire for vital exhaustion) were performed and assessment of the function of the salivary glands made in 26 patients with primary SS, 8 with secondary SS, and 9 with sicca symptoms but without SS. Data were analysed with BMDP new system version 1.0 statistical program.
Results: Psychological profiles were similar in all groups. Hb, RF, ANA, and SSA differentiated between the groups. Results of salivary scintigraphy were predicted to 51% by ANA, SSA, SSB, IgG, IgA, diagnosis, vitality, and role limitations due to emotional problems. No predictors were found for the resting salivary flow. Salivary scintigraphy was pathological in 21/26 (81%) and in 8/8 (100%) patients with secondary SS, but only in 2/9 (22%) patients with sicca symptoms without SS (p=0.002) (sensitivity 85.3%, specificity 77.8%).
Conclusions: Patients with sicca symptoms but without SS have sickness behaviour similar to that of patients with SS. The results of salivary scintigraphy can be predicted by diagnosis and autoimmune findings; psychological characteristics added 20% to this predictive value. Distinction between SS and patients with sicca symptoms but without SS is difficult, but in addition to autoantibodies, salivary scintigraphy can be used for this purpose.
doi:10.1136/ard.62.10.964
PMCID: PMC1754342  PMID: 12972475
7.  Nerve growth factor and neuropeptides circulating levels in systemic sclerosis (scleroderma) 
Annals of the Rheumatic Diseases  2001;60(5):487-494.
OBJECTIVE—To determine the circulating levels of nerve growth factor (NGF), neuropeptide Y (NPY), and vasoactive intestinal peptide (VIP) in systemic sclerosis (SSc), and to correlate these levels with clinical and laboratory features.
METHODS—Forty four patients with SSc were evaluated for circulating NGF (immunoenzymatic assay), NPY and VIP (radioimmunoassay), anticentromere and antitopoisomerase I autoantibodies, lung disease (pulmonary function tests with carbon monoxide transfer factor (TLCO), ventilation scintiscan with 99mTc DTPA radioaerosol, high resolution computed tomography (HRCT), pulmonary pressure (echo colour Doppler)), heart disease (standard and 24 ECG, echocardiography), cutaneous involvement (skin score), joint involvement (evidence of tender or swollen joints, or both), peripheral nervous system (PNS) involvement (electromyography), rheumatoid factor, angiotensin converting enzyme (fluorimetric method), von Willebrand factor (ELISA), and erythrocyte sedimentation rate (ESR) (Westergren).
RESULTS—Circulating NGF levels in SSc were significantly increased compared with controls (p<0.00001) and significantly higher in the diffuse than in the limited subset of patients (p<0.01). Patients with articular disease had significantly higher levels of NGF. A significant indirect correlation between NGF levels and TLCO was detected (p<0.01), but no correlation was found between NGF and HRCT, DTPA, skin score, PNS involvement and angiotensin converting enzyme and von Willebrand factor levels, antitopoisomerase or anticentromere antibodies, and ESR. NGF levels increased progressively as the disease worsened. Similarly, VIP circulating levels were significantly increased in patients with SSc (p<0.001), whereas the increase of NPY levels did not reach statistical significance. However, both neuropeptides, following the same trend as NGF, increased as the disease worsened (skin score and lung disease).
CONCLUSIONS—The increase of NGF and VIP in patients with SSc, the former in the diffuse subset of the disease, and in patients with prominent articular disease, may suggest a link between neurotransmitters and the disease pathogenesis. Neuropeptide circulating levels seem to increase only in patients with the most severe disease.


doi:10.1136/ard.60.5.487
PMCID: PMC1753627  PMID: 11302871
9.  Expression of epidermal growth factor and transforming growth factor α in interfacial membranes retrieved at revision total hip arthroplasty 
Annals of the Rheumatic Diseases  2000;59(10):822-827.
BACKGROUND—The interfacial membrane between bone and implant has been shown to be a key tissue in the process of aseptic loosening of total hip arthroplasty. The cells within the interfacial membrane produce numerous inflammatory mediators which, through complex mechanisms, cause periprosthetic osteolysis and aseptic loosening. Both epidermal growth factor (EGF) and transforming growth factor α (TGFα) have similar biological functions. They have been found to stimulate bone resorption.
