Browse

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

ID PMID Title PublicationDate abstract
10069726 Diagnostic accuracy of salivary scintigraphic indices in xerostomic populations. 1999 Mar PURPOSE: Three decades of work to enhance the diagnostic accuracy of salivary scintigraphy have generated various plausible decision criteria. This study evaluates four commonly cited numeric indices in studies of xerostomic populations and how accurately they identify Sjögren's syndrome, chronic sialadenitis, radiation sialadenitis, and drug effects and distinguish each from the other. METHODS: Stimulated dynamic salivary scintigraphy was performed on 295 xerostomic patients and on 31 controls. The nonparametric area under the receiver operating characteristic curves expressed the diagnostic accuracy of the following scintigraphic indices: the parotid:submandibular ratio of unstimulated glandular activity, the peak:baseline uptake ratio, its time of occurrence, and the stimulated excretion fraction. RESULTS: The stimulated excretion fraction distinguished Sjögren's syndrome and radiation sialadenitis from healthy states with respective accuracies of 0.78 and 0.90. The maximum diagnostic payoff in Sjögren's syndrome occurred at a cutoff of 73%, yielding a 73% rate of test sensitivity and a 73% rate of specificity. The other three indices were not useful. Even the stimulated excretion fraction performed indifferently or poorly in most other diagnostic tasks. CONCLUSIONS: In the scintigraphic examination of xerostomic and healthy populations, an acceptable diagnostic utility of the stimulated excretion fraction was evident only in Sjögren's syndrome and radiation sialadenitis. When presented with differential diagnostic alternatives not involving radiation sialadenitis, none of the four numeric indices performed acceptably.
9621821 [Keratoconjunctivitis sicca in Sjögren's syndrome: diagnostic significance of relative pr 1998 Mar Six protein components were detected in the tears by exclusive high-pressure liquid chromatography. By their molecular weight, these components were identified as lacrimal prealbumin, human serum albumin, lactoferin, IgG, and IgA. The relative content of these proteins in tears correlates with the clinical picture of kerato-conjunctivitis sicca. Correlation coefficients (ci) were -0.66 for lysozyme, -0.58 for prealbumin, 0.70 for serum albumin, -0.63 for lactoferrin, and 0.65 for IgA. Linear regression analysis showed that the relative content of IgA and serum albumin rapidly increased in the course of disease. The relative content of lysozyme, lactoferrin, and prealbumin dropped, but two times slower. The authors propose assessing the quantitative changes in the lacrimal protein composition by a special diagnostic parameter: P = sigma(dni-di)ci/C, where dni and di are the mean relative levels of the protein component in health and disease, C the sum of absolute values of correlation coefficients for all components (C = sigma[ci]). The (dni-di) value reflects the effect of disease on changes in the relative content of each protein component and the ci/C value the intensity of this effect. This parameter can be used for assessing the involvement of the eyes in Sjogren's syndrome and monitoring the efficacy of treatment.
10357124 Prophylactic antibiotics in recurrent parotitis in a patient with Sjogren's syndrome. 1999 We describe a 41-year-old patient with primary Sjogren's syndrome with a 16-year history of recurrent parotitis. The institution of prophylactic antibiotic coverage has succeeded, to date, in maintaining her in remission for 4 years.
9806368 Predictors of lymphoma development in primary Sjögren's syndrome. 1998 Oct OBJECTIVE: To determine the clinical and laboratory predictors of lymphoma development in primary Sjögren's syndrome (pSS). METHODS: Seventy-two patients with pSS were studied. Demographic data, clinical features, serum gamma-globulin levels, autoantibodies, and HLA status were reviewed. For statistical analysis, Mann-Whitney U-test, Fisher's exact test, logistic regression analysis, Kaplan-Meier method, and log-rank tests were applied. RESULTS: Five patients developed a distinct non-Hodgkin's lymphoma of mucosa-associated lymphoid tissue (MALT). A history of swollen salivary glands, lymphadenopathy, and leg ulcers predicted lymphoma development. CONCLUSION: Patients with pSS are at increased risk of lymphoma development, and those who have the above risk factors must be carefully observed.
9415661 Cyclophosphamide induced water intoxication in a woman with Sjögren's syndrome. 1997 Dec Water intoxication is a well described complication of high dose intravenous (i.v.) cyclophosphamide therapy combined with forced hydration. Less well known is that water intoxication can develop even after low dose iv cyclophosphamide. To draw attention to this potentially life threatening complication, we describe a woman who developed acute water intoxication after treatment with low dose iv cyclophosphamide for a sensory neuropathy secondary to Sjögren's syndrome. Rheumatologists should be aware of this serious adverse effect of iv cyclophosphamide because this drug is being used increasingly for treatment of a variety of rheumatological diseases. The pathogenesis, clinical characteristics, treatment, and methods for prevention of cyclophosphamide induced water intoxication are discussed.
