Browse

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

ID PMID Title PublicationDate abstract
15311118 Is corticosteroid coinjection necessary for radiosynoviorthesis of patients with hemophili 2004 Sep PURPOSE: Radiation synovectomy is frequently combined with intraarticular corticosteroid injection in the treatment of rheumatoid arthritis to reduce local inflammation and lymphatic clearance of radiocolloid. However, this practice is not universally accepted because corticosteroids have local and systemic toxicity such as osteonecrosis and cartilage damage and whether simultaneous corticosteroid injection together with radiocolloids is necessary in other forms of chronic synovitis like patients with hemophilia remains to be determined. MATERIALS AND METHODS: In this study, we performed radiosynoviorthesis in 14 joints of 12 patients with hemophilia with chronic knee synovitis without corticosteroid coadministration and measured radiocolloid leakage from the joint space. Five mCi Y-90 radiocolloid was injected under local anesthesia and the needle was flushed with additional lidocaine injection instead of corticosteroid. The joint was then manipulated through a full range of extension and flexion to distribute the particles homogeneously throughout the joint space. The joint was then splinted for 48 hours to minimize leakage from the joint space. After the immobilization period, radiocolloid leakage was evaluated using a gamma camera with a 20% window centered over the maximum Bremsstrahlung photopeak of Y-90. Regions of interest were drawn to the injection site on the knee joint and to the ipsilateral inguinal lymph node area. Leakage of radiocolloid was calculated by dividing the background-corrected counts/pixel at the inguinal region by the counts/pixel at the injection site. RESULTS: One of 12 patients who had knee arthroplasty was previously found to have a high amount of leakage. In this patient, 70% of radiocolloid at the injection site drained into the pelvic lymph nodes. In the remaining 11 patients, no lymph nodes were visualized in the groin area and the measured average leakage for these patients was 2.3% (range, 0-13). CONCLUSION: We concluded that in cases of appropriate particle size and strict immobilization of knee joints, leakage of radiocolloid was minimal and steroid coinjection might not be necessary for radiosynoviorthesis of patients with hemophilia with chronic knee synovitis.
15253953 Use of oral glucocorticoids and risk of cardiovascular and cerebrovascular disease in a po 2004 Aug OBJECTIVE: To assess whether use of oral glucocorticoids is associated with cardiovascular and cerebrovascular morbidity. DESIGN AND SETTING: Nested case-control study within a cohort of patients (> or = 50 years old) with at least one prescription for oral or non-systemic glucocorticoids. Data were from the general practice research database. PATIENTS: 50 656 patients were identified with a first record for ischaemic heart disease (International classification of diseases, ninth revision (ICD-9) codes 410, 411, 413, and 414), ischaemic stroke or transient ischaemic attack (ICD-9 codes 430-436), or heart failure (ICD-9 code 428) between 1988 and 1998. One control was matched to each case by sex, age, general practice, underlying disease, and calendar time. MAIN OUTCOME MEASURE: Odds ratio (OR) of cardiovascular or cerebrovascular events in patients using oral glucocorticoids compared with non-users. RESULTS: There was a significant association between ever use of oral glucocorticoids and any cardiovascular or cerebrovascular outcome (adjusted OR 1.25, 95% confidence interval (CI) 1.21 to 1.29). The association was stronger for current use of oral glucocorticoids than for recent or past use. Among current users, the highest ORs were observed in the group with the highest average daily dose, although the dose-response relation was not continuous. Current use was associated with an increased risk of heart failure (adjusted OR 2.66, 95% CI 2.46 to 2.87), which was consistent between patients with rheumatoid arthritis, patients with chronic obstructive pulmonary disease, and patients without either of the two conditions. Also, current use was associated with a smaller increased risk of ischaemic heart disease (OR 1.20, 95% CI 1.11 to 1.29). CONCLUSIONS: Oral glucocorticoid use was identified as a risk factor for heart failure. However, the evidence remains observational and only a randomised controlled trial of glucocorticoid treatment versus other disease modifying agents is likely to distinguish the importance of the underlying disease activity from its treatment in predicting cardiovascular outcomes.
15005008 Effects of physiological concentrations of steroid hormones and interleukin-11 on basal an 2004 Jan OBJECTIVE: IL-8 is a CXC chemokine involved in the pathogenesis of articular damage in rheumatoid arthritis. Local hyperproduction of IL-8 has been suggested to play a role in subchondral bone loss, since it suppresses osteoblast activity and promotes osteoclasts recruitment. Osteoblasts are a source of IL-8; its secretion is regulated by a number of hormones and cytokines. The aim of the present study was to evaluate the single and combined effects of physiological concentrations of cortisol, 17 beta-estradiol and IL-11 upon basal and IL-1 beta-inducible production of IL-8 in two human osteoblast-like cell lines, Saos-2 and MG-63. METHODS: Cells were incubated with cortisol (0.01 to 1 microM), 17 beta-estradiol (10 to 1000 pg/ml), IL-11 (1 to 100 ng/ml), in presence or absence of IL-1 beta (10 ng/ml), for 20 h. Combinations of 17 beta-estradiol and cortisol, and of IL-11 and cortisol, were also tested. After incubation, IL-8 levels in supernatants were measured by ELISA. RESULTS: Cortisol dose-dependently inhibited spontaneous IL-8 secretion in both cell lines, although statistical significance was attained in the MG-63 cells only (P < 0.01); no effect of 17 beta-estradiol was apparent. With regard to IL-1 beta-inducible production, cortisol dose-dependently inhibited IL-8 release in both cell lines (P < 0.01); 17 beta-estradiol resulted in only a non-significant decrease in Saos-2, but not in MG-63 cells. 17 beta-estradiol did not alter the effects of cortisol in experiments involving co-incubation. IL-11 did not have any effect on spontaneous IL-8 release, but exerted a significant inhibitory effect on IL-1 beta-inducible release in MG-63 cells (P < 0.05); no additional effect was observed upon the degree of cortisol-dependent inhibition. CONCLUSION: Cortisol is a potent physiological inhibitor of IL-8 production by osteoblast-like cells. The results of the present study support the use of exogenous supplemental glucocorticoids to prevent the deleterious effects of excess IL-8. The estrogenic milieu and local concentrations of IL-11 have little if any effect on the IL-8-dependent mechanisms of disease.