OBJECTIVE—To investigate the presence, cellular localisation, and extent of expression of EGF and TGFα in interfacial membrane retrieved from revision total hip arthroplasty and compare it with that in synovial membrane from primary total hip arthroplasty.
METHODS—Ten interfacial membranes and 10 synovial membranes were stained with avidin-biotin-peroxidase complex for EGF and TGFα. The staining process was done using the Lab Vision Autostainer. The results were measured by a semiautomatic VIDAS image analysis system.
RESULTS—Immunoreactivity for both EGF and TGFα was found in the endothelial cells of blood vessels, macrophages, and fibroblasts, both in interfacial membranes and synovial membranes. However, the number of EGF (980 (370)) and TGFα (1070 (360)) positive cells per mm2 was greater in interfacial membranes than in the synovial membranes (220 (200), 270 (100); p<0.01).
CONCLUSION—It is suggested that owing to their increased expression in interfacial membrane, EGF and TGFα may have an important pathogenetic role in stimulating periprosthetic bone resorption in aseptic loosening of total hip arthroplasty.


doi:10.1136/ard.59.10.822
PMCID: PMC1753009  PMID: 11005785
10.  Mutational analysis of the HGO gene in Finnish alkaptonuria patients 
Journal of Medical Genetics  1999;36(12):922-923.
Alkaptonuria (AKU), the prototypic inborn error of metabolism, has recently been shown to be caused by loss of function mutations in the homogentisate-1,2-dioxygenase gene (HGO). So far 17 mutations have been characterised in AKU patients of different ethnic origin. We describe three novel mutations (R58fs, R330S, and H371R) and one common AKU mutation (M368V), detected by mutational and polymorphism analysis of the HGO gene in five Finnish AKU pedigrees. The three novel AKU mutations are most likely specific for the Finnish population and have originated recently.


Keywords: alkaptonuria; homogentisate-1,2-dioxygenase; Finland
PMCID: PMC1734273  PMID: 10594001
11.  Analysis of 16 different matrix metalloproteinases (MMP-1 to MMP-20) in the synovial membrane: different profiles in trauma and rheumatoid arthritis 
Annals of the Rheumatic Diseases  1999;58(11):691-697.
OBJECTIVE—To define the pattern of mRNA expression of all human matrix metalloproteinases (MMPs) described to date in rheumatoid arthritis (RA) and traumatic synovial membrane, in order to differentiate between a physiological tissue remodelling pattern and that associated with inflammatory tissue destruction.
METHODS—Analysis of SwissProt protein and EMBL/GenBank nucleotide sequence banks, protein sequence alignment, reverse transcriptase-polymerase chain reaction and nucleotide sequencing were used.
RESULTS—MMP-2 (gelatinase A), MMP-3 (stromelysin-1), MMP-11 (stromelysin-3) and MMP-19 were constitutively expressed. MMP-1 (fibroblast type collagenase), MMP-9 (gelatinase B) and MMP-14 (MT1-MMP) were expressed in all RA, but only in 55-80% of trauma samples. MMP-13 (collagenase-3) and MMP-15 (MT2-MMP) were expressed exclusively in RA (80-90% of the samples). MMP-20 (enamelysin) was absent and MMP-8 (collagenase-2) was rarely found in RA or trauma. All other MMPs (-7, -10, -12, -16, -17) had an intermediate pattern of expression.
CONCLUSIONS—Some MMPs without interstitial collagenase activity seem to have a constitutive pattern of expression and probably participate in physiological synovial tissue remodelling. Some MMPs are exclusively associated to RA synovitis, for example, MMP-13, which preferentially degrades type II collagen and aggrecan, and MMP-15, which activates proMMP-2 and proMMP-13 and is involved in tumour necrosis factor α processing. This clear cut rheumatoid/inflammatory MMP profile, more complex than has been previously appreciated, may facilitate inflammatory tissue destruction in RA.


PMCID: PMC1752794  PMID: 10531073
12.  Expression of laminins and their integrin receptors in different conditions of synovial membrane and synovial membrane-like interface tissue 
Annals of the Rheumatic Diseases  1999;58(11):683-690.