10211881 Systemic viral interleukin-10 gene delivery prevents cartilage invasion by human rheumatoi 1999 Apr OBJECTIVE: To assess the effects of viral interleukin-10 (vIL-10) gene delivery on human rheumatoid synovial tissue. METHODS: SCID mice were engrafted subcutaneously with human rheumatoid synovial tissue and homologous cartilage before systemic injection of 10(9) plaque-forming units of type 5 E1a Elb-deficient non-replicative adenovirus vector containing the vIL-10 gene under control of the cytomegalovirus promoter (AdvIL-10; n = 10) or a control gene (AdvIL-10mut; n = 7). Three weeks later, the graft was removed for histologic analysis of cartilage invasion by synovial tissue. The number of CD3-positive mononuclear cells was assessed in the synovial tissue by immunohistology. Messenger RNA (mRNA) expression of matrix metalloproteinase 3 (MMP-3), tissue inhibitor of metalloproteinases 1 (TIMP-1), and proinflammatory cytokines was determined by polymerase chain reaction. RESULTS: Systemic vIL-10 gene transfer resulted in high sustained production of vIL-10 protein in SCID mouse sera (mean +/- SD 25 +/- 5 ng/ml on day 40 post vector injection). Moreover, vIL-10 mRNA expression was detected in the synovial tissue 3 weeks after intravenous injection of AdvIL-10, reflecting the gene transfer in the human graft. In animals treated with AdvIL-10, cartilage invasion by rheumatoid synovial tissue was significantly inhibited compared with the control vector (mean +/- SD histologic score 2.5 +/- 0.52 versus 0.75 +/-0.8; P < 0.0001). The number of T cells infiltrating the synovium and perichondral resorption in the animals treated with AdvIL-10 gene were not significantly modified relative to the control vector. In animals treated with AdvIL-10, the MMP-3-TIMP-1 balance was partially restored, independent of the effect on mRNA expression of tumor necrosis factor a, IL-1, IL-6, or IL-8. CONCLUSION: Systemic vIL-10 gene transfer prevented cartilage invasion by synovial tissue engrafted in SCID mice. This model offers the opportunity to study the biologic effects of gene transfer in vivo in rheumatoid synovium.
11682523 Recombinant flagellin A proteins from Borrelia burgdorferi sensu stricto, B. afzelii, and 2001 Nov Genes for flagellin A (FlaA) proteins from European borrelial strains of Borrelia burgdorferi sensu stricto, B. afzelii, and B. garinii were cloned and sequenced. An identity of 92 to 93% was observed in the flaA sequences of the different species. Polyhistidine-tagged recombinant FlaA (rFlaA) proteins were produced in Escherichia coli and used as antigens in Western blotting (WB) and enzyme-linked immunosorbent assay (ELISA). In immunoglobulin G (IgG) WB, 71% (10 of 14) of the sera from neuroborreliosis and 86% (12 of 14) of those from Lyme arthritis patients reacted with one to three rFlaAs. In IgG ELISA, 74% (14 of 19) and 79% (15 of 19) of patients with neuroborreliosis and arthritis, respectively, were positive. The immunoreactivity in local European patient sera was stronger against rFlaA from B. garinii and B. afzelii than against rFlaA from B. burgdorferi sensu stricto. Neither IgG nor IgM ELISA was sensitive in the serodiagnosis of erythema migrans. Serum samples from patients with syphilis and systemic lupus erythematosus showed mild cross-reactivity in IgG tests. Sera from Yersinia enterocolitica or beta-hemolytic Streptococcus infections showed only occasional responses. With IgM ELISA, 58% (11 of 19) and 37% (7 of 19) of patients with neuroborreliosis and arthritis, respectively, were positive. Cross-reactive antibodies to FlaA, especially in serum samples from patients with rheumatoid factor positivity and Epstein-Barr virus infection, reduced the specificity of IgM serodiagnosis. Therefore, rFlaA seems to have a limited role for IgM serodiagnosis, yet rFlaA might be useful in the IgG serodiagnosis of disseminated Lyme borreliosis.
