Browse

Search for: rheumatoid arthritis    methotrexate    autoimmune disease    biomarker    gene expression    GWAS    HLA genes    non-HLA genes   

ID PMID Title PublicationDate abstract
9221760 Myelin basic protein-specific T helper 2 (Th2) cells cause experimental autoimmune encepha 1997 Jul 21 Chronic inflammatory autoimmune diseases such as multiple sclerosis, diabetes, and rheumatoid arthritis are caused by CD4(+) Th1 cells. Because Th2 cells antagonize Th1 cell functions in several ways, it is believed that immune deviation towards Th2 can prevent or cure autoimmune diseases. Experimental autoimmune encephalomyelitis (EAE) is a demyelinating disease used as a model for multiple sclerosis. Using an adoptive transfer system we assessed the role of Th1 and Th2 cells in EAE. In vitro generated Th1 and Th2 cells from myelin basic protein (MBP)-specific TCR transgenic mice were transferred into normal and immunodeficient mice. Th1 cells caused EAE in all recipients after a brief preclinical phase. Surprisingly, Th2 cells also caused EAE in RAG-1 KO mice and in alphabeta T cell-deficient mice, albeit after a longer preclinical phase. Normal or gammadelta T cell-deficient mice were resistant to EAE induced by Th2 cells. The histopathological features of this disease resembled those of an allergic process. In addition, disease induction by Th1 cells was not altered by coadmininstration of Th2 cells in any of the recipients. These findings indicate that MBP-specific Th2 cells have the potential to induce EAE and that the disease induced by previously activated Th1 cells cannot be prevented by normal lymphocytes nor by previously activated Th2 cells.
18031104 Interleukin-11. 1997 Dec Interleukin-11 (IL-11) is a cytokine which interacts with a variety of haemopoietic and non-haemopoietic cell types. Recombinant human IL-11 (rhIL-11; oprelvekin) is produced in Escherichia coli and differs from the naturally occurring protein only in the absence of the amino-terminal proline residue. In synergy with other factors, rhIL-11 stimulates the growth of myeloid, erythroid, and megakaryocyte progenitor cells in vitro. In vivo, rhIL-11 is active in mice, rats, dogs, guinea pigs, hamsters and non-human primates, where the principal activity measured was stimulation of megakaryocytopoiesis and thrombopoiesis. rhIL-11 has shown benefit in 2 clinical trials by significantly reducing severe chemotherapy-induced thrombocytopenia. In addition to its thrombopoietic activity, rhIL-11 has also shown activity in models of acute gastrointestinal mucosal damage. rhIL-11 enhanced survival in mice following cytoablative therapy and in a hamster model of chemotherapy-induced oral mucositis, where treatment with rhIL-11 was associated with decreased mucosal damage, accelerated healing and reduced numbers of deaths. rhIL-11 is currently in clinical trials for the treatment of chemotherapy-induced mucositis. In rat models of acute colonic injury and inflammatory bowel disease, rhIL-11 treatment reduced intestinal mucosal damage and alleviated clinical signs. rhIL-11 has direct effects on activated macrophages to reduce the production of pro-inflammatory mediators. In animal models of endotoxaemia, rhIL-11 treatment reduced serum levels of pro-inflammatory cytokines and blocked hypotension. rhIL-11 increased survival in models of Gram-negative sepsis and toxic shock. Based on these studies, rhIL-11 is currently in clinical trials for treatment of Crohn's disease. Other inflammatory conditions are being further evaluated. Mechanistically, rhIL-11 functions at many levels to control inflammation, ameliorate tissue damage and maintain haemostasis in the face of trauma or infection. rhIL-11 has direct effects on hepatocytes, inducing the production of acute phase reactant proteins, haem oxygenase and tissue inhibitor of metalloproteinase-1 (TIMP-1). TIMP-1 expression can also be induced in synoviocytes and chondrocytes by treatment with rhIL-11. rhIL-11 administration has been associated with increased plasma levels of von Willebrand factor and fibrinogen. rhIL-11 treatment potentially offers multiple benefits for cancer chemotherapy patients, such as prevention of thrombocytopenia, gastrointestinal epithelial protection and subsequent reduction of mucositis, and amelioration of inflammatory complications. In addition, rhIL-11 is being evaluated further in the treatment of inflammatory disorders such as inflammatory bowel disease, rheumatoid arthritis and sepsis.