OBJECTIVE—To demonstrate the expression of laminins (Lns) and their integrin (Int) receptors in different synovial samples and synovial membrane-like interface tissues from well fixed and aseptically loosened total hip replacement (THR), and the potential role of Ln-Int interaction in the production of collagenases and cytokines.
METHODS—Immunohistochemical staining was done to detect the distribution of EHS Ln, Ln α2, α3, α5, β1, β2 chains and Int α1, α2, α3, α6, β1, β4 subunits in different samples. Double immunofluorescence labelling was used to find colocalisation of Int α6 subunit and collagenase-1/collagenase-3/TNFα/IL6.
RESULTS—General Ln immunoreactivity was detected in all specimens. Ln α5, β1 and β2, but not α2 and α3 chains were seen in the synovial lining and the basement membrane of blood vessels with the intensity/extent of labelling in the following rank order: rheumatoid arthritis (RA) loosened prostheses, osteoarthritis, well fixed prostheses, traumatic knees. Among Int subunits, staining for β1 was usually the strongest, followed by staining for Int α6, α1, α3, and α2 subunits, with the same rank order for overall expression of Lns. Int β4 subunit was not detectable in most of the specimens. Double labelling focused on Int α6 subunit disclosed its frequent colocalisation with collagenases 1 and 3 and with tumour necrosis factor α and interleukin 6 in synovial lining.
CONCLUSION—Synovial lining contains Ln-10, Ln-11, and Int α6β1 and α1β1 receptors. In aseptic loosening of THR, interface tissue has a similar Ln subtype and Int receptor composition as RA synovium, which confirms its "lining-like" phenotype. Synovial lining does not contain Ln-5 (α3β3γ2) or Int α6β4, which are components of epithelial hemidesmosomes. The expression of Lns and their Int receptors is upregulated in inflammation. The close spatial relation between Ln and its Int receptors in synovial lining cells containing proteinases and cytokines suggests a potential role in joint destruction and prosthetic loosening.


PMCID: PMC1752798  PMID: 10531072
13.  Expression of tenascin-C in aseptic loosening of total hip replacement 
Annals of the Rheumatic Diseases  1998;57(10):619-623.
OBJECTIVE—To assess if the bonding interlayer between the implant and bone in aseptic loosening of total hip replacement (THR) is qualitatively deteriorated by excessive accumulation of anti-adhesive glycoprotein, tenascin-C.
METHODS—Alkaline phosphatase-anti-alkaline phosphatase (APAAP) method was used for immunohistochemical staining of tenascin-C in interface tissue and control synovial tissue.
RESULTS—Tenascin-C was found to be a major component of the extracellular matrix at a hitherto unrecognised site, namely the synovial membrane-like interface tissue between implant and bone in aseptic loosening of THR. The overall tenascin-C staining (median score 4.0) was greatly increased in aseptic loosening compared with synovial membrane (median score 2.0; p<0.001) and fibrous capsule (median score 2.0; p<0.001) from primary THR operations. Topological analysis disclosed that tenascin-C was also found at the critical implant-interface and interface-bone surfaces.
CONCLUSION—Local tenascin-C expression is increased as a result of a chronic foreign body type reaction associated with excessive cytokine production and tissue injury mediated by microtrauma and neutral endoproteinases. This qualitative and topological deterioration of the bonding interlayer by an increase of anti-adhesive tenascin-C expression may inadvertantly contribute to loosening.

 Keywords: tenascin; aseptic loosening; total hip replacement
PMCID: PMC1752487  PMID: 9893574
14.  Neuropeptides of the autonomic nervous system in Sjögren's syndrome 
Annals of the Rheumatic Diseases  1997;56(12):737-740.
OBJECTIVE—To assess the activity level of the autonomic nervous system in Sjögren's syndrome (SS) and to correlate this with stress.
METHODS—Patients with SS (n=12) and healthy controls (n=10) were analysed for the content of vasoactive intestinal peptide (VIP) and neuropeptide Y (NPY) in their stimulated saliva by radioimmunoassays and for stress by the use of a modified Jenkins Activity Survey (JAS).