14679295 The health assessment questionnaire (HAQ) is strongly predictive of good outcome in early 2004 Apr OBJECTIVE: Scoring poorly on the health assessment questionnaire (HAQ) has recently been shown to be a strong predictor of morbidity and mortality in rheumatoid arthritis (RA), while a good HAQ score is predictive of a better outcome. In patients presenting with early diffuse scleroderma prognosis is variable. Our goal was to determine possible baseline predictors of future good outcomes. METHODS: We used the raw data from two randomized controlled trials (RCTs) in early diffuse scleroderma: methotrexate (Pope et al.) and D-penicillamine (Clements et al.). Subjects in the methotrexate trial were divided into the following groups: (1) those with at least 20% improvement in the primary outcome measurements [patient global assessment, physician global assessment, UCLA skin tethering score, modified Rodnan skin score (MRSS), DLCO as % predicted and HAQ disability] at 1 yr vs (2) the others. Baseline factors (including age, gender, skin scores, physician and patient global assessments, HAQ disability and pain scores, DLCO and physical parameters) were analysed to find baseline variables strongly correlated with later improvement. These variables were explored in the D-penicillamine trial to determine if (in a separate trial) they were still predictive of improved outcome at 1 and 2 yr. Adjusted models were used to find baseline predictors of good outcome. The median HAQ-DI was 1.3 (methotrexate) and 1.0 (D-penicillamine). RESULTS: A baseline HAQ disability score of less than the median was predictive of at least a 20% improvement at 1 and 2 yr with odds ratios of 1.77 to 5.05, in four of the five outcome measurements (in both groups); with strongly significant P values for 3 of 5 outcomes (UCLA skin score, MRSS, patient global skin score; P<0.02) from the methotrexate study group. These three outcomes were strongly correlated with improvement (r between 0.25 and 0.35). Although data from the D-penicillamine trial were less convincing, in both trials the less than median HAQ-DI and HAQ pain scores showed a stronger association with improved outcome, more so than age, gender, skin score and baseline global assessment. CONCLUSION: A low baseline HAQ (defined as less than the median HAQ score) is predictive of improved outcome in diffuse scleroderma at 1 and 2 yr.
14552704 Clinical pharmacology of selective COX-2 inhibitors. 2003 May The discovery of cyclooxygenase (COX)-2 has provided the rationale for the development of a new class of nonsteroidal antiinflammatory drugs (NSAIDs), the selective COX-2 inhibitors (denominated coxibs), with the aim of reducing the gastrointestinal (GI) toxicity associated with the administration of NSAIDs by virtue of COX-1 sparing. Rofecoxib and celecoxib are the first selective COX-2 inhibitors approved by the FDA and EMEA for the treatment of rheumatoid arthritis (RA), osteoarthritis (OA) and for relief of acute pain. Rofecoxib has been shown to spare COX-1 activity ex vivo, in platelets and gastric mucosa, when administered at therapeutic doses or above. In a large clinical trial, COX-2 inhibitors have been demonstrated to halve the incidence of serious upper GI events vs a nonselective NSAID. Recently, other selective COX-2 inhibitors with different COX-1/COX-2 selectivity and pharmacokinetic features have been developed, i.e. valdecoxib, parecoxib, etoricoxib and lumiracoxib. The improved biochemical selectivity of valdecoxib vs celecoxib in vitro (COX-1/COX-2 ratio: 60 vs 30, respectively) may be clinically relevant leading to an improved GI safety. Interestingly, parecoxib, a pro-drug of valdecoxib, is the only injectable coxib. Etoricoxib, showing only a slightly higher COX-2 selectivity than rofecoxib in vitro (COX-1/COX-2 ratio: 344 vs 272, respectively), has been reported to cause a similar specific COX-2 inhibition ex vivo that should translate into comparable GI safety. Lumiracoxib, the most selective COX-2 inhibitor in vitro (COX-1/COX-2 ratio: 400), is the only acidic coxib. It has been hypothesized that this pecular chemical feature may lead to an enhanced concentration in inflammatory sites that may translate into an improved clinical efficacy. The results of clinical trials have shown that coxibs have a comparable clinical efficacy and renal toxicity and an improved GI safety vs nonselective NSAIDs. Whether the different pharmacodynamic and pharmacokinetics features of the various coxibs will produce detectable differences in efficacy and toxicity remains to be evaluated in appropriate comparative randomized clinical studies.