11128662 Synovial fluid induced nuclear factor-kappaB DNA binding in a monocytic cell line. 2000 Dec OBJECTIVE: To determine the effects of synovial fluids (SF) on DNA binding activity of transcription factor nuclear factor-kappaB (NF-kappaB) in the Mono Mac 6 monocytic/macrophage cell line as a model for the interaction between SF and synovial tissue macrophages in arthritis. METHODS: Mono Mac 6 cells were incubated with SF from the knee joints of human subjects with rheumatoid arthritis (RA), undifferentiated seronegative oligoarthritis, and osteoarthritis (OA). Nuclear extracts prepared from the Mono Mac 6 cells and RA synovial tissue were analyzed by electrophoretic mobility shift analysis (EMSA) for NF-kappaB DNA binding proteins. RESULTS: Induction of NF-kappaB DNA binding by the p65(RelA)/p50 heterodimer was observed in response to incubation of Mono Mac 6 cells with SF (20% in culture medium) from 5 of 8 subjects with RA, 4 of 5 with OA, and none of 3 with undifferentiated seronegative oligoarthritis. Incubation of SF with neutralizing antibodies against tumor necrosis factor-alpha (TNF-alpha), but not antibodies against interleukin 6 (IL-6), significantly reduced the induction of p65/p50 binding activity in SF from subjects with RA and OA. Unexpectedly, a slowly migrating SF inducible NF-kappaB-binding complex was observed in EMSA of Mono Mac 6 cells after incubation with SF from 5 of 8 RA and 2 of 5 OA subjects. The induction of this complex by SF was not affected by neutralization of TNF-alpha or IL-6 in SF, and the complex was not inducible by TNF-alpha, IL-1beta, TNF-alpha/IL-1beta, IL-6, platelet derived growth factor, lipopolysaccharide, or tetradecanoyl phorbol acetate. The slowly migrating complex could not be supershifted with antibodies against NF-kappaB, Jun, or the transcriptional coactivators p300 or CBP. A NF-kappaB-binding complex with similar slow mobility was observed in nuclear extracts prepared from fresh human RA synovial tissue. CONCLUSION: Biological activity of TNF-alpha in SF from RA and OA subjects is capable of inducing p65/p50 NF-kappaB DNA binding activity in macrophages. A property of SF that is independent of TNF-alpha and other cytokines is responsible for the induction of a novel slowly migrating NF-kappaB-binding complex. Soluble mediators in SF of subjects with RA and OA can therefore modulate binding of nuclear proteins to the NF-kappaB binding site in macrophages and may play a role in inflammatory gene expression in arthritis.
11518037 Polymorphonuclear leukocyte adhesion to articular cartilage is inhibited by cartilage surf 2001 Jul The present studies deal with polymorphonuclear neutrophil (PMN) adhesion inhibitory properties of cartilage surface proteoglycans. Normal human PMN were used in adhesion experiments with bovine cartilage surfaces exposed to neutrophil elastase and reconstituted with fibronectin (Fn) or on plastic-bound Fn. An extract of cartilage surface small proteoglycans (SE) and purified fibromodulin (FM), decorin (DCN), biglycan (BGN), and aggrecan (AGN) on the surface of normal cartilage were used to test for inhibition of Fn-dependent cell adhesion. The PMN did not adhere to intact articular cartilage surfaces, whereas significant adhesion was measured using cartilage explants digested with elastase and reconstituted with Fn. Incubation of elastase-treated, Fn-reconstituted cartilage with 45 microg/ml SE inhibited PMN adhesion by 50.7 +/- 5.8% (P < 0.0001). Addition of 50 microg/ml purified FM to the reconstituted articular surfaces inhibited cell adhesion by 71.2 +/- 13.9% (P < 0.0001). Inhibition of PMN adhesion to plastic-bound Fn was seen with 1.7 microg/ml SE (20.4 +/- 8.0%). Maximal inhibition of 67.4 +/- 14.8% (P < 0.01) was obtained with 17.0 microg/ml SE. With FM, concentrations of 4.3 microg/ml resulted in 34.7 25.2 inhibition (P < 0.001), and maximal inhibition of 66.3 16.2% (P < 0.01) was obtained with 43.0 microg/ml. Similar results were obtained with purified bovine DCN and BGN. The main component of cartilage matrix, AGN, failed to inhibit cell adhesion significantly. The results indicate that macromolecules normally present on articular cartilage surfaces act as a barrier to PMN adhesion. Since cartilage surface proteins are susceptible to breakdown by proteases from synovial fluid inflammatory cells, we postulate that the degradation of this barrier may be responsible for increasing PMN adhesion and subsequent cartilage damage in inflammatory arthritis.