RESULTS—The data are expressed as median (interquartile range). Salivary VIP output (pg/min) and NPY output (pg/min) were high in SS compared with healthy controls (30.0 (15.6, 36.6) versus 12.3 (9.2, 24.0), p=0.045, 4.8 (0.6, 24.1) versus 0.7 (0.0, 2.4), p=0.038, respectively). Patients experienced only a little, but not significantly, more stress than the healthy controls (stress index −2.8 (−7.7, 6.9) versus −5.2 (−12.9, 2.7), p>0.05). Stress in general was associated with high salivary VIP concentrations (r=0.41, p=0.05).
CONCLUSIONS—These findings show that adequately processed saliva (containing aprotinin and EDTA as neuropeptidase inhibitors) contains measurable amounts of marker peptides of the autonomic nervous system. Secondly, VIP concentration but not output may be affected by stress, which may act by decreasing watery salivary flow. In patients with SS, VIP and NPY outputs are increased. This may indicate increased leakage into saliva or efforts to compensate for the diminished salivary flow, or both.


PMCID: PMC1752311  PMID: 9496153
15.  Complement in acute and chronic arthritides: assessment of C3c, C9, and protectin (CD59) in synovial membrane. 
Annals of the Rheumatic Diseases  1996;55(12):888-894.
OBJECTIVES: To investigate the role of complement cascade induced damage and protection against it in acute arthritides compared to rheumatoid arthritis and other chronic joint derangements. METHODS: C3c, C9, and protectin (CD59) were examined by avidin-biotin-peroxidase complex staining. RESULTS: Marked deposits of C3c and C9 were found in synovial vasculature and intercellular matrix of the lining in rheumatoid arthritis and in acute arthritides (including bacterial, reactive, and osteoarthritis flare up). Furthermore, protectin was not visible in synovial lining cells and was relatively weakly expressed in stromal and endothelial cells in rheumatoid arthritis; also in acute arthritides protectin expression was weak. In contrast, C3c and C9 deposits were not found in chronic conditions associated with degenerative diseases (osteoarthritis and osteochondritis dissecans) or mechanical causes (patellar luxation and a ruptured meniscus), in which also the protectin expression was prominent in synovial lining, endothelial and some stromal cells. CONCLUSIONS: Activation of the complement in rheumatoid arthritis and in acute arthritides seems to be associated with a decreased protection of synovial cells against cellular effects and lysis mediated by membrane attack complex.
Images
PMCID: PMC1010340  PMID: 9014582
16.  Neutral endopeptidase (EC 3.4.24.11) in labial salivary glands in healthy controls and in patients with Sjögren's syndrome. 
Annals of the Rheumatic Diseases  1996;55(8):513-519.
OBJECTIVE: Neuropeptides from nerve fibres can cause neurogenic inflammation. The potency of these peptides in vitro has led to the hypothesis that enzyme degradative systems are operative in vivo to limit their action. To consider this question neutral endopeptidase (NEP) in labial salivary glands in patients with Sjögren's syndrome was studied. METHODS: Synthesis of NEP mRNA in situ in labial salivary glands was studied using the reverse transcriptase polymerase chain reaction (RT-PCR). Immunohistochemical staining was used to localise the NEP enzyme protein and its neuropeptide substrates and fluorophotometry to measure the corresponding enzyme activities in saliva. RESULTS: NEP was found in nerve fibres and in perivascular, periductal, and periacinar axon terminal varicosities. Double labelling of PGP 9.5 and NEP confirmed this neuronal localisation of NEP. Although some fibroblast-like cells and occasional intravascular neutrophils were NEP positive, NEP mRNA was not found in labial salivary glands. Patients with Sjögren's syndrome and healthy controls did not have nerves containing NEP or neuropeptides (vasoactive intestinal peptide, substance P, or calcitonin gene related peptide (CGRP)) in lymphocyte foci. Salivary NEP activity was not decreased in patients compared with controls. CONCLUSION: NEP in labial salivary glands is almost totally of neuronal origin and plays a part in proteolytic modulation of neuropeptides in salivary glands and saliva. These regulatory interactions seem to be altered in focal lymphocyte accumulations in Sjögren's syndrome.
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PMCID: PMC1010230  PMID: 8774178
17.  Assessment of the European classification criteria for Sjögren's syndrome in a series of clinically defined cases: results of a prospective multicentre study. The European Study Group on Diagnostic Criteria for Sjögren's Syndrome. 