11600736 Low levels of nitric oxide (NO) in systemic sclerosis: inducible NO synthase production is 2001 Oct OBJECTIVE: To investigate nitric oxide (NO) production and inducible NO synthase expression by cultured peripheral blood mononuclear cells (PBMC) in patients with systemic sclerosis (SSc). METHODS: Eighteen patients with SSc were compared with two control groups: 16 patients with rheumatoid arthritis (RA) and 23 patients with mechanical sciatica. Nitrate was determined by fluorimetry in plasma and by spectrophotometry in supernatants. Inducible NO synthase (iNOS) was detected in cultured PBMC by immunofluorescence, immunoblotting and flow cytometry with or without treatment of the cells with interleukin (IL) 1beta+ tumour necrosis factor alpha (TNF-alpha), IL-4 or interferon gamma (IFN-gamma) from day 1 to day 5. RESULTS: NO metabolite concentrations were lower in SSc patients (mean+/-s.e.m. 34.3+/-2.63 micromol/l) than in RA (48.3+/-2.82 micromol/l; P<0.02) and sciatica (43.3+/-5.24 micromol/l; P<0.03) patients. iNOS was detected in cultured monocytes in all three groups but induction occurred on day 1 in RA, day 2 in sciatica and only on day 3 in SSc, whatever the stimulus. CONCLUSIONS: The concentrations of NO metabolites are decreased in SSc patients and the metabolism of these compounds in PBMC is altered. Low levels of NO, a vasodilator, may be involved in vasospasm, which is critical in SSc. This may have therapeutic implications.
11332589 A study report of 174 units of placental umbilical cord whole blood transfusion in 62 pati 2001 BACKGROUND: In the animal kingdom, even herbivorous animals swallow the placenta after the birth of the baby (for example, the cow). In the human system, we do not know about the proper utilization of the placenta and membranes although there are suggestions regarding this on the basis of research on placental umbilical cord blood stem cells as an alternative to bone marrow transplantation. In this present series of placental umbilical cord whole blood transfusions, we wanted to examine the safety aspect of other components of cord blood transfusion, e.g., fetal RBC, growth factors and cytokine filled plasma, etc., in different indications of blood transfusion, from the pediatric to the geriatric age group, in malignant and non-malignant disorders affecting our patients. METHODS: One hundred and seventy-four units of umbilical cord whole blood were collected aseptically from the umbilical vein after caesarean section in standard pediatric blood transfusion bags, after the removal of the baby from the operative field and after confirming the stable condition of the mother. The volume of cord blood varied from 50 ml to 140 ml with a mean of 86 ml+/-16 ml. RESULTS AND ANALYSIS: The cord blood was transfused immediately (within three days of collection) to 62 patients from nine years to 78 years of age, of whom 32 were suffering from varying stages and grades of malignancy from 1 April 1999 till date i.e., 11 Aug 2000, after obtaining adequate consent and following the precautions of standard blood transfusion protocol. The remaining 30 patients included patients suffering from thalassemia major, aplastic anemia, systemic lupus erythematosus, chronic renal failure, rheumatoid arthritis, ankylosing spondylitis and a geriatric group of patients with benign prostatic hypertrophy. All have tolerated the procedure without any immunological or non-immunological reactions. CONCLUSION: On the basis of our experience with 174 units of placental umbilical cord whole blood transfusion in malignant and non-malignant conditions (within three days of collection and preservation at 1-6 degrees C in a refrigerator), we are of the opinion that this is a safe transfusion protocol which takes advantage of the safety of nature's finest biological sieve, i.e., the placenta, as an alternative to adult whole blood transfusion. It also has the advantage of a higher oxygen carrying capacity of fetal hemoglobin in addition to many growth factors and other cytokine filled cord blood plasma along with its hypoantigenicity.
11265258 Antigenic specificity of anti-neutrophil cytoplasmic antibody. 2001 Jan PURPOSE: To determine the antigens recognized by sera containing classic anti-neutrophil cytoplasmic antibodies (c-ANCAs) and perinuclear anti-neutrophil cytoplasmic antibodies (p-ANCAs). METHODS: A total of 160 serum samples (all from a reference laboratory) that were originally collected from different clinics for ANCA tests were examined for c-ANCA and p-ANCA by indirect immunofluorescence (IIF). All positive sera were further tested for reactivity to proteinase 3 (PR3), myeloperoxidase (MPO), lactoferrin (LF), and lysozyme (LZ) by enzyme-linked immunosorbent assay (ELISA). In addition, sera from 110 patients with systemic lupus erythematosus (SLE), 51 patients with rheumatoid arthritis (RA), and 40 healthy subjects were also tested for reactivity to these antigens. RESULTS: HF detected ANCA in 81 (51%) of the 160 clinical serum samples. Of these 81 serum samples, 21 (26%) contained c-ANCA and 60 (74%) contained p-ANCA. P-ANCA was more commonly found in antinuclear antibody (ANA)-positive sera than in ANA-negative sera (p < 0.01). Of the 21 serum samples positive for c-ANCA, 12 (57%) reacted to PR3, four (19%) to LF, four (19%) to LZ, and three (14%) to MPO on ELISA. By contrast, of the 60 sera positive for p-ANCA, 15 (25%) reacted to MPO, 13 (22%) to PR3, eight (13%) to LF, and four (7%) to LZ. The prevalence of ANCA specificities in serum samples from SLE patients were as follows: anti-PR3, 0%; anti-MPO, 1%; anti-LF, 27%; and anti-LZ, 29%. The prevalence of ANCA specificities in serum samples from RA patients were as follows: anti-PR3, 6%; anti-MPO, 2%; anti-LF, 8%; anti-LZ, 4%. CONCLUSION: Sera positive for c-ANCA and p-ANCA reacted to diverse cytoplasmic antigens from neutrophils. P-ANCA was found in 55% of ANA-positive serum samples. LF and LZ were most commonly found in serum samples from patients with SLE.