12804511 Continuous passive motion following total knee arthroplasty. 2003 BACKGROUND: Knee arthroplasty (KA) is a common intervention that can enhance the quality of life for patients with osteoarthritis (OA) and rheumatoid arthritis (RA). Post-surgery rehabilitation protocols often include continuous passive motion (CPM). However, CPM protocols vary considerably amongst institutions. OBJECTIVES: The purpose of the current meta-analysis is to evaluate the effectiveness of continuous passive motion following total knee arthroplasty. SEARCH STRATEGY: An electronic search of MEDLINE (1966 to 2002), EMBASE (1988 to 2002), CINAHL (1982 to 2002), HEALTH STAR (1991 to 1994) and CURRENT CONTENTS (1997 to 2002) was conducted to identify randomized controlled trials. SELECTION CRITERIA: Following an a priori protocol, only randomized controlled trials of CPM for the treatment of participants post KA were eligible. Subjects were 18 years of age or older and had a pre-surgery diagnosis of degenerative joint disease. Both the experimental and control groups received physiotherapy. In addition to the physiotherapy intervention, the experimental group received CPM. DATA COLLECTION AND ANALYSIS: Two reviewers independently selected trials for inclusion. Data were then extracted and the quality of the trial assessed using predetermined forms. Outcome measures of interest were: active and passive knee range of motion (ROM) length of hospital stay, pain, swelling and quadriceps strength. A fixed effects model was used throughout for continuous variables, except where heterogeneity existed; in which case, a random effects model was used. Results were analyzed as weighted mean differences (WMD) with 95% confidence intervals (CI). Standardized mean differences (SMD) were used when different scales were used to measure the same concept (e.g. pain). Dichotomous outcomes were presented as a relative risk. MAIN RESULTS: Fourteen trials were retained for analysis. Results favouring CPM were found for the main comparison of CPM combined with physiotherapy (PT) versus PT alone at end of treatment. For the primary outcomes of interest, CPM combined with PT was found to statistically significantly increase active knee flexion (WMD 4.30 degrees, 95% CI: 1.96, 6.63) and decrease length of stay (WMD -0.69 days, 95% CI: -1.35, -0.03). CPM was also found to decrease the need for post-operative manipulation (RR 0.12, 95% CI: 0.03, 0.53). CPM did not significantly improve passive knee flexion and passive or active knee extension. REVIEWER'S CONCLUSIONS: CPM combined with PT, may offer beneficial results compared to PT alone in the short term rehabilitation following total knee arthroplasty.
12804506 Single dose oral celecoxib for postoperative pain. 2003 BACKGROUND: Celecoxib is a selective cyclooxygenase-2 (COX-2) inhibitor prescribed for the relief of chronic pain in osteoarthritis and rheumatoid arthritis. The drug is believed to be associated with fewer adverse effects than conventional non-steroidal anti-inflammatory drugs (NSAIDs). However, the effectiveness of celecoxib in the treatment of acute pain has not yet been assessed by systematic review. OBJECTIVES: To assess the analgesic efficacy and adverse effects of a single oral dose of celecoxib for moderate to severe postoperative pain. SEARCH STRATEGY: We searched the Cochrane Library Controlled Trials Register, MEDLINE, Biological Abstracts, PubMed and the Oxford Pain database. Date of the most recent search: May 2002. SELECTION CRITERIA: Randomised controlled trials (RCTs) of adults prescribed any dose of oral celecoxib or placebo for acute postoperative pain were included. DATA COLLECTION AND ANALYSIS: Two trials (418 subjects) met the inclusion criteria for this review. The trials were assessed for quality and the data extracted by two independent reviewers. Summed pain relief (TOTPAR) or pain intensity difference (SPID) was extracted and converted into dichotomous information yielding the number of patients with at least 50% pain relief over 4-6 hours. These derived results were used to calculate the relative benefit (RB) and number-needed-to-treat (NNT) for one patient to achieve at least 50% pain relief. MAIN RESULTS: The number-needed-to-treat for celecoxib 200 mg compared with placebo was 4.5 (CI 3.3 to 7.2). For every 4.5 patients experiencing moderate to severe acute pain treated with celecoxib 200 mg one more will experience at least 50% pain relief that would not have done had they received placebo. The median time to remedication over 24 hours was 5.1 hours with celecoxib 200 mg and 1.5 hours with placebo. Quantitative analysis of adverse effects was not possible but no serious or unexpected adverse effects were reported. REVIEWER'S CONCLUSIONS: Single dose oral celecoxib is an effective means of postoperative pain relief, similar in efficacy to aspirin 600/650 mg, and paracetamol 1000 mg. The two trials included used celecoxib 200 mg, a dose 50% less than is recommended for acute pain. More trials are needed to estimate efficacy for recommended dose of 400 mg, and to reinforce current findings for 200 mg, and provide data for pooled quantitative estimates of adverse effects.
15600120 [Shoulder arthroplasty in traumatological indications, surgical technique]. 2004 PURPOSE OF THE STUDY: Shoulder arthroplasty in traumatological indications has a considerably worse prognosis than when the indication is osteoarthritis or rheumatoid arthritis. The problem lies in the technique of rotator cuff reconstruction and the restoration of adequate bio-mechanical properties of the shoulder joint. In this study, the difficult reconstruction of four-part fractures of the proximal end of the humerus was improved by the development of a new type of shoulder joint endoprosthesis. MATERIAL AND METHODS: Our endoprosthesis permits fixation of bone fragments of the greater and lesser tubercles to the shaft and to the diaphyseal fragment by using screws or a toothed plate designed for this purpose and produced in various shapes. In addition to the modularity of the head, the endoprosthesis has a component facilitating better recovery of biomechanical properties of the proximal end of the humerus, and this is a variable neck of the prosthesis. The modularity of the neck makes it possible to adjust the colodiaphysal angle and to adjust the head in relation to the stem in eight different positions. The shoulder replacement described, produced in two modifications by ProSpon (Czech Republic) and MIL (France), was used in surgical treatment of 43 acute fractures and 33 cases of post-traumatic destruction. The clinical outcome was assessed using the Constant rating score. RESULTS: In patients with acute trauma of a shoulder, an average of 59 points (range, 23-82) was achieved. The average maximal elevation was 88 degrees, with a range of 40 to 140 degrees. In 25% of the patients, no postoperative pain was present; mild pain at strain was reported by 73% of the patients and pain limiting the arm's activity by 3%. In patients with post-traumatic destruction of a shoulder, the average value vas 53.5 points (range, 20-88) and the average maximal elevation was 85 degrees (range, 30-130). No postoperative pain was reported by 36%, mild pain at strain was recorded in 52% and activity-limiting pain in 12% of the patients. DISCUSSION: The currently reported views are in agreement with our opinion that, at present, every method of shoulder replacement should enable the surgeon to achieve, as easy and reliably as possible, the reconstruction of fragments with the attachments of the rotator cuff. With our system, shoulder arthroplasty for the reconstruction of the proximal humerus, using the supplementary fixation components described, allowed us to treat even the most serious cases of traumatic destruction of the proximal humerus. CONCLUSIONS: To facilitate the treatment of trauma in displaced, three- or four-part fractures of the proximal end of the humerus, a new technique of reconstruction with the use of an endoprosthesis designed by us was developed. Fixation and reconstruction of fragments of the greater and lesser tubercles are carried out with screws and a special toothed plate that provides good fixation of the fragments to the stem. Compared with the current method of fragment fixation with simple suture, this technique offers an easy way of restoring the biomechanical properties in the region of the proximal end of the humerus and improves the stability of osteosynthesis. This aids in early mobilization and functional therapy of the patient, which results in a better overall outcome of the treatment.