Annals of the Rheumatic Diseases  1996;55(2):116-121.
OBJECTIVE: To assess the recently proposed preliminary criteria for the classification of Sjögren's syndrome (SS) in a multicentre European study of a new series of clinically defined cases. METHODS: The criteria included six items: I = ocular symptoms; II = oral symptoms; III = evidence of keratoconjunctivitis sicca; IV = focal sialoadenitis by minor salivary gland biopsy; V = instrumental evidence of salivary gland involvement; VI = presence of autoantibodies. Each centre was asked to provide five patients with primary SS, five with secondary SS, five with connective tissue diseases (CTD) but without SS, and five controls (patients with ocular or oral features that may simulate SS). The preliminary six item classification criteria set was applied to both the SS patients and the non-SS controls, and the performance of the criteria in terms of sensitivity and specificity was tested. RESULTS: The criteria set was tested on a total of 278 cases (157 SS patients and 121 non-SS controls) collected from 16 centres in 10 countries. At least four of the six items in the criteria set (limiting item VI to the presence of Ro(SS-A) or La(SS-B) antibodies) were present in 79 of 81 patients initially classified as having primary SS (sensitivity 97.5%), but in only seven of 121 non-SS controls (specificity 94.2%). When the presence of item I or II plus any two of items III-V of the criteria set was considered as indicative of secondary SS, 97.3% (71 of 73) of the patients initially defined as having this disorder and 91.8% (45 of 49) of the control patients with CTD without SS were correctly classified. CONCLUSION: This prospective study confirmed the high validity and reliability of the classification criteria for SS recently proposed by the European Community Study Group.
PMCID: PMC1010105  PMID: 8712861
18.  Transforming growth factor beta 2 in labial salivary glands in Sjögren's syndrome. 
Annals of the Rheumatic Diseases  1995;54(9):744-747.
OBJECTIVE--To compare the distribution and the amount of transforming growth factor beta (TGF beta) in labial salivary glands (LSG) in patients with Sjögren's syndrome (SS) and healthy controls. METHODS--LSG from SS patients (n = 10) and healthy controls (n = 6) were labelled with peroxidase-antiperoxidase staining for TGF beta 2, which was quantitated in image analysis using Video Interactive Display System software. RESULTS--In all LSGs in SS and healthy controls, TGF beta 2 was found in endothelial cells of the capillaries and in the capsular and stromal fibroblasts. In LSGs in SS, TGF beta 2 was also found in some lymphocytes in the inflammatory cell foci and in fibroblasts in fibrotic areas. The TGF beta 2 staining index (microns 2/mm2 tissue) was greater in SS than in control LSGs (3670 (SEM 430) v 2061 (176); p < 0.01), with no difference between the primary and secondary forms of SS (p > 0.05). CONCLUSION--The localisation and the level of expression of TGF beta 2 indicate its involvement in local tissue fibrosis, and may reflect attempts at immunosuppression.
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PMCID: PMC1009991  PMID: 7495347
19.  Collagenase in Sjögren's syndrome. 
Annals of the Rheumatic Diseases  1994;53(12):836-839.
OBJECTIVE--To study collagenase production in labial salivary glands in patients with Sjögren's syndrome (SS). METHODS--Collagenases were localised in labial salivary glands by immunohistochemistry. Collagenase activity against triple helical type I collagen monomers in stimulated saliva was measured using sodium dodecyl sulphate polyacrylamide gel electrophoresis and laser densitometry; tissue inhibitor metalloproteinase (TIMP) was measured by enzyme linked immunosorbent assay. RESULTS--Cells containing collagenase of matrix metalloproteinase (MMP)-1 type were more frequent and more intensely staining in SS than in healthy glands. Only SS saliva contained functional enzyme (11.7 (6.8) x 10(-6) IU/1). Cells containing MMP-8 type neutrophil collagenase were not found in situ, which was in accordance with sialochemical findings/doxycycline inhibition studies. TIMP was found in both SS and normal saliva. CONCLUSIONS--Fibroblast, but not neutrophil type, collagenase is synthesised, secreted, and subsequently activated, but is not inhibited by TIMP in labial salivary glands or saliva in SS. Collagenase may destroy glandular and salivary duct tissue and perturb factors influencing the morphogenetic extracellular matrix.