11133864 IL-18 not required for IRBP peptide-induced EAU: studies in gene-deficient mice. 2001 Jan PURPOSE: Interleukin (IL)-18 has been described as a proinflammatory cytokine in rheumatoid arthritis and bacterial infectious diseases. The present study was designed to determine the role of IL-18 in a model of ocular experimental autoimmune uveitis (EAU). The initial studies were conducted to detect the expression of IL-18 in normal mouse eye tissue, and the later studies investigated induction of EAU in mice with an IL-18(-/-) phenotype. METHODS: IL-18 detection was performed by using 5-bromo-4-chloro-3-indoyl-ss--D-galactopyranoside (X-Gal) staining on frozen sections of eyes from mice (129/CD1, DBA1, and Balb/c), either of normal phenotype (+/+) or of deficiency (+/-, -/-) in the IL-18 gene which had been replaced by introduced genes including LacZ under the control of an IL-18 promotor. Severity of EAU was assessed in DBA1 and 129/CD1 wild-type (WT) or IL-18 knockout (KO) mice after immunization with the uveitogenic antigen: interphotoreceptor retinal binding protein (IRBP) peptide 161-180. Lymphocyte proliferation and cytokine production were also measured in WT and IL-18 KO DBA1 mice 15 days after immunization. RESULTS: IL-18 is constitutively expressed in the epithelial cells in iris, ciliary body, and retina. EAU-resistant mice (129/CD1) with an IL-18(-/-) phenotype remained resistant after immunization with IRBP peptide (P161-180). However, EAU-susceptible mice (DBA1) exhibited disease with similar histologic characteristics, despite a generalized reduction of interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha on an IL-18(-/-) phenotype. DBA1 IL-18(-/-) also demonstrated reduced IL-10 production. CONCLUSIONS: The IL-18 gene is not necessary for the initiation or pathogenesis of EAU induced by IRBP peptide 161-180. IL-18 is expressed in the epithelial cells in iris, ciliary body, and retina in the eyes, but its role in the eye remains undetermined.
11005786 Serum levels of YKL-40 and C reactive protein in patients with hip osteoarthritis and heal 2000 Oct BACKGROUND: YKL-40 is a 40 kDa glycoprotein secreted by chondrocytes and synoviocytes. It has been suggested that it is a surrogate marker of synovial inflammation and joint destruction in rheumatoid arthritis (RA) and osteoarthritis (OA) and related to C reactive protein (CRP) serum levels in RA. OBJECTIVE: To study serum levels of YKL-40 in patients with hip OA and its relation with CRP. METHODS: YKL-40 and CRP were assayed in serum samples from 45 patients (24 women, 21 men, mean age 65) with symptomatic OA of the hip and 33 healthy controls. YKL-40 was assayed by immunoassay and CRP by ultrasensitive immunonephelometry. OA severity was assessed by the measurement of joint space width with a computer analysis system of digitised hip radiographs. Statistical analysis was performed to determine correlations between serum markers and radiological joint space width. RESULTS: The mean (standard error) YKL-40 level was 90.3 (8.2) ng/ml in patients with hip OA and 66.9 (8.2) ng/ml in controls (p=0.03). The mean CRP level was 2.93 (3.03) mg/l in OA and 1.40 (1.61) mg/l in controls (p=0.006). The serum levels of YKL-40 and CRP increased with age and were significantly correlated (Spearman test: r(s)=0.42, p=0.005) in patients but not in controls. Neither YKL-40 nor CRP correlated with radiographic joint space width. CONCLUSIONS: Serum YKL-40 was significantly increased in patients with hip OA. The correlation between YKL-40 and CRP suggests that YKL-40 may be a marker of joint inflammation in OA. Longitudinal studies are required to assess the usefulness of YKL-40 in the monitoring of patients with hip OA.