15564062 The effects of cyclic mechanical strain and tumor necrosis factor alpha on the response of 2004 Dec OBJECTIVES: Cells of the knee meniscus respond to changes in their biochemical and biomechanical environments with alterations in the biosynthesis of matrix constituents and inflammatory mediators. Tumor necrosis factor alpha (TNF-alpha) is a pro-inflammatory cytokine that is involved in the pathogenesis of both osteoarthritis and rheumatoid arthritis, but its influence on meniscal physiology or mechanobiology is not fully understood. The objectives of this study were to examine the hypothesis that cyclic mechanical strain of meniscal cells modulates the biosynthesis of matrix macromolecules and pro-inflammatory mediators, and to determine if this response is altered by TNF-alpha. METHODS: Cells were isolated from the inner two-thirds of porcine medial menisci and subjected to biaxial tensile strain of 5-15% at a frequency of 0.5Hz. The synthesis of proteoglycan, protein, nitric oxide (NO), and prostaglandin E(2) were determined. RESULTS: Cyclic tensile strain increased the production of nitric oxide through the upregulation of nitric oxide synthase 2 (NOS2) and also increased synthesis rates of prostaglandin E(2), proteoglycan, and total protein in a manner that depended on strain magnitude. TNF-alpha increased the production of NO and total protein, but inhibited proteoglycan synthesis rates. TNF-alpha prevented the mechanical stimulation of proteoglycan synthesis, and this effect was not dependent on NOS2. CONCLUSIONS: These findings indicate that pro-inflammatory cytokines can modulate the responses of meniscal cells to mechanical signals, suggesting that both biomechanical and inflammatory factors could contribute to the progression of joint disease as a consequence of altered loading of the meniscus.
15382150 Fluorescent CXCL12AF647 as a novel probe for nonradioactive CXCL12/CXCR4 cellular interact 2004 Oct BACKGROUND: Chemokines drive the migration of leukocytes via interaction with specific G protein-coupled 7-transmembrane receptors. The chemokine ligand/receptor pair stromal cell-derived factor-1 (SDF-1, CXCL12)/CXCR4 is gaining increasing interest because of its involvement in the metastasis of several types of cancer and in certain inflammatory autoimmune disorders such as rheumatoid arthritis. In addition, CXCR4 serves as an important coreceptor for cellular entry of T-tropic strains of human immunodeficiency virus (HIV). Therefore, potent and specific CXCR4 antagonists may have therapeutic potential as anti-HIV, anti-cancer, and anti-inflammatory drugs. METHODS AND RESULTS: Chemokine receptor antagonists can be identified by their ability to inhibit ligand binding to the receptor protein. Until now, chemokine binding assays were mostly performed with radiolabeled chemokine ligands such as [(125)I]CXCL12. To overcome the practical problems associated with such radioactive chemokine binding assays, we have developed a flow cytometric technique using a new, commercially available Alexa Fluor 647 conjugate of CXCL12 (CXCL12(AF647)). Calcium flux, chemotaxis, and p44/42 mitogen-activated protein kinase phosphorylation assays showed that the agonistic activity of the fluorescent CXCL12 was unchanged as compared with that of unlabeled CXCL12. Human T-lymphoid (CXCR4(+)) SupT1 cells and CXCR4-transfected, but not CCR5- or CXCR3-transfected, human astroglioma U87.CD4 cells specifically bound CXCL12(AF647) in a concentration-dependent manner. Unlabeled CXCL12 and the well-known CXCR4 inhibitors, AMD3100 and T22, blocked the binding of CXCL12(AF647) to SupT1 cells with 50% inhibitory concentrations of 92, 13, and 8 ng/ml, respectively. We have also used this method to evaluate CXCL12 binding and CXCR4 expression level in different subsets of human peripheral blood mononuclear cells. CONCLUSION: CXCL12(AF647) is a valuable, more convenient alternative for [(125)I]CXCL12 in ligand/receptor interaction studies.
