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ID PMID Title PublicationDate abstract
16098234 Autoimmune hepatitis in India: profile of an uncommon disease. 2005 Aug 15 BACKGROUND: Autoimmune hepatitis (AIH) has been reported to show considerable geographical variation in frequency and clinical manifestations. It is considered a rare cause of liver disease in India. The present study was undertaken to determine the incidence, clinical, biochemical and histological profile of AIH in this part of the world. METHODS: Patients presenting with acute or chronic liver disease between January 1999 and June 2002 were evaluated prospectively. AIH was diagnosed using the international autoimmune hepatitis group criteria. Workup included clinical, biochemical, USG, viral markers, UGI endoscopy, AI markers (ANA, SMA, Anti-LKM, AMA, RF, p-ANCA) using indirect immunofluorescence and liver biopsy if possible. RESULTS: Forty-one of 2401 (1.70%) patients were diagnosed to have autoimmune liver disease. Out of these, 38 had autoimmune hepatitis and the rest 3 had primary biliary cirrhosis. The mean age of the patients of autoimmune hepatitis was 36.2 (15.9) years, 34 (89.4%) were females, and the duration of symptoms was 20.3 (20.5) months. Nineteen (50%) of them presented with chronic hepatitis, 13 (34.2%) as cirrhosis, 5 (13.1%) with acute hepatitis and 1 (2.6%) with cholestatic hepatitis. The presentations were jaundice in 21 (55.2%), pedal edema and hepatomegaly in 17 (44.7%), splenomegaly in 13 (34.2%), encephalopathy, abdominal pain in 9 (23.6%) and fever in 8 (21%). Twelve had esophageal varices and 3 had bled. Biochemical parameters were ALT 187 (360) U/L, AST 157 (193) U/L, ALP 246 (254) U/L, globulin 4.1 (1.6) g/dL, albumin 2.8 (0.9) g/dL, bilirubin 5.2 (7.4) mg/dL, prothrombin time 17 (7) sec and ESR 47 (17) sec. The autoimmune markers were SMA (24), ANA (15), both SMA and ANA (4), AMA (1), rheumatoid factor (2), pANCA (1), and Anti-LKM in none. Thirty (79%) patients had definite AIH and eight (21%) had probable AI hepatitis. Associated autoimmune diseases was seen in 15/38 (39.4%), diabetes 4, hypothyroidism 3, vitiligo 2, thrombocytopenia 2, rheumatoid arthritis 2, Sjogren's syndrome 1 and autoimmune polyglandular syndrome III in 1. Viral markers were positive in two patients, one presenting as acute hepatitis and HEV-IgM positive and another anti-HCV positive. CONCLUSION: In India, autoimmune hepatitis is uncommon and usually presents with chronic hepatitis or cirrhosis, acute hepatitis being less common. Age at presentation was earlier but clinical parameters and associated autoimmune diseases were similar to that reported from the west. Primary biliary cirrhosis is rare. Type II AIH was not observed.
17396337 [Dysthyroidism and connective pathology]. 2006 Dec AIM: The aim of the study is to evaluate the degree of the relationship between dysthyroidism and connective pathology, both autoimmune diseases, presenting, sometimes, an early common symptom: the Raynaud phenomenon. METHOD: We studied 30 patients subdivided as follows: 18 affected by mixed connective pathology, 6 by scleroderma, 2 by CREST, 4 by scleroderma and Sjogren syndrome. We focused our attention on the chronology and the duration of the diagnosis, correlated to the laboratory parameters and the hypothesis of the pathogenetic pathway. RESULTS: 36.6% were positive to both the pathologies. One of the 11 patients resulted positive to hyperthyroidism and mixed connective, 10 patients resulted positive to hyperthyroidism subdivided in: 6 affected by sclerodermia and by 4 sclerodermia and S. of Sjogren. All the patients were positive to ANA without correlation between those values and the microsomal or antithyreoglobulin antibodies: the last two were present in 33%. The laboratory parameters indicating the inflammatory state were in the normal range, a light hypercholesterolemia was found in all patients. CONCLUSION: There is a suggestive relationship between the connective pathology and dysthyroidism,therefore it can be useful to evaluate always the association of both pathologies for the future identification of the immunogenetic alteration factors, the evaluation of the composition and the turnover of the collagen, subdividing the patients in relation to the clinical and the laboratory parameters, follow up to middle and long term.