10879785 Relapsing polychondritis. 2000 Jun BACKGROUND: Relapsing polychondritis (RPC) is a rare, chronic, and potentially fatal multisystemic inflammatory disorder targeting cartilaginous structures. This disorder is frequently associated with rheumatoid arthritis, systemic vasculitis, connective tissue diseases, and/or hematologic disorders. RPC afflicts patients with recurrent and often progressive episodes of inflammation with the potential for destruction of the affected structures. Tissues involved include the ears, joints, nose, larynx, trachea, eyes, heart valves, kidneys,and skin. Ocular manifestations commonly include episcleritis, scleritis, conjunctivitis, iridocyclitis, chorioretinitis, and proptosis. Lid edema, orbital inflammation, muscle palsies, and corneal melting may also occur. CASE REPORT: An 83-year-old man previously diagnosed with RPC presented to our clinic with acute unilateral chemosis, conjunctivitis, lid edema, proptosis, and extraocular muscle restriction. After orbital cellulitis was ruled out, further evaluation revealed posterior scleritis with choroidal detachment OS. A course of oral indomethacin and topical antibiotic-steroid combination drops was implemented in the treatment of the ocular manifestations. The quick positive response to the anti-inflammatory agents confirmed the diagnosis of ocular complications secondary to RPC. DISCUSSION: The presenting ocular signs and symptoms of RPC often resemble other commonly encountered ocular conditions. It is important for the eye care practitioner to be familiar with the ocular manifestations of RPC because the eyes are sometimes the initial site of involvement and may be a marker of severity. Early diagnosis and intervention may significantly improve the patient's outcome. This case report with literature review will hopefully bring to light features of this disease which will help the eye care practitioner in the diagnosis and management of this condition.
10776922 The association of calprotectin level in gingival crevicular fluid with gingival index and 2000 Mar BACKGROUND: Calprotectin, a major cytosol protein of leukocytes, exists in plasma and other body fluids of healthy human subjects. Since the calprotectin concentration rises markedly in some inflammatory diseases including rheumatoid arthritis, this protein has been thought to be a marker of inflammatory disease. Recently, we identified calprotectin in human dental calculus and gingival crevicular fluid (GCF), and found that the calprotectin concentration in GCF from patients with periodontitis was significantly higher than that in GCF from healthy subjects. In the present study, the association of GCF calprotectin level with GCF volume, gingival index (GI), and levels of biochemical markers including collagenase and aspartate aminotransferase (AST) in GCF was investigated to clarify the relationship between GCF calprotectin level and periodontal inflammation. METHODS: Ninety GCF samples collected from periodontal pockets with a probing depth of more than 4 mm in 54 patients with adult periodontitis were used for these assays. The GCF volume was measured, and GI in each site was recorded. The calprotectin content in GCF samples was determined by ELISA using a specific antibody. The activity of collagenase or AST was measured by a respective assay kit. RESULTS: The total amount of calprotectin and GCF volume showed a highly significant correlation (r = 0.64, P <0.0001), whereas the calprotectin concentration had no correlation with the GCF volume (r = 0.01, P= 0.924). The mean calprotectin concentration in GCF increased with the degree of GI, and the concentration in individual samples was significantly correlated with the GI score (r = 0.56, P<0.0001). Significant positive correlations were observed in GCF calprotectin versus collagenase (r = 0.57, P <0.0001) and GCF calprotectin versus AST levels (r = 0.40, P <0.005). CONCLUSIONS: From the present results and our previous findings, it is shown that the GCF calprotectin level significantly correlates not only with clinical indicators but also with current biochemical marker levels and that calprotectin may be a useful marker for periodontal inflammation.
10695563 The role of CagA status in gastric and extragastric complications of Helicobacter pylori. 1999 Dec Two major markers of virulence have been described in H. pylori. The first is a secreted protein (VacA) that is toxic to human cells in tissue culture. This cytotoxin causes vacuolation of epithelial cells in vitro and induces epithelial cell damage in mice. The second is a 40-Kb pathogenicity island for which the gene cagA (cytotoxin-associated gene A) is a marker. Approximately 60% of H. pylori isolates in Western countries are cagA+. The protein encoded by cagA+ has a molecular weight of 120-140 kDa and exhibits sequence heterogeneity among strains isolated from Western and Eastern countries. Although no specific function has been identified for CagA, there is increasing evidence that cagA+ strains are associated with increased intensity of gastric inflammation and increased mucosal concentration of particular cytokines including interleukin 8. Inactivation of picB (Hp 0544) or any of several other genes in the cag island ablates the enhanced IL-8 secretion of human gastric epithelial cells in tissue culture. Furthermore, persons colonized with cagA+ strains have an increased risk of developing more severe gastric diseases such as peptic ulcer and distal (non-cardia) gastric cancer than those harboring cagA- strains. We investigated the role of cagA status in both gastroduodenal and extragastroduodenal disease with H. pylori. Among the diseases limited to the antrum and body of the stomach and the duodenum, we demonstrated a correlation between CagA seropositivity and peptic ulcer disease. We also showed correlation between distal gastric cancer rated and CagA prevalence in populations in both developed and developing countries. In addition, we found that for several Asian populations, the relationship between CagA seropositivity and gastroduodenal diseases was complex. For extragastroduodenal diseases, our results confirmed previous reports that demonstrated that CagA status did not play a role in diseases such as rheumatoid arthritis and hyperemesis gravidarum. However, we found a clear negative association between the presence of a positive response to CagA and esophageal diseases. Therefore, CagA seropositivity (and thus gastric carriage) is associated with increased risks of certain diseases (involving the lower stomach and duodenum) and decreased risks of GERD and its sequelae. This apparent paradox can best be explained by differences in the interaction of cagA+ and cagA- strains with their hosts.