15310311 Efficacy of mizoribine in the treatment of systemic lupus erythematosus in children. 2004 Aug BACKGROUND: Mizoribine (MZR) is a novel immunosuppressant developed in Japan. As MZR is reported to be less toxic than other cytotoxic drugs, it is frequently used in Japan in the treatment of adult patients with rheumatoid arthritis or lupus nephritis. The objective of this study was to evaluate the efficacy of MZR in children with SLE. Nine female children with lupus nephritis who had undergone renal biopsy before starting MZR, were involved in this study. Their mean disease duration was 4.8 years at the time MZR treatment was initiated. Patients who had received intensive medications, such as methyl-prednisolone pulse therapy, intravenous cyclophosphamide pulse therapy, and/or other immunosuppressants, within the 4 months prior to the start of the study, were excluded. METHODS: Patients treated with 3 mg/kg per day of MZR were monitored every month for up to 1 year. The efficacy of MZR was evaluated by the changes from baseline values of serum C3, serum C4, anti-dsDNA antibody titer, erythrocyte sedimentation rate (ESR), urinary protein, dosage of prednisolone (PSL), and the sum of the scores defined by these parameters. RESULTS: Favorable changes were observed in C3 and ESR after 2 months and 3 months of MZR therapy, respectively. At 3 months of MZR therapy, the sum of scores defined by the parameters for disease activity indicated that MZR was more effective in non-class IV nephritis patients (n = 5) than in class IV nephritis patients (n = 4) (P = 0.0197). All nine children involved in the study tolerated the MZR therapy well during the study. CONCLUSION: MZR was safe in lupus children, but its efficacy was limited in patients with non-class IV nephritis. Further study is necessary, in which higher dosages and/or earlier use of MZR is provided to a larger number of children.
15007115 Idiopathic hypertrophic pachymeningitis. 2004 Mar 9 BACKGROUND: Hypertrophic pachymeningitis is an uncommon disorder that causes a localized or diffuse thickening of the dura mater and has been associated with rheumatoid arthritis, syphilis, Wegener's granulomatosis, tuberculosis, and cancer. Few series of the idiopathic variety have been described, particularly with respect to MRI correlation to clinical outcome and treatment. OBJECTIVE: To investigate the clinical and laboratory evaluation, course, and treatment of patients with idiopathic hypertrophic pachymeningitis (IHP), to correlate the MRI findings with the clinical course, and to review the literature on IHP. METHODS: Retrospective case series of 12 patients (9 men, 3 women), with a mean age of 55 years (range 39 to 88 years), who had IHP by imaging studies, meningeal or orbital biopsy, or both. The clinical features, laboratory evaluation, contrast-enhanced MRI, treatment, and clinical outcome were documented for each case. The mean duration of follow-up was 3.5 years (range 3 months to 16 years). RESULTS: The main clinical features at presentation were headache (11 cases), loss of vision (7 cases), diplopia (4 cases), papilledema (2 cases), other cranial nerve involvement (3 cases), ataxia (2 cases), and seizures (1 case). On the initial MRI, the location of abnormal enhancement of the dura mater correlated with the clinical findings and the sphenoid wing area was affected in all patients. The sedimentation rate was elevated in five cases. The CSF had increased protein in six cases and lymphocytosis in four cases. Biopsy of the dura mater in five cases and the orbital soft tissue in one case showed infiltrates of small mature lymphocytes, plasma cells, and epithelioid histiocytes, but no neoplasia, vasculitis, or infectious agents. Cultures of the CSF and biopsy material remained sterile. Corticosteroid therapy improved the vision in 7 of 8 cases and controlled headache in 10 of 11 cases. Five cases had partial improvement of other neurologic symptoms and signs. Recurrence developed with steroid tapering in six cases. One case had progressive deterioration and died. In four cases methotrexate or azathioprine was added with reduction of the steroid dose. Follow-up MRI performed in 11 patients correlated 80% with the clinical state (p = 0.01). CONCLUSION: IHP can be suspected on MRI and defined pathologically on biopsy. Untreated, the clinical course is usually marked by severe headache and progressive neurologic deterioration and vision loss. Although initially steroid-responsive, clinical manifestations frequently recur with corticosteroid taper, requiring the addition of immunosuppressive agents in some cases.
14632917 Calprotectin release from human neutrophils is induced by Porphyromonas gingivalis lipopol 2003 Dec OBJECTIVES: Calprotectin is a cytosolic protein with antibacterial action in leukocytes and its level increases in some inflammatory diseases, including periodontal diseases, rheumatoid arthritis and ulcerative colitis. Recently, we found that the lipopolysaccharide of Porphyromonas gingivalis (P-LPS) induced calprotectin release from human neutrophils. P-LPS, a major virulence factor of periodontal pathogens, is known to induce the production and release of inflammatory cytokines through CD14, Toll-like receptor (TLR) and nuclear factor kappaB (NF-kappaB). In the present study, we investigated whether calprotectin release by P-LPS is induced via the CD14-TLR-NF-kappaB pathway and the cellular mechanism of calprotectin release in human neutrophils. MATERIAL AND METHODS: Human neutrophils were isolated from the peripheral blood of healthy donors and pre-incubated in medium containing antibodies against CD14, TLR2 and TLR4, or several inhibitors of NF-kappaB, microtubules and microfilaments, and then incubated with P-LPS. The calprotectin amount in the culture medium was determined using ELISA, and the nuclear extracts from cells were used for the examination of NF-kappaB binding activity using electrophoretic mobility shift assays. RESULTS: P-LPS increased calprotectin release from neutrophils and its induction was inhibited by anti-CD14 and anti-TLR2 antibodies, but not by two anti-TLR4 antibodies. NF-kappaB inhibitors suppressed P-LPS-induced NF-kappaB binding activity and calprotectin release. The inhibitors of microtubule and microfilament polymerization significantly decreased P-LPS-induced calprotectin release. CONCLUSION: These results suggest that calprotectin release is induced by P-LPS via the CD14-TLR2-NF-kappaB signal pathway in human neutrophils and may be dependent on microtubule and microfilament systems.