16941199 Central nervous system lymphoma in a patient with Sjogren's syndrome and autoimmune thyroi 2007 Aug We present a case of central nervous system (CNS) lymphoma in a patient with Sjogren's syndrome (SS) and autoimmune thyroiditis (Hashimoto's thyroiditis) overlap. A 60-year-old woman, who had the diagnosis of SS for 16 years, had been admitted for visual loss, fever, weight and appetite loss for 3 months. Cranial magnetic resonance imaging was in accordance with CNS lymphoma, and biopsy from right parietal region showed diffuse large B-cell lymphoma of the CNS. This is the first report of diffuse large B-cell lymphoma of the CNS in SS and autoimmune thyroiditis (Hashimoto's thyroiditis) overlap.
16749244 CLS meets the aquaporin family: clinical cases involving aquaporin systems. 2006 Spring Virtually all human cells incorporate aquaporins, or water channel proteins, into their cell membrane. Indeed, many cells produce several aquaporins, each adapted for a specific physiologic function. Thus, it is not surprising that aquaporin malfunctions are associated with numerous important clinical conditions. This article describes the clinical aspects of malfunctions in aquaporins or their regulation. Although water can diffuse across biological membranes (osmosis) without the aid of a transport system, researchers had predicted for decades that rapid reabsorption by renal tubule cells must be aided by a channel or pore. Yet, not until the 1990s were the first members of the aquaporin (AQP) family identified. Led by Dr. Peter Agre, recipient of the 2003 Nobel Prize in Chemistry, researchers have since amassed an astounding amount of information about AQPs and their function. For example, the flow rate of water through AQP1 is an extraordinary three billion water molecules per second per aquaporin channel, while a relative trickle of water crosses the hydrophobic lipid bilayer of cell membranes devoid of AQPs. Our understanding of renal physiology and pathophysiology has advanced greatly as we account for the subtle implications of various AQP systems. For example, nephrogenic diabetes insipidus (NDI), the inability to produce concentrated urine, can result from several different malfunctions in the hormonally controlled AQP2 system. The list of diseases known to involve AQPs now includes: early onset of cataracts, Sjogren's syndrome, cerebral and pulmonary edemas, cirrhotic liver development of ascites, and congestive heart failure (CHF).
16302679 Clinical and serological features of 35 patients with anti-Ki autoantibodies. 2005 The objective of this study was to analyse clinical and serological associations of anti-Ki antibodies. Thirty-five patients with anti-Ki antibodies, detected by CIE, selected from laboratory routine, were studied. All patients were affected by autoimmune diseases: SLE and pSS were the most frequent diagnoses. The cohort was constituted by 27 female and eight males. Main clinical features were skin involvement (60%), xerophtalmia (48.6%), Raynaud's phenomenon (43%), photosensitivity (34%), xerostomia (31.4%). CNS involvement was present in four (11.4%) and renal disease in seven cases (20%). ANA, anti-dsDNA and RF were detected in 100%, 60% and 34.5%. In SLE, anti-Ki was detected in 6% of cases, more frequently in males compared to other SLE patients without anti-Ki (P < 0.004). Nineteen anti-Ki positive patients affected by SLE showed more frequently malar rash and multiple autoantibody specificities compared to 16 anti-Ki positive patients with other diseases (P = 0.044 and P = 0.0003, respectively). Our study confirms a preferential occurrence of anti-Ki antibodies in patients with sicca and skin involvement. Malar rash and multiple ANA specificities were significantly associated with SLE compared to other diseases in our study. Anti-Ki were detected in 6% of patients with SLE with a significant prevalence in males.