10692491 Hematotoxicity of the chinese herbal medicine Tripterygium wilfordii hook f in CD34-positi 2000 Mar T2, a chloroform/methanol extract of the herb Tripterygium wilfordii Hook f, has been used in China for the treatment of autoimmune and inflammatory diseases for many years. Recent experimental evidence has confirmed that T2 has potent anti-inflammatory and immunosuppressive activity, and a United States Food and Drug Administration-approved clinical trial is currently exploring the efficacy of T2 in the treatment of rheumatoid arthritis. Despite the potential therapeutic benefits of T2, there is ample documentation that T2 is toxic, targeting, among other things, the hematopoietic system, and its use has resulted in cases of leukopenia, thrombocytopenia, and aplastic anemia. This investigation was undertaken to characterize the in vitro effects of T2 on primary human CD34-positive (CD34+) bone marrow cells. Our results demonstrate that T2 has a potent inhibitory effect on the clonogenic response of human bone marrow cells to exogenously added hematopoietic growth factors. The inhibition of colony formation by T2 is not the result of direct cytotoxicity or increased apoptosis and indicates a functional suppression of hematopoiesis. Additional experiments demonstrate that T2 also alters transcriptional regulation in bone marrow cells by inhibiting nuclear factor-kappaB. This transcription factor is found in CD34+ bone marrow cells and has been recently shown to be a requirement for colony formation. These results demonstrate that therapeutic concentrations of T2 exert a significant hematotoxic effect by inhibiting growth factor response in CD34+ bone marrow cells and suggest that inhibition of nuclear factor-kappaB may play a role in the blood dyscrasias encountered with the use of this drug.
10672987 Mechanisms of chloroquine-induced body-scratching behavior in rats: evidence of involvemen 2000 Feb Chloroquine is commonly used in the chemotherapy of malaria fever, and as an antiinflammatory disease-modifying agent in patients with rheumatoid arthritis or systemic lupus erythematosus. Administration of chloroquine (20.0 mg/kg IP) significantly (p < 0.05) increased the frequency of body scratching in rats to 29.5+/-9 in 30 min, compared to saline control animals (6.5+/-2/30 min). Morphine, a mu-opiate receptor agonist (1.0 mg/kg IP), potentiated the chloroquine-induced rat body scratching to 40+/-6.6, while the mu-opiate receptor antagonist, naltrexone (0.25 mg/kg, IP, given 15 min prior) blocked the chloroquine induced body scratching to 4.5+/-2 (p < 0.05 ANOVA). In addition, the frequency of chloroquine (20.0 mg/kg IP)-induced body scratching was significantly reduced to 9.1+/-3 in 30 min in rats rendered tolerant to morphine (p < 0.05 ANOVA) compared to the scratching frequency of 40+/-6.6 in morphine-naive rats. These suggests an involvement of mu-opioid receptors and/or endogenous opioid peptides in chloroquine induced body scratching in rats. Promethazine, a histamine-receptor antagonist (1.0 mg/kg IP, given 15 min prior to chloroquine) and the corticosteroid, dexamethasone (1.0 mg/kg, IP, given 15 min prior) separately and significantly (p < 0.01) inhibited the chloroquine-induced scratching in rats, in a similar manner to clinical studies in malaria. Collectively, the novel results implicate opioidergic mechanisms, and confirm the efficacy of antihistamine and corticosteroids in chloroquine body scratching in rats. It also strongly suggests that the chloroquine-induced body-scratching behavior in the rat may be a useful experimental model for chloroquine-induced pruritus in humans.