14530908 Prevalence of osteoporosis and its reproductive risk factors among Jordanian women: a cros 2003 Nov Extensive differences in the osteoporosis epidemiological pattern among geographic and ethnic groups have been reported. The evidence concerning association of multiple pregnancies, lactations, and other menstrual history factors with low bone mineral density (BMD) remains inconclusive. Previous local studies addressing these issues in Jordan are very restricted. We present a cross-sectional study of Jordanian women who visited outpatient clinics between August 2000 and August 2002 at two community hospitals in Amman City. BMD measurement was performed for all subjects, while comprehensive appraisal of clinical issues related to reproductive status and past medical history was carried out using a structured questionnaire administered to 50% of the subjects. We also attempted to examine the current hypothesis of possible influence of hyperlipidemia and thyroid abnormalities on decreased BMD. According to WHO criteria, 119 (29.6%) were identified as having osteoporosis, 176 (43.8%) were osteopenic, and 107 (26.6%) had normal BMD. The multiple-linear regression analyses at different bone sites revealed that age, years of menopause, low-density lipoprotein (LDL), and follicle-stimulating hormone (FSH) have strong independent associations with decreased BMD at all lumbar and femoral neck regions. The negative effect associated with number of children (live births) and frequency of lactations was only evident at femoral neck. Although years of menstruation, age at menopause, days of menstrual cycle, number of pregnancies, and duration of hormone replacement therapy (HRT) were positively correlated with BMD, they had weaker associations than previous variables. Moreover, in the final multivariable logistic regression model, variables which rendered significantly independent risk factors after adjustment for age and BMI were: current smokers of more that 25 cigarettes/day, postmenopausal women irrespective of HRT use, menopausal years of > or =5 year intervals, natural early menopause, gastrointestinal disease, rheumatoid arthritis, osteoarthritis, hypertension, and thyroid replacement therapy. Ever-lactation, frequent lactation of 4 or more times, duration of lactation interval of 1-6 months and clinical hyperthyroidism were significant protective factors. Hysterectomy with or without oophorectomy, premature ovarian failure, gravidity, menstrual flow pattern, family history of osteoporosis, clinical hypothyroidism, hyperlipidemia, HRT, and corticosteroids therapy were not independent predictors of osteoporosis among our population. It was concluded that the prevalence of this worldwide public health problem among the Jordanian female population is extremely high, and is even found in younger age categories compared to previous international surveys. Though, the number of pregnancies in our multiparous female population showed a negative impact on femoral neck BMD, no evidence of increased risk of osteoporosis among ever-pregnant women was noted. Conversely, the current data analysis highlight many potential risk factors including associated medical illnesses, and other hormonal alterations experienced during menopausal period. Therefore, increased health awareness and intensive screening programs are mandatory for early detection of low bone mass.
12766879 Role of tumor necrosis factor-alpha in graft-versus-host disease and graft-versus-leukemia 2003 May Tumor necrosis factor-alpha (TNF-alpha) antagonist therapy has proven effective in inflammatory conditions such as rheumatoid arthritis and Crohn's disease. There is substantial evidence that TNF-alpha also plays a role in the development of graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation, which along with leukemia relapse remains one of the 2 major impediments to success of the approach. Using a recently developed potent rat/mouse chimeric monoclonal antibody directed against murine TNF-alpha (CNTO2213), the authors investigated the effect of TNF-alpha blockade on GVHD mediated by either CD4(+) or CD8(+) donor T cells. The results indicated that the treatment had only a moderate effect on both a CD8(+) T cell-mediated major histocompatibility complex-matched GVHD model involving multiple minor histocompatibility antigens and a p-->F(1) acute GVHD model directed against a haplo-mismatched major histocompatibility complex barrier involving both CD4(+) and CD8(+) T cells. In contrast, treatment with the anti-TNF-alpha antibody had a highly significant effect (100% survival rate) on the CD4(+) T cell-mediated component of this latter model. Importantly, anti-TNF-alpha antibody did not block the development of a graft-versus-leukemia effect against a murine myeloid leukemia challenge in either a syngeneic or allogeneic p-->F(1) setting. This suggests that the inhibition of TNF-alpha during allogeneic hematopoietic cell transplantation may be able to diminish the inflammatory GVHD reaction without hindering effective graft-versus-leukemia responses.