15897744 Abundant IgG4-positive plasma cell infiltration characterizes chronic sclerosing sialadeni 2005 Jun Chronic sclerosing sialadenitis (CSS) is a cryptogenic tumor-like condition of the salivary gland(s). While immune-mediated processes are suspected in its pathogenesis, and CSS is occasionally reported to be associated with sclerosing pancreatitis, an IgG4-related disease, the exact immunopathologic processes of CSS remain speculative. In this study, we examined the clinicopathologic findings of CSS (12 cases) in comparison with sialolithiasis (8 cases) and Sjogren's syndrome (13 cases), and tried to clarify whether CSS is an IgG4-related disease or not. Submandibular gland(s) were affected in all cases of CSS. CSS cases could be divided into two types: 5 cases were associated with sclerosing lesions in extrasalivary glandular tissue (systemic type), while only salivary gland(s) were affected in the remaining 7 cases (localized type). In the former type, which showed male predominance, bilateral salivary glands were frequently affected, and eosinophilia and elevations of gamma-globulin and IgG in serum were frequently found. Histologically, all cases of CSS showed marked lymphoplasmacytic infiltration admixed with fibrosis and the destruction of glandular lobules. Obliterative phlebitis was found in the affected salivary glands in all cases of CSS. Immunohistochemically, the proportion of IgG4/IgG-positive plasma cells was more than 45% in CSS, while it was less than 5% in controls. The resemblance of the clinicopathologic features of CSS with those of sclerosing pancreatitis suggests the participation of a similar immunopathologic process with IgG4 disturbance in CSS. The abundance of IgG4-positive plasma cells in the lesions would be useful for distinguishing CSS from other forms of sialadenitis.
15804706 Anti-Ro/SSA and La/SSB antibodies. 2005 Feb The Ro/La system is considered as an heterogeneous antigenic complex, constituted by three different proteins (52 kDa Ro, 60 kDa Ro and La) and four small RNAs particles. Anti-Ro/SSA are the most prevalent specificity among many autoimmune diseases, such as systemic lupus erythematosus (SLE), SS/SLE overlap syndrome, subacute cutaneous LE (SCLE), neonatal lupus and primary biliary cirrhosis. In contrast, anti-La/SSB is more associated with Sjögren's syndrome (SS). The differences between 52 kDa, 60 kDa Ro and La could explain why different assays did not show equivalent performance in anti-Ro and anti-La autoantibodies detection. The RNA precipitation assay had the highest sensitivity and specificity, usually considered as the reference methods. CIE is considered the most reliable to detect anti-Ro/SSA antibodies in routine practice, performing better than immunoblotting (IB) and some ELISAs. It shows a high sensitivity (89%) and specificity (100%). ELISA is generally considered a safe, rapid, sensitive and specific tecnique. Therefore, its high sensitivity often corresponds to a very low clinical specificity and the assay can give false positive results. Therefore, it is very important to search anti-Ro and anti-La only in selected patients, using the assay with high specificity and good predictive value, in order to have clinically significant and true positive results.
15797493 Sjogren's syndrome: concomitant H. pylori infection and possible correlation with clinical 2005 Mar OBJECTIVE: To identify whether or not there are clinical markers that correlate with Helicobacter pylori (H. pylori) infection in patients with Sjogren's syndrome (SS) and its implication to handling this group of patients. METHODS: Four groups of patients were studied. Group 1, 36 patients with primary SS; group 2, 31 patients with secondary SS; group 3, 46 patients with various connective tissue diseases not suffering from sicca symptoms, and group 4, 64 healthy controls. Clinical assessment was done and a score for disease manifestation was given for every SS patient. Serum IgG and IgM antibodies to H. pylori were assessed by ELISA. RESULTS: The prevalence and mean titer of H. pylori infection in patients with SS in group 1 (80.6%) and 2 (71%) were significantly higher than in group 3 (60.9%) and 4 (56.3%) (P < 0.01). There was significant correlation between H. pylori infection and age, disease duration, global score for disease status and C-reactive protein (CRP) in SS patients. On the other hand, there was no significant correlation with body mass index, and erythrocyte sedimentation rate (ESR). CONCLUSION: Patients with SS are more prone to have H. pylori infection in comparison to other connective tissue diseases. Serum antibody titer to H. pylori correlated with index for clinical disease manifestations, age, disease duration and CRP. Assessment of H. pylori infection in older patients suffering from active SS for a relatively long duration is recommended, especially those suffering form primary SS for more than 3 years.