10523549 Serodiagnosis of human granulocytic ehrlichiosis by a recombinant HGE-44-based enzyme-link 1999 Nov Current antibody testing for human granulocytic ehrlichiosis relies predominantly on indirect fluorescent-antibody assays and immunoblot analysis. Shortcomings of these techniques include high cost and variability of test results associated with the use of different strains of antigens derived from either horses or cultured HL-60 cells. We used recombinant protein HGE-44, expressed and purified as a maltose-binding protein (MBP) fusion peptide, as an antigen in a polyvalent enzyme-linked immunosorbent assay (ELISA). Fifty-five normal serum samples from healthy humans served as a reference to establish cutoff levels. Thirty-three of 38 HGE patient serum samples (87%), previously confirmed by positive whole-cell immunoblotting, reacted positively in the recombinant ELISA. In specificity analyses, serum samples from patients with Lyme disease, syphilis, rheumatoid arthritis, and human monocytic ehrlichiosis (HME) did not react with HGE-44-MBP antigen, except for one sample (specificity, 98%). We conclude that recombinant HGE-44 antigen is a suitable antigen in an ELISA for the laboratory diagnosis and epidemiological study of HGE.
10382797 The Michigan Hand Outcomes Questionnaire (MHQ): assessment of responsiveness to clinical c 1999 Jun Responsiveness is an important property of an outcomes questionnaire. It can be defined as the ability of an instrument to capture important changes in a patient's health status over time. The authors previously designed the Michigan Hand Outcomes Questionnaire (MHQ), a hand-specific outcomes instrument that contains six distinct scales: (1) overall hand function, (2) activities of daily living, (3) pain, (4) work performance, (5) aesthetics, and (6) patient satisfaction with hand function. In the first study, the authors demonstrated that the MHQ is a reliable and valid instrument for the hand. The purpose of this second study is to assess the responsiveness, or sensitivity, of the MHQ to clinical change in patient status. A total of 187 consecutive patients with chronic hand disorders completed a baseline MHQ prior to receiving treatment at a university plastic surgery clinic. Approximately 6 to 18 months after completing the first questionnaire, patients were sent a follow-up MHQ by mail. The second questionnaire was identical to the first, with the exception of one additional question added to each of the six MHQ scales. This additional question asked patients to rate the change in their hands since completing the last questionnaire using a seven-point response scale. Spearman's correlation coefficient was used to correlate the responses from patients' self-assessment questions with the actual score change (after score - before score). The response rate for the second administration was 49% (92 questionnaires returned)-a fairly good rate of return for mail surveys. There were no significant differences in gender, race, education, and income between responders and nonresponders. When patients' self-assessment of change was correlated with the change in the six scale scores over time, all six correlations were statistically significant, with p < 0.05. The correlations ranged from 0.25 for the aesthetics scale to 0.43 for the pain scale. The MHQ was responsive using patients' self-assessment of their clinical change. Future studies will evaluate the responsiveness of the MHQ compared with objective physiological measures such as grip strength, range of motion, and the Jebson-Taylor test. Additionally, research is underway to assess the responsiveness of the MHQ for specific procedures, including metacarpophalangeal arthroplasties for rheumatoid arthritis and microvascular toe-to-hand reconstructions.
10368775 Modulation of osteoclast differentiation and function by the new members of the tumor necr 1999 Jun Osteoblasts/stromal cells are essentially involved in osteoclast differentiation and function through cell-to-cell contact (Fig. 8). Although many attempts have been made to elucidate the mechanism of the so-called "microenvironment provided by osteoblasts/stromal cells," (5-8) it has remained an open question until OPG and its binding molecule were cloned. The serial discovery of the new members of the TNF receptor-ligand family members has confirmed the idea that osteoclast differentiation and function are regulated by osteoblasts/stromal cells. RANKL, which has also been called ODF, TRANCE, or OPGL, is a member of the TNF ligand family. Expression of RANKL mRNA in osteoblasts/stromal cells is up-regulated by osteotropic factors such as 1 alpha, 25(OH)2D3, PTH, and IL-11. Osteoclast precursors express RANK, a TNF receptor family member, recognize RANKL through cell-to-cell interaction with osteoblasts/stromal cells, and differentiate into pOCs in the presence of M-CSF. RANKL is also involved in the survival and fusion of pOCs and activation of mature osteoclasts. OPG, which has also been called OCIF or TR1, is a soluble receptor for RANKL and acts as a decoy receptor in the RANK-RANKL signaling system (Fig. 8). In conclusion, osteoblasts/stromal cells are involved in all of the processes of osteoclast development, such as differentiation, survival, fusion, and activation of osteoclasts (Fig. 8). Osteoblasts/stromal cells can now be replaced with RANKL and M-CSF in dealing with the whole life of osteoclasts. RANKL, RANK, and OPG are three key molecules that regulate osteoclast recruitment and function. Further studies on these key molecules will elucidate the molecular mechanism of the regulation of osteoclastic bone resorption. This line of studies will establish new ways to treat several metabolic bone diseases caused by abnormal osteoclast recruitment and functions such as osteopetrosis, osteoporosis, metastatic bone disease, Paget's disease, rheumatoid arthritis, and periodontal bone disease.