21656989 Gold nanocages. 2004 Optical fluorescence imaging is increasingly used to monitor biological functions of specific targets (1-3). However, the intrinsic fluorescence of biomolecules poses a problem when fluorophores that absorb visible light (350–700 nm) are used. Near-infrared (NIR) fluorescence (700–1,000 nm) detection avoids the background fluorescence interference of natural biomolecules, providing a high contrast between target and background tissues. NIR fluorophores have a wider dynamic range and minimal background as a result of reduced scattering compared with visible fluorescence detection. They also have high sensitivity, resulting from low infrared background, and high extinction coefficients, which provide high quantum yields. The NIR region is also compatible with solid-state optical components, such as diode lasers and silicon detectors. NIR fluorescence imaging is becoming a noninvasive alternative to radionuclide imaging in small animals (4, 5). Photoacoustic imaging (PAI) is an emerging hybrid biomedical imaging modality based on the photoacoustic effect. In PAI, non-ionizing optical pulses are delivered into biological tissues. Some of the delivered energy is absorbed and converted into heat, leading to transient thermoelastic expansion and thus ultrasonic emission. The generated ultrasonic waves are then detected by ultrasonic transducers to form images. It is known that optical absorption is closely associated with physiological properties, such as hemoglobin concentration and oxygen saturation. As a result, the magnitude of the ultrasonic emission (i.e., the photoacoustic signal), which is proportional to the local energy deposition, reveals physiologically specific optical absorption contrast and tissue structures. However, exogenous NIR contrast agents are necessary to overcome the intrinsic low tissue- and hemoglobin- absorption and scattering of tissue. On the other hand, these small molecules exhibit fast clearance, small optical absorption cross section, and non-targeted specificity. Therefore, there is a need for contrast agents with long blood circulation and targeted specificity. Gold (Au) nanoparticles have been studied as molecular imaging agents because of their bright NIR fluorescence emission around 700–900 nm and low toxicity (6, 7). They can be tuned to emit in a range of wavelengths by changing their sizes, shapes, and composition, thus providing broad excitation profiles and high absorption coefficients. They can be coated and capped with hydrophilic materials for additional conjugation with biomolecules, such as peptides, antibodies, nucleic acids, and small organic compounds for in vitro and in vivo studies. Au nanoparticles have been approved by the United States Food and Drug Administration for treatment of patients with rheumatoid arthritis. Au nanoparticles have been studied as contrast agents in X-ray/computed tomography, NIR optical coherence tomography, PAI, and photoacoustic tomography (PAT) (8). NIR Au nanocages are biocompatible, have low toxicity, and are tunable to strong NIR absorption (9). They have an outer edge of ~50 nm and an inner edge of ~42 nm, with a wall thickness of ~4 nm. Yang et al. (10) performed PAT of the cerebral cortex of rats with poly(ethylene glycol)-coated Au nanocages (PEG-AuNCs) as the optical contrast agent. The investigators observed an enhanced optical contrast in the vasculature in the cerebral cortex. Song et al. (11) demonstrated the use of Au nanocages as a PAI probe for detection of sentinel lymph node (SLN) of rats.
21595126 (68)Ga-Tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-Glu-cyclo(Arg-Gly-Asp-D-Phe-Ly 2004 Integrins are a family of heterodimeric glycoproteins on cell surfaces that mediate diverse biological events involving cell–cell and cell–matrix interactions (1). Integrins consist of an α and a β subunit and are important for cell adhesion and signal transduction. The α(v)β(3) integrin is the most prominent receptor affecting tumor growth, tumor invasiveness, metastasis, tumor-induced angiogenesis, inflammation, osteoporosis, and rheumatoid arthritis (2-7). Expression of the α(v)β(3) integrin is strong on tumor cells and activated endothelial cells, whereas expression is weak on resting endothelial cells and most normal tissues. Antagonists of α(v)β(3) are being studied as antitumor and antiangiogenic agents, and the agonists of α(v)β(3) are being studied as angiogenic agents for coronary angiogenesis (6, 8, 9). A tripeptide sequence consisting of Arg-Gly-Asp (RGD) has been identified as a recognition motif used by extracellular matrix proteins (vitronectin, fibrinogen, laminin, and collagen) to bind to a variety of integrins, including α(v)β(3). Various radiolabeled antagonists have been introduced for imaging of tumors and tumor angiogenesis (10). Most cyclic RGD peptides are composed of five amino acids. Haubner et al. (11) reported that various cyclic RGD peptides exhibit selective inhibition of binding to α(v)β(3) (inhibition concentration (IC(50)), 7–40 nM) but not to integrins α(v)β(5) (IC(50), 600–4,000 nM) or α(IIb)β(3) (IC(50), 700–5,000 nM). Various radiolabeled cyclic RGD peptides have been found to have high accumulation in tumors in nude mice (12). Dijkgraaf et al. (13) reported the development of (111)In-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-Glu-cyclo(Arg-Gly-Asp-D-Phe-Lys) ((111)In-DOTA-E-c(RGDfK)) for single-photon emission computed tomography imaging α(v)β(3) receptors in nude mice bearing ovarian carcinoma tumors. In this chapter, Dijkgraaf et al. (14) also reported the evaluation of (68)Ga-DOTA-E-c(RGDfK) for positron emission tomography (PET) imaging α(v)β(3) receptors in tumor, which is the topic of this chapter.
20641575 4-[(18)F]Fluorobenzoyl-NAVPNLRGDLQVLAQKVART. 2004 Integrins are a family of heterodimeric glycoproteins on cell surfaces that mediate diverse biological events involving cell–cell and cell–matrix interactions (1). Integrins consist of an α and a β subunit and are important for cell adhesion and signal transduction. The α(v)β(3) integrin is the most prominent receptor affecting tumor growth, tumor invasiveness, metastasis, tumor-induced angiogenesis, inflammation, osteoporosis, and rheumatoid arthritis (2-7). Expression of the α(v)β(3) integrin is strong on tumor cells and activated endothelial cells, whereas expression is weak on resting endothelial cells and most normal tissues. The α(v)β(3) antagonists are being studied as antitumor and antiangiogenic agents, and the agonists are being studied as angiogenic agents for coronary angiogenesis (6, 8, 9). A tripeptide sequence consisting of Arg-Gly-Asp (RGD) has been identified as a recognition motif used by extracellular matrix proteins (vitronectin, fibrinogen, laminin, and collagen) to bind to a variety of integrins, including α(v)β(3) and α(v)β(6). Various radiolabeled antagonists have been introduced for imaging of tumors and tumor angiogenesis (10). The α(v)β(6) integrin plays an important role in the development of epithelial cells and is nearly undetectable in adult normal tissues. However, levels of the α(v)β(6) integrin can be upregulated during tissue remodeling and wound healing (11). On the other hand, α(v)β(6) integrin is strongly expressed on tumor cells of the oral cavity, pancreas, breast, ovary, colon, and stomach (12-14). The α(v)β(6) integrin affects tumor growth, tumor invasiveness, and metastasis (13). α(v)β(6) binds to the RGD motif in fibronectin, tenascin, and the viral protein 1 (VP1) of the foot-and-mouth disease virus (FMDV) (15). FMDV binds to cells through the RGD motif of the GH loop of the VP1. A consensus α(v)β(6)-binding motif DLXXL was identified with phage display screening with minimal binding to α(v)β(3), α(IIb)β(3), and α(v)β(5) (16). A peptide of 20 amino acids, NAVPNLRGDLQVLAQKVART (A20FMDV2), was identified as a ligand binding to α(v)β(6) integrin (15). A20FMDV2 was radiolabeled with N-succinimidyl 4-[(18)F]fluorobenzoate ([(18)F]SFB) to study in vivo biodistribution of the tracer in tumor-bearing mice (17). [(18)F]FB-A20FMDV2 was found to have specific accumulation in α(v)β(6)-positive tumor.