16797160 Autoantibodies from Sjögren's syndrome induce activation of both the intrinsic and extrin 2006 Aug Sjögren's syndrome (SS) is an autoimmune rheumatic disease that targets salivary and lachrymal glands, characterized by a high concentration of serum autoantibodies directed against nuclear and cytoplasmic antigens. It is known that autoantibodies can enter viable cells and this phenomenon has functional consequences including activation of apoptotic process. The objective of this work was to explore whether autoantibodies contained in IgG purified from Sjögren sera trigger apoptotic process in an experimental model represented by the human salivary gland cell line A-253. To define if the intrinsic or extrinsic pathways are activated, we examined which caspases are critical for inducing cell death. The results have demonstrated that morphological changes and DNA laddering, consistent with apoptotic cell death, occurred in A-253 cells treated with IgG from Sjögren sera. Sjögren IgG induced cleavage and activation of the effector caspase-3 and degradation of the caspase-3 substrate poly(ADP-ribose)polymerase. Both the intrinsic and extrinsic apoptotic pathways were activated, since both caspase-8 and caspase-9 cleavages occurred. In conclusion, autoantibodies contained in IgG purified from Sjögren sera mediate apoptosis of the A-253 cell line in a caspase-dependent manner.
15744116 [Neonatal lupus syndrome]. 2005 Feb Neonatal lupus syndrome is a passively acquired autoimmune syndrome in which pathogenic autoantibodies (anti-SSA/Ro, anti-SSB/La, and both, or rarely anti-U(1)RNP antibodies) are transmitted from a mother to her fetus through the placenta. The major clinical manifestations in the infants are cardiac (congenital heart block), dermatologic (skin lesion), hepatic (elevated hepatic enzymes), and hematologic (cytopenia). Congenital complete heart block (CCHB) is irreversible, while noncardiac manifestations are transient, resolving by one-year-old of age without specific treatments. Two prospective studies show that the prevalence of CCHB in children from a woman previously known to have anti-SSA/Ro antibodies is approximately 2%. However, when the previous pregnancy is complicated by CCHB and skin lesion, the recurrence rates of these symptoms go much higher to 10.5% and 26%, respectively, in the subsequent pregnancy.
16572451 Antimuscarinic antibodies in primary Sjögren's syndrome reversibly inhibit the mechanism 2006 Apr OBJECTIVE: Sjögren's syndrome (SS) is an autoimmune condition affecting salivary glands, for which a clearly defined pathogenic autoantibody has yet to be identified. Autoantibodies that bind to the muscarinic M3 receptors (M3R), which regulate fluid secretion in salivary glands, have been proposed in this context. However, there are no previous data that directly show antisecretory activity. This study was undertaken to investigate and characterize the antisecretory activity of anti-M3R. METHODS: Microfluorimetric Ca2+ imaging and patch clamp electrophysiologic techniques were used to measure the secretagogue-evoked increase in [Ca2+]i and consequent activation of Ca2+-dependent ion channels in individual mouse and human submandibular acinar cells. Together, these techniques form a sensitive bioassay that was used to determine whether IgG isolated from patients with primary SS and from control subjects has antisecretory activity. RESULTS: IgG (2 mg/ml) from patients with primary SS reduced the carbachol-evoked increase in [Ca2+]i in both mouse and human acinar cells by approximately 50%. IgG from control subjects had no effect on the Ca2+ signal. Furthermore, the inhibitory action of primary SS patient IgG on the Ca2+ signal was acutely reversible. We repeated our observations using rabbit serum containing antibodies raised against the second extracellular loop of M3R and found an identical pattern of acutely reversible inhibition. Anti-M3R-positive serum had no effect on Ca2+-dependent ion channel activation evoked by the direct intracellular infusion of inositol 1,4,5-triphosphate. CONCLUSION: These observations show for the first time that IgG from patients with primary SS contains autoantibodies capable of damaging saliva production and contributing to xerostomia. The unusual but not unprecedented acute reversibility of the effects of anti-M3 autoantibodies is the subject of further research.
17474179 [Graft-versus-host disease as the cause of symptoms mimicking Sjögren's syndrome]. 2006 A case of chronic graft-versus-host disease (chronic GvHD) mimicking symptoms associated with idiopathic Sjögren's syndrome is presented. Hypotheses on the pathophysiological origin of clinical syndromes associated with graft-versus-host disease are discussed.