10189491 The extent of drilling in lateral approaches to the cranio-cervical junction area from a s 1999 The trans-condylar approach to the craniocervical junction area (CCJA) requires a more or less extensive drilling of the two first cervical joints (C0-C1 and C1-C2). The extent of drilling necessary to resect a lesion at the CCJA was analyzed from a series of 125 cases including 114 tumours and 11 non-tumoural processes treated using a lateral approach (postero-lateral or antero-lateral) over a 15-year period (1980-1995). The extent of drilling was estimated on CT scanner axial views from the reduction of the joints surface and three groups were determined: A/less than one third B/between one third and one half, and C/more than one half. The extent of drilling was compared with the lesion location in relation to the bone limits of the CCJA: within these limits, outside them and into the bony structures. It was also analyzed with regard to pathology when separated into three groups non-osseous tumours, osseous tumours and chordomas, and non tumoural processes. Only 26 cases had a significant drilling, i.e., more than one third of the joint surfaces and of these, 14 were more than one half. In all these 14 cases, the bone structures were already invaded and 13 of them were, to some extent, beyond the bone limits of the CCJA. Of the 12 cases with drilling between one third and one half, 11 involved the bone structures and 1 was located inside the CCJA bone limits. Drilling of more than one third was required only in the case of bone lesions: 10 out of 23 bone tumours, all the 14 cases of chordomas, one case of rheumatoid arthritis and one case of C1-C2 joint spondylosis. In the other cases including mostly non-osseous tumours, drilling was limited to less than one third, though a high rate of complete removal was achieved (98%). Stabilization by arthrodesis with posterior grafting (N = 10) or by lateral bone grafting (N = 5) was achieved in all cases involving more than one half drilling, and in one case of tuberculosis. By adequately choosing the surgical approach, the extent of drilling can always be minimal. Extensive bone resection is only necessary when the tumour has already destroyed the joints. In that case, lateral or posterior fusion is an efficient technique.
9973312 Synergy between cyclo-oxygenase-2 induction and arachidonic acid supply in vivo: consequen 1999 Feb Prostanoids produced via the action of cyclo-oxygenase-2 (COX-2) appear central to many inflammatory conditions. Here we show in LPS-treated rats, however, that COX-2 induction alone does not greatly increase prostanoid production in vivo. For this, a second, arachidonic acid liberating stimulus is also required. Thus, only after intravenous injection of bradykinin or exogenous arachidonic acid was a marked increase in prostanoid formation seen. There is, therefore, synergy between proinflammatory mediators: both induction of COX-2 protein and an increase in the supply of arachidonic acid are required to greatly enhance prostanoid production. Second, we show that supplying arachidonic acid to increase prostanoid production reduces the effectiveness of both currently used nonsteroidal antiinflammatory drugs (NSAIDs) (diclofenac) and novel COX-2-selective inhibitors (NS-398, celecoxib) as inhibitors of COX-2 activity. Our data lead to two important conclusions. First, increased prostanoid production in inflammation is a two-component response: increased COX-2 expression and increased arachidonic acid supply. Second, the supply of arachidonic acid to COX-2 determines the effectiveness of NSAIDs. NSAIDs and selective COX-2 inhibitors, therefore, will generally be less effective at more inflamed sites, providing a rationale for the very high doses of NSAIDs required in human conditions such as rheumatoid arthritis.--Hamilton, L. C., Tomlinson, A. M., Mitchell, J. A., Warner, T. D. Synergy between cyclo-oxygenase-2 induction and arachidonic acid supply in vivo: consequences for nonsteroidal antiinflammatory drug efficacy.