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PMCID: PMC1005486  PMID: 7864694
20.  Inhibitory effect of cephalothin on matrix metalloproteinase activity around loose hip prostheses. 
The inhibitory effects of drugs on matrix metalloproteinase (MMP) activity in tissues around sites of loose total hip arthroplasty (THA) prostheses were studied. For activity measurements, a DNP-S (dinitrophenyl-Pro-Gln-Gly-Ile-Ala-Gly-Gln-D-Arg) peptide degradation assay was performed by means of high-performance liquid chromatography. Neutral salt tissue extracts revealed significantly elevated MMP activity in THA samples compared with that in noninflamed synovial tissue from the knee joint. This elevation was markedly inhibited by cephalothin, but not by doxycycline, tetracycline, or gentamicin. These results indicate that cephalothin can inhibit MMP activity in reactive periprosthetic tissue and thus reduce, by a nonantimicrobial mechanism, the tissue destruction associated with the loosening of THA implants.
PMCID: PMC163093  PMID: 8787916
21.  Collagenases and the serine proteinases elastase and cathepsin G in steroid-induced Pneumocystis carinii pneumonia. 
Journal of Clinical Microbiology  1995;33(4):829-834.
Pneumocystis carinii pneumonia (PCP) is characterized by the formation of leaky alveoli and a foamy alveolar exudate. To induce PCP, male Wistar rats were immunosuppressed by oral dexamethasone treatment for 12 weeks, during which time all rats developed PCP. Bronchoalveolar lavage fluid (BALF) was analyzed at that time and at 1, 2, and 4 weeks after the cessation of dexamethasone treatment, during which time the rats were recovering from PCP and immunosuppression (and was compared with the BALF obtained from healthy control rats), for type IV collagenase, elastase, cathepsin G, and collagenase activities. Scores for 72-kDa (matrix metalloproteinase type [MMP-2]) and 92-kDa (MMP-9) type IV collagenase-gelatinase activities correlated with those for BALF macrophages (r = 0.58; P < 0.001) and neutrophils (r = 0.66; P < 0.001), respectively, suggesting that they may, in part, be derived from these cells. However, MMP-2 was constitutively expressed and may play a role in normal tissue remodeling. MMP-9 activity was highest in the group with PCP (1.8 +/- 0.37; P > 0.05), with a gradual decline (1.0 +/- 0.48 by week 4; P > 0.05) toward normal (0.67 +/- 0.42) during recovery, which suggests a role for it in tissue-destructive inflammatory events. In rats with PCP the endogenously active collagenase was present at high levels compared with those in healthy controls (2.6 +/- 0.69 versus 0.17 +/- 0.17, respectively; P < 0.01), but they returned to normal by week 4 of recovery (0.42 +/- 0.30; P > 0.05). Collagenase activity showed a correlation with cyst number (r = 0.57; P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
PMCID: PMC228050  PMID: 7790446
22.  Methylprednisolone acetate induced release of cartilage proteoglycans: determination by high performance liquid chromatography. 
Annals of the Rheumatic Diseases  1992;51(2):214-219.
A high performance liquid chromatography (HPLC) procedure suitable for the simultaneous determination of the molecular size and concentration of macromolecular hyaluronate and proteoglycans in synovial fluid has been developed. Irrigation of the equine tarsocrural joint with 20 ml physiological saline (PSS) caused a mild inflammation with an increase of proteoglycans in the synovial fluid over the baseline arthrocentesis control sample. Proteoglycan and hyaluronate in the synovial fluid did not interact to form hyaluronate-proteoglycan aggregates, but separated as distinct chromatographic peaks. This suggests that the cartilage derived proteoglycans in synovial fluid in the inflamed joint have been proteolytically cleaved from the non-covalent aggregates containing link protein and hyaluronate. Hyaluronidase digestion completely abolished the hyaluronate peak without affecting the proteoglycans. This seems to indicate that proteoglycan in synovial fluid is unable to interact with hyaluronate in synovial fluid to form cartilage type aggregates. Proteolytic degradation and the time dependent release into the synovial fluid of such digested proteoglycan also resulted from the intra-articular injection of methylprednisolone acetate into normal tarsocrural joints and joints irrigated with PSS. These proteoglycans were insensitive to hyaluronidase but may consist of a protein moiety with attached glycosaminoglycans, as suggested by their sensitivity to proteinase and keratanase/chondroitinase digestion. These observations with cartilage treated with methylprednisolone acetate and mildly stimulated articular cartilage are inconsistent with earlier work on osteoarthritic and rheumatoid articular cartilage and have interesting implications for the pathogenesis and for the therapeutic action of intraarticular corticosteroids. A rapid HPLC procedure applicable to unprocessed small volume samples of synovial fluid gives information simultaneously on hyaluronate and proteoglycan in synovial fluid which is not attainable with immunoradiometric or isotope tracer techniques. It therefore appears to be useful for the analysis of cartilage turnover and destruction in health and disease.