16507129 No evidence for an association between the -871 T/C promoter polymorphism in the B-cell-ac 2006 Polyclonal B cell activation might be related to pathogenic over-expression of B-cell-activating factor (BAFF) in primary Sjögren's syndrome (pSS) and other autoimmune diseases. We therefore investigated whether BAFF over-expression in pSS could be a primary, genetically determined event that leads to the disease. The complete BAFF gene was sequenced in Caucasian pSS patients and control individuals. The only single nucleotide polymorphism frequently observed, namely -871 T/C in the promoter region, was then genotyped in 162 French patients with pSS and 90 French control individuals. No significant differences in allele (T allele frequency: 49.7% in patients with pSS versus 50% in controls; P = 0.94) and genotype frequencies of BAFF polymorphism were detected between pSS patients and control individuals. BAFF gene polymorphism was not associated with a specific pattern of antibody secretion either. T allele carriers had significantly increased BAFF protein serum levels (mean values of 8.6 and 5.7 ng/ml in patients with TT and TC genotypes, respectively, versus 3.3 ng/ml in patients with CC genotype; P = 0.01), although no correlation was observed between BAFF polymorphism and mRNA level. In conclusion, BAFF gene polymorphism is neither involved in genetic predisposition to pSS nor associated with a specific pattern of antibody production.
17013432 [Metabolic syndrome in inflammatory rheumatic diseases]. 2006 Jul Toward the end of the last century a better knowledge of cardiovascular (CV) risk factors and their associations led investigators to propose the existence of a unique pathophysiological condition called "metabolic" or "insulin resistance syndrome". Among all, insulin-resistance and compensatory hyperinsulinemia are considered its most important treatment targets. Different definitions have been provided by World Health Organization (WHO) and by The Third Report of The National Cholesterol Education Program's Adult Treatment Panel (NCEP-ATP III). In particular, abdominal obesity, hypertension, low HDL cholesterol and hyperglicemia are the most common items used for its definition. The presence of MetS is effective in predicting the future risk of diabetes and coronaropathies. The evidence of a higher CV risk rate among different rheumatic inflammatory diseases has recently been associated with high prevalence of MetS in some cases. Rheumatoid or psoriatic arthritis have the large series among arthritis, whereas systemic lupus erythematosus among connective tissue disorders. This review analyses all most important studies about the evidence of MetS in rheumatic patients and the main clinical and prognostic significance of this relation.
16396700 Prevalence of musculoskeletal conditions in an Italian population sample: results of a reg 2005 Nov OBJECTIVE: The objective of the MAPPING study was to estimate the prevalence of musculoskeletal conditions in an Italian population sample. METHODS: Questionnaires were sent to a random sample of 3664 individuals aged 18 years and over, stratified for age and gender, selected from the practice lists of 16 general practices. Trained rheumatologists carried out structured visits in which subjects were asked about musculoskeletal symptoms and socio-demographic characteristics, and underwent a standardized physical examination. Cases were defined by previously validated criteria. RESULTS: A total of 2155 subjects participated in the study (response rate 58.8%). The overall prevalence of musculoskeletal conditions in the general adult population was 26.7% (95% CI 25.4-28.5), being significantly higher among women than men (p < 0.0001). Disease prevalence increased significantly with age (p < 0.0001). The most common disease group was symptomatic peripheral osteoarthritis (SPOA), with a prevalence of 8.95% (95% CI 6.81-10.7), followed by soft tissue disorders--STD (8.81%; 95% CI 7.16-10.29), low back pain--LBP (5.91%; 95% CI 4.89-6.89), and inflammatory rheumatic disease--IRD (3.06%; 95% CI 2.38-3.93). The estimated rates of disease prevalence were as follows: rheumatoid arthritis: 0.46% (95% CI 0.33-0.59); psoriatic arthritis: 0.42% (95% CI 0.31-0.61); ankylosing spondylitis: 0.37% (95% CI 0.23-0.49); polymyalgia rheumatica: 0.37% (95% CI 0.29-0.44); undifferentiated connective tissue disease: 0.14% (95% CI 0.09-0.21); crystal arthropathies, including gout 0.46% (95% CI 0.34-0.57) and chondrocalcinosis: 0.42% (95% CI 0.33-0.58); symptomatic knee osteoarthritis (OA): 5.39% (95% CI 3.41-7.99); hip-OA: 1.61% (95% CI 1.39-1.87); hand-OA: 1.95 (95% CI 1.22-2.48); fibromyalgia: 2.22% (95% CI 1.36-3.19); shoulder tendinitis/adhesive capsulitis: 3.06% (95% CI 2.11-4.09); carpal tunnel syndrome: 1.90% (95% CI 1.06-2.29), localized regional pain syndromes of the neck: 0.88% (95% CI 0.561.29), and lateral epicondylitis 0.74% (95% CI 0.47-1.33). CONCLUSIONS: The MAPPING study indicates that musculoskeletal conditions are common in the general adult population of Italy. These data are useful in planning the provision of healthcare.