9802931 Peripheral blood lymphocytes in SLE--hyperexpression of CD154 on T and B lymphocytes and i 1998 Oct Abnormalities in the regulation of both cell-mediated and humoral immunity have been implicated in the pathophysiology of systemic lupus erythematosus (SLE). Cognate contact-dependent T-B cell interactions involving CD154 (CD40 ligand) on activated T cells and CD40 on B lymphocytes have a critical role in antibody production. Abnormal CD154 expression on lymphocytes may play a role in the production of potentially pathogenic autoantibodies and defects in self-tolerance mechanisms may be important. Failure of intrathymic or peripheral deletion of autoreactive T cells may also result in an autoimmune phenotype. Elevated levels of CD3(+)CD4(-)/8(-) (double negative) T cells (DNT) in the peripheral blood are a surrogate marker for defects of this type. The expression of CD154 on T and B cells was evaluated and levels of double negative T cells in the peripheral blood were assessed by two and three colour flow cytometric analyses. We studied peripheral blood lymphocytes in 48 patients with SLE. Twenty-five normal subjects and 12 patients with rheumatoid arthritis (RA) were studied as disease controls. T cells in 22/48 (45%) lupus patients expressed CD154 between 20-80% (median=52%). In normal controls and RA patients 8-18% T cells were CD154(+). Twelve patients (30%) had elevated expression of CD154 (20-50%) on B cells. In the control RA patients, less than 15% T cells were CD154(+). Twelve of 48 SLE patients had elevated numbers of DNT cells (18-27%). The control subjects had DNT cell numbers <10. These observations suggest that defects in either the intrathymic or peripheral deletion of potentially pathogenic T lymphocytes may play a role in the pathogenesis of SLE. The high expression of CD154 on both T and B cells may also be important in mediating the production of potentially harmful autoantibodies.
9705303 Leflunomide inhibits pyrimidine de novo synthesis in mitogen-stimulated T-lymphocytes from 1998 Aug 21 The mode of action of Leflunomide, an immunomodulatory drug used in rheumatoid arthritis, is debated. This study, using 14C-labeled de novo purine and pyrimidine synthesis precursors, proves conclusively that the prime target in proliferating human T-lymphocytes is pyrimidine biosynthesis at the level of dihydroorotic-acid dehydrogenase. Leflunomide (25 and 50 microM), like Brequinar (0.5 and 1 microM), a demonstrated dihydroorotic-acid dehydrogenase inhibitor, was cytostatic, not cytotoxic, with proliferation being halted in the G1 phase. Both drugs restricted the normal 4-8-fold mitogen-induced expansion of pyrimidine pools over 72 h to concentrations found in nonstimulated T-cells and [14C]bicarbonate incorporation into UTP, ATP, and GTP. Uridine (50 microM) restored expansion of all pools, but [14C]bicarbonate incorporation into ATP and GTP only, not UTP. [14C]Hypoxanthine salvage was also restricted, indicating that purine salvage pathways are compromised likewise by both inhibitors. [14C]Glycine studies confirmed that restriction of de novo purine synthesis occurred secondary to inhibition of proliferation since this was reversed by uridine rescue, except at 100 microM Leflunomide. 100 microM Leflunomide markedly depleted ATP and GTP pools also, which would have serious consequences for ATP-dependent enzymes essential to the immune response, thereby explaining non-pyrimidine-related effects reported for Leflunomide at 100 microM and above.
9650470 Hybrid total knee arthroplasty: a 3- to 6-year outcome analysis. 1998 Jun We retrospectively analyzed the outcomes of hybrid total knee arthroplasty (TKA) with Miller Galante I (MG I) prostheses in 113 consecutive patients (140 knees). The mean follow-up period was 4.8 years (range 3.2-6.6). There were 135 cases of osteoarthritis and five of rheumatoid arthritis. The average age of patients at the time of surgery was 62.6 years. The Hospital for Special Surgery knee score along with radiographs were used to evaluate preoperative and postoperative knee status, and the Cybex isokinetic test was used to assess muscle strength at the final follow-up. The average knee score improved from 64 points preoperatively to 90 points postoperatively (p < 0.05). The mean motion are of the knee improved from 108 degrees preoperatively to 116 degrees at the final evaluation. A total of 122 knees were pain free on walking and 130 knees were completely pain free at rest. A total of 134 knees achieved good to excellent clinical results. The radiographic results showed that the mechanical axis of the lower extremity was realigned from a mean of 12 degrees varus preoperatively to a mean of 1 degree varus postoperatively. No obvious radiolucent zones were found on the lateral view of the femoral components in 60.7% of the knees, or on the anteroposterior or lateral views around the tibial components in 49.3% and 82.9% of knees, respectively. The Cybex isokinetic test at the final follow-up examination revealed that the hamstring/quadriceps peak torque ratio was 0.8 at a speed of 60 degrees per second and 0.96 at 180 degrees per second, indicating that quadriceps muscle strength did not recover to within the range of healthy subjects. There were 23 (16.4%) complications, including polyethylene wear of patellar components (14), patellofemoral maltracking (4), septic loosening (2), aseptic loosening (2), and superficial infection (1). Revision surgery improved the functional outcomes in all of these knees. Based on our experience, we do not recommend the use of the MG I prosthesis in total knee arthroplasty (TKA) because of the high rate of patellar complications. Strengthening of the quadriceps must be emphasized in postoperative rehabilitation. Hybrid fixation might be a useful alternative fixation mode in TKA procedures.