20641247 (99m)Tc-Hydrazinonicotinic acid-Glu-[cyclo(Arg-Gly-Asp-D-Phe-Lys)](2). 2004 Integrins are a family of heterodimeric glycoproteins on cell surfaces that mediate diverse biological events involving cell–cell and cell–matrix interactions (1). Integrins consist of an α and a β subunit and are important for cell adhesion and signal transduction. The α(v)β(3) integrin is the most prominent receptor affecting tumor growth, tumor invasiveness, metastasis, tumor-induced angiogenesis, inflammation, osteoporosis, and rheumatoid arthritis (2-7). Expression of the α(v)β(3) integrin is strong on tumor cells and activated endothelial cells, whereas expression is weak on resting endothelial cells and most normal tissues. Antagonists of α(v)β(3) are being studied as antitumor and antiangiogenic agents, and the agonists of α(v)β(3) are being studied as angiogenic agents for coronary angiogenesis (6, 8, 9). A tripeptide sequence consisting of Arg-Gly-Asp (RGD) has been identified as a recognition motif used by extracellular matrix proteins (vitronectin, fibrinogen, laminin, and collagen) to bind to a variety of integrins, including α(v)β(3). Various radiolabeled antagonists have been introduced for imaging of tumors and tumor angiogenesis (10). Most cyclic RGD peptides are composed of five amino acids. Haubner et al. (11) reported that various cyclic RGD peptides exhibit selective inhibition of binding to α(v)β(3) (inhibition concentration (IC(50)), 7–40 nM) but not to integrins α(v)β(5) (IC(50), 600–4,000 nM) or α(IIb)β(3) (IC(50), 700–5,000 nM). Various radiolabeled cyclic RGD peptides have been found to have high accumulation in tumors in nude mice (12). Hydrazinonicotinic acid (HYNIC) is a coupling agent for (99m)Tc labeling of peptides that can achieve high specific activities without affecting the receptor-binding ability of the amino acid sequence. (99m)Tc is bound to the hydrazine group, and other coordination sites can be occupied by one or more coligands. Liu et al. (13) reported the success of radiolabeling the cyclo(Arg-Gly-Asp-D-Phe-Lys) (c(RGDfK)) dimer linked by glutamic acid that was conjugated with HYNIC. Trisodium triphenylphosphine-3,3’,3’’-trisulfonate (TPPTS) and tris(hydroxymethyl)-methylglycine (tricine) as coligands. (99m)Tc-HYNIC-E-[c(RGDfK)](2)(tricine)(TPPTS) showed high tumor accumulation in nude mice bearing human tumor xenografts.
12465160 Interleukin 17, a nitric oxide-producing cytokine with a peroxynitrite-independent inhibit 2002 Dec OBJECTIVE: To compare the potency of 2 cytokines, interleukin 17 (IL-17) and IL-1beta, on rat cartilage proteoglycan synthesis with special attention to nitric oxide (NO) and peroxynitrite formation. METHODS: Chondrocytes in alginate beads were stimulated with human recombinant (rh) IL-17 (0.03 to 300.0 ng/ml) and/or rhIL-1beta (0.25 to 25.0 ng/ml) in the presence or not of L-NMMA or CuDips. Alternatively, rats were injected with either IL-17 (10.0 micro g) or IL-1beta (1.0 micro g) into each knee joint. NO concentrations were determined by a spectrofluorimetric assay, proteoglycan synthesis by 35SO4-2 incorporation, peroxynitrite generation by immunostaining for 3-nitrotyrosine, and IL-1beta mRNA expression by reverse transcription-polymerase chain reaction. RESULTS: IL-17 inhibited proteoglycan synthesis and increased NO production, both in vitro and in vivo, without inducing expression of IL-1beta mRNA in cartilage. Additive effects were observed when IL-17 was combined with low concentrations of IL-1. Surprisingly, a similar NO synthesis between IL-1 and IL-17 led to a less suppressive effect of IL-17 on cartilage anabolism than with IL-1. Both in vitro and in vivo, peroxynitrite formation was extensive with IL-1beta, but negligible or nonexistent with IL-17. L-NMMA and CuDips completely corrected the suppressive effect of IL-1beta on proteoglycan synthesis, unlike with IL-17. CONCLUSION: These data showed that NO is weakly involved in the IL-17 mediated inhibition of proteoglycan synthesis in rat. NO overload may not be predictive of any inhibitory effect on cartilage anabolism, but instead superoxide is a key regulator of NO contribution to chondrocyte dysfunction. Since IL-17 is a NO-producing cytokine with additive effects when combined with IL-1, it may play a pivotal role in cartilage destruction during rheumatoid arthritis, for which infiltrating cells produce high levels of superoxide and proinflammatory cytokines.