16084221 Role of the growth hormone/insulin-like growth factor-1 paracrine axis in rheumatic diseas 2005 Aug OBJECTIVES: Hypothalamic-pituitary axis abnormalities have been associated with systemic disturbances in several rheumatic diseases. Longitudinal analysis of erythrocyte, serum, urinary and synovial fluid growth hormone (GH), insulin-like growth factor-1 (IGF-1), and somatostatin levels could provide important surrogate measures of disease activity in rheumatic diseases. METHODS: The authors reviewed the population and longitudinal studies literature on GH, IGF-1, and somatostatin levels in rheumatic disorders using the PubMed and Medlines databases from the National Library of Medicine. In addition to the literature search, primary data were analyzed for basal somatostatin levels in patients with hand, knee, and spine osteoarthritis (OA) as well as primary and secondary hip OA. RESULTS: A review of the literature supports the view that hypothalamic-pituitary axis dysfunction accompanies clinical symptoms in many rheumatic diseases. In studies from our laboratory, serum GH levels were elevated in patients with OA, rheumatoid arthritis (RA), fibromyalgia, and diffuse idiopathic skeletal hyperostosis but not in patients with gout, pseudogout, or systemic lupus erythematosus. In OA and RA, synovial fluid GH levels exceeded serum GH levels. However, the literature remains controversial regarding the significance of changes in IGF-1 levels in rheumatic disorders. Many studies support an inverse relationship between age and IGF-1. Elevated serum GH levels in various rheumatic diseases were not coupled to changes in serum IGF-1 in diffuse idiopathic skeletal hyperostosis, RA, and fibromyalgia. In particular, serum IGF-1 levels in OA were shown to be lower or no different compared with age-matched normal subjects. Further, in OA, impaired articular chondrocyte response to IGF-1 was attributed, in part, to low synovial fluid IGF-1 that further compromised IGF-1 chondrocyte responses as a result of increased levels of synovial fluid IGF-1 binding proteins. Of note, serum somatostatin levels and "specific" somatostatin receptor levels were often lower in RA and systemic lupus erythematosus, but basal serum somatostatin levels were generally not altered in OA. CONCLUSIONS: The results of these analyses support the view that some rheumatic diseases such as OA and diffuse idiopathic skeletal hyperostosis, heretofore considered to be purely focal and degenerative, could be reclassified as systemic metabolic disturbances. We propose that serum GH, IGF-1, and somatostatin levels be monitored on a longitudinal basis during the course of medical therapy of rheumatic diseases to determine the extent to which changes in clinical symptoms (exemplified by reduced pain and inflammation and improved range of joint motion) are accompanied by changes in the basal concentration of these hypothalamic/pituitary-related hormones.