PMCID: PMC1005661  PMID: 1550406
23.  Systemic lupus erythematosus patient guide: influence on knowledge of the disease. 
Annals of the Rheumatic Diseases  1991;50(12):900-902.
The knowledge of patients with systemic lupus erythematosus about their disease before and after reading a patient guide was tested. The scores for incorrect answers decreased from 28 to 24% after reading the guide, showing that it increased the patients' knowledge of the disease. The patients with an academic background had the best scores before reading the guide, but they did not improve their scores as much as patients with lower educational qualifications. The differences between the groups studied were not significant in a one way analysis of variance. Forty seven questions about the psychology and coping mechanisms of the patients were factorized. These factors, together with data on the duration and severity of SLE and the age of the patient, were used in multiple linear regression analysis, but had no significant predictive value for an improvement in knowledge. The scores in psychological tests were the same before and after reading the guide. It is concluded that the patient guide for SLE increases knowledge of the disease, but does not affect the psychological response of the patient. The improvement in knowledge cannot be predicted on the basis of various psychological and clinical factors or the social background of the patient.
PMCID: PMC1004577  PMID: 1768155
24.  Reduction of matrix metalloproteinase 8-neutrophil collagenase levels during long-term doxycycline treatment of reactive arthritis. 
The aim of this work was to determine whether human polymorphonuclear neutrophilic interstitial collagenase (matrix metalloproteinase 8 [MMP-8]) levels are reduced during long-term doxycycline treatment in humans with reactive arthritis. Serum MMP-8 levels were reduced (mean +/- standard error of the mean, 678.9 +/- 185.6 versus 491.2 +/- 144.8 ng of MMP-8 per ml), but not statistically significantly. However, the reduction of salivary MMP-8 levels was statistically significant (3,729 +/- 1,905.3 versus 1,866 +/- 780.0 ng of MMP-8 per ml, P < 0.05). This study demonstrated that a 2-month regimen of doxycycline can reduce MMP-8 levels in serum and especially in body fluids (i.e., saliva) containing inflammatory exudates and thus may contribute to reduced tissue destruction.
PMCID: PMC284468  PMID: 8192476
25.  Mast cells in the labial salivary glands of patients with Sjögren's syndrome: a histochemical, immunohistochemical, and electron microscopical study. 
Annals of the Rheumatic Diseases  1990;49(9):685-689.
Mast cells in labial salivary glands obtained from patients with xerostomia with or without focal sialadenitis/Sjögren's syndrome were studied. There was no significant correlation between the intensity of local lymphocyte infiltration and the morphometrically analysed number of mast cells staining positive with toluidine blue. Histamine staining with heterologous 11C antiserum showed significantly fewer positive cells than staining with toluidine blue (mean (SD) 62 (10) v 138 (30)). This suggests heterogeneity of the mast cell population. Furthermore, there was a correlation between the focus score and the number of mast cells containing histamine. This suggests that the proliferation of mast cells containing histamine may be locally regulated by the immune inflammation, possibly through mediators from macrophages and fibroblasts. In contrast, the number of mast cells staining positive with toluidine blue could not be used as a marker of the degree of local inflammation. Although transmission electron microscopic analysis did not disclose signs of 'en masse' mast cell degranulation, mast cells may have a role in the local disease process.
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PMCID: PMC1004204  PMID: 2241284

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