15934075 Elevated levels of soluble fractalkine in active systemic lupus erythematosus: potential i 2005 Jun OBJECTIVE: To determine levels of the soluble form of the chemokine fractalkine (sFkn) and its receptor, CX(3)CR1, in patients with systemic lupus erythematosus (SLE) with neuropsychiatric involvement (NPSLE) and in SLE patients without neuropsychiatric involvement, and to assess their relationship with disease activity and organ damage. METHODS: Levels of sFkn in serum and cerebrospinal fluid (CSF) were measured by enzyme-linked immunosorbent assay. Expression of Fkn and CX(3)CR1 was quantified using real-time polymerase chain reaction. Surface expression of CX(3)CR1 on peripheral blood mononuclear cells (PBMCs) was determined by flow cytometry. Disease activity and organ damage were assessed using the SLE Disease Activity Index (SLEDAI) and the Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) Damage Index, respectively. RESULTS: Serum sFkn levels were significantly higher in patients with SLE than in patients with rheumatoid arthritis (RA) or healthy controls. In addition, significant correlations between serum sFkn levels and the SLEDAI, the SLICC/ACR Damage Index, anti-double-stranded DNA and anti-Sm antibody titers, immune complex levels (C1q), and serum complement levels (CH50) were observed. Expression of CX(3)CR1 was significantly greater in PBMCs from patients with active SLE than in those from RA patients or healthy controls. Levels of sFkn were also significantly higher in CSF from untreated patients with newly diagnosed NPSLE than in SLE patients without neuropsychiatric involvement; treatment reduced both serum and CSF levels of sFkn in patients with SLE. CONCLUSION: Soluble Fkn and CX(3)CR1 may play key roles in the pathogenesis of SLE, including the neuropsychiatric involvement. Soluble Fkn is also a serologic marker of disease activity and organ damage in patients with SLE, and its measurement in CSF may be useful for the diagnosis of NPSLE and followup of patients with NPSLE.
16427328 Peroxynitrite-modified collagen-II induces p38/ERK and NF-kappaB-dependent synthesis of pr 2006 May OBJECTIVE: Peroxynitrite (ONOO(-)) is formed in the inflamed and degenerating human joint. Peroxynitrite-modified collagen-II (PMC-II) was recently discovered in the serum of patients with osteoarthritis (OA) and rheumatoid arthritis (RA). Therefore we investigated the cellular effects of PMC-II on human mesenchymal progenitor cells (MPCs) as a model of cartilage and cartilage repair cells in the inflamed and degenerating joint. DESIGN: MPCs were isolated from the trabecular bone of patients undergoing reconstructive surgery and were differentiated into a chondrogenic lineage. Cells were exposed to PMC-II and levels of the proinflammatory mediators nitric oxide (*NO) and prostaglandin E(2) (PGE(2)) measured. Levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), phosphorylated mitogen activated protein kinases (MAPKs) and nuclear factor kappa B (NF-kappaB) activation were measured by enzyme linked immunosorbent assay (ELISA) together with specific MAPK and NF-kappaB inhibitors. RESULTS: PMC-II induced ()NO and PGE(2) synthesis through upregulation of iNOS and COX-2 proteins. PMC-II also lead to the phosphorylation of MAPKs, extracellularly regulated kinase 1/2 (ERK1/2) and p38 [but not c-Jun NH(2)-terminal kinase (JNK1/2)] and the activation of proinflammatory transcription factor NF-kappaB. Inhibitors of p38, ERK1/2 and NF-kappaB prevented PMC-II induced ()NO and PGE(2) synthesis, iNOS and COX-2 protein expression and NF-kappaB activation. CONCLUSION: iNOS, COX-2, NF-kappaB and MAPK are known to be activated in the joints of patients with OA and RA. PMC-II induced iNOS and COX-2 synthesis through p38, ERK1/2 and NF-kappaB dependent pathways suggesting a previously unidentified pathway for the synthesis of the proinflammatory mediators, ()NO and PGE(2), further suggesting that inhibitors of these pathways may be therapeutic in the inflamed and degenerating human joint.
15751078 Glucocorticoids inhibit osteocalcin transcription in osteoblasts by suppressing Egr2/Krox2 2005 Mar OBJECTIVE: Glucocorticoids are widely used for the management of rheumatoid arthritis. Osteoporosis is a major side effect of glucocorticoid therapy and is attributable to inhibition of bone formation. We developed an osteoblast culture system in which glucocorticoids strongly inhibit development of the osteoblast phenotype, including expression of the bone-specific osteocalcin (OC) gene. Using this gene as a model, the goal of this study was to discover glucocorticoid-sensitive transcriptional mechanisms in osteoblasts. METHODS: Dexamethasone (DEX; 1 microM) was administered to murine MC3T3-E1 osteoblastic cultures under conditions that inhibit mineralized extracellular matrix formation and OC messenger RNA levels by >10-fold. Because standard (short-term) transient transfection assays with OC promoter-reporter constructs did not recapitulate the strong DEX-mediated repression, mapping of OC negative glucocorticoid response elements (GREs) was performed initially by stable transfection and then with long-term transient transfection assays. Transcription factor binding to the OC negative GRE was studied by electrophoretic mobility shift assays. RESULTS: Several-fold repression of OC-luciferase constructs was recapitulated in stable and long-term transient transfection assays, in which the transfected cells were allowed to progress to a sufficiently advanced developmental stage. Analysis of a 5' promoter deletion series mapped an OC negative GRE to a 15-bp G/C-rich motif (-161/-147) located just upstream of the binding site for the osteoblast master transcription factor Runx2. Oligonucleotides encompassing this element and MC3T3-E1 cell extracts formed a protein-DNA complex that contained an Egr/Krox family member(s). Complex formation was competed by either an oligonucleotide containing 2 consensus Egr motifs or by anti-Egr2/Krox20 antibodies. Three copies of this Krox-binding element conferred 20-fold transcriptional activation on the 147-bp basal OC promoter in osteoblasts, and the enhancer activity was inhibited by DEX. Enhancer activity was not observed in 10T1/2 fibroblasts unless these cells were cotransfected with Runx2. CONCLUSION: An Egr2/Krox20-binding site located immediately upstream of the Runx2 site of the mouse OC promoter was identified as an enhancer in osteoblasts, whose activity is repressed by glucocorticoids. Sequence similarity suggests that such a mechanism is likely operative in both murine and human cells. Because glucocorticoids inhibit Egr2/Krox20 expression in osteoblasts, and because trabecular bone formation is arrested in Egr2/Krox20-knockout mice, the inhibition of Egr2/Krox20 activity likely contributes to glucocorticoid-induced osteoporosis.
16827380 [Early clinical outcome of total knee arthroplasty for flexion-contracture deformity knees 2006 Jun OBJECTIVE: To make a retrospective analysis on an early clinical outcome of total knee arthroplasty (TKA) for the knees with different degrees of flexion-contracture deformities. METHODS: Ninety-seven knees of 65 patients undergoing total knee arthroplasty with the Scorpion posterior-stabilized knee prosthesis from January 2000 to December 2003 were reviewed, including 51 osteoarthritis patients (74 knees) and 14 rheumatoid arthritis patients (23 knees). Thirty-three patients underwent unilateral TKA, and 32 patients underwent bilateral TKA. The average range of motion (ROM) before operation was 82.8 degrees (range, 5-140 degrees). According to the preoperative flexion-contracture degrees of the knees, these patients were divided into 2 groups, group A and group B. Group A consisted of the patients with flexion-contracture less than 20 degrees (range, 0-15 degrees), and group B consisted of the patients with flexion-contracture not less than 20 degrees (range, 20-60 degrees). In group A, the average flexion-contracture degree, ROM, KSS (knee society score), and function score were 10.7 +/- 8.0 degrees, 104.6 +/- 20.0 degrees, 29.1 +/- 18.0, and 32.6 +/- 20.7, respectively. But the corresponding data were much worse in group B than in group A, which were 28.2 +/- 7.8 degrees, 60.8 +/- 26.6 degrees, 12.1 +/- 13.2, and 26.8 +/- 18.1. All the operations were primary total knee arthroplasty, and they were performed by the same group of surgeons. The time for the prosthesis installed lasted for 25.6 minutes, and the average tourniquet time was 34.7 minutes. Three or four days after operation, the patients began the continuous passive motion (CPM) and active functional exercise of the knee. RESULTS: The patients were followed up for an average of 2 years and 7 months(range, 8 mon-3.5 yr). During the follow-up period, the average flexion-contracture degree, ROM, KSS, and function score in group A were 0.4 +/- 2.1 degrees, 108.6 +/- 19.0 degrees, 82.1 +/- 13.8, and 72.3 +/- 29.1, respectively; and the corresponding data in group B were 1.3 +/- 3.2 degrees, 98.6 +/- 16.40, 75.9 +/- 8.2, and 81.4 +/- 26.9, respectively. There was no significant difference between the 2 groups. No revision or deep infection was found. CONCLUSION: The curative effect is mainly determined by the surgeon's good operational skills, rich clinical experience, and familiarity with the prosthesis, and it is not influenced by severity of the knee flexion-contracture deformity. The knee ROM after TKA, which has a "toward middle ROM" phenomenon, is influenced by many clinical factors. It is very important for the patient to perform a functional exercise of the knee as early as possible after operation.