10807299 Improving rheumatologists' screening for alcohol use and sexual activity. 2000 May OBJECTIVES: To design, implement, and assess the impact of an office-based intervention designed to improve rheumatologists' identification of risk behaviors, especially alcohol use and sexual activity, among adolescents and young adults with chronic rheumatologic conditions. DESIGNS: Prospective intervention study. SETTING: Midwestern academic pediatric rheumatology practice. PARTICIPANTS: Ten attending rheumatologists and fellows and 178 patients (mean age, 18.1 years; 67% female; 88% white; 69% with juvenile rheumatoid arthritis) seen in the practice during the baseline and intervention years. MAIN OUTCOME MEASURES: Change in the rate of screening for alcohol use and sexual activity from the baseline to the intervention year, and physician perceptions of the intervention. RESULTS: Screening for alcohol use increased from 4.2% (9/208) at baseline to 31.6% (56/177) after the intervention (P<.001). Of those patients undergoing screening at follow-up, 20 (36%) of 56 patients reported any alcohol use and 11 (20%) reported current alcohol use. Of those reporting current use, 7 (64%) were counseled or referred. Methotrexate use increased the likelihood of alcohol screening (43% [33/76] vs 26% 123/871; P = .02). Screening for sexual activity increased from 12.4% (27/ 218) to 36.2% (64/177) (P<.001) from baseline to follow-up. Of 52 females undergoing screening at follow-up, 31 (60%) were sexually active. Eleven (41%) of 27 sexually active females were not using contraception other than condoms (4 were not asked about contraception); 7 (82%) of these were referred for contraceptive counseling. Seven rheumatologists completed in-depth semistructured interviews after the intervention. All reported time as a main barrier to screening. Other barriers included logistical problems, discomfort with the subject area, ambivalence about whether risk behavior screening is the province of pediatric rheumatologists, and perceived lack of applicability to their patients. CONCLUSIONS: Despite knowledge and concern about the interaction of immunosuppressive therapy and risk behaviors, few rheumatologists adequately screen the behavior of their adolescent and young adult patients. Time constraints, organizational issues, and physician beliefs remain barriers to widespread screening.
10342386 Musculoskeletal manifestations of osteomalacia: report of 26 cases and literature review. 1999 Apr OBJECTIVE: This study was undertaken to describe the musculoskeletal manifestations in a selected population of 26 patients with biopsy-proven osteomalacia (OM) and provide a literature update. METHODS: The 26 patients with biopsy-proven OM were selected from a total number of 79 patients who underwent anterior iliac crest biopsy. The diagnosis of OM was confirmed by the presence of an osteoid volume greater than 10%, osteoid width greater than 15 microm, and delayed mineralization assessed by double-tetracycline labeling. RESULTS: OM was caused by intestinal malabsorption in 13 patients, whereas six other patients presented with hypophosphatemia of different causes. Five elderly patients presented with hypovitaminosis D, and in two patients the OM was part of renal osteodystrophy. Twenty-three patients presented with bone pain and diffuse demineralization, whereas three other patients had normal or increased bone density. Characteristic pseudofractures were seen in only seven patients. Six of the 23 patients with diffuse demineralization had an "osteoporotic-like pattern" without pseudofractures. Prominent articular manifestations were seen in seven patients, including a rheumatoid arthritis-like picture in three, osteogenic synovitis in three, and ankylosing spondylitis-like in one. Two other patients were referred to us with the diagnosis of possible metastatic bone disease attributable to polyostotic areas of increased radio nuclide uptake caused by pseudofractures. Six patients also had proximal myopathy, two elderly patients were diagnosed as having polymalgia rheumatica, and two young patients were diagnosed as having fibromyalgia. One of the patients who presented with increased bone density was misdiagnosed as possible fluorosis. CONCLUSION: OM is usually neglected when compared with other metabolic bone diseases and may present with a variety of clinical and radiographic manifestations mimicking other musculoskeletal disorders.
9815503 Salmonella Urosepsis Complicated by Metastatic osteomyelitis of the Chest Wall. 1997 Sep 1 Although tens of thousands of Salmonella infections occur annually in this country, most involve the gastrointestinal tract with involvement of the urinary tract being quite infrequent.1-3 I would like to report a case of urosepsis due to Salmonella with eventual development of metastatic osteomyelitis of a rib that proved refractory to treatment. A 59-year-old Latin American male who resided in the Texas Rio Grande Valley presented to an emergency room with inability to void, having first noted a decreased urinary stream and dribbling a few months earlier. In-and-out bladder catheterization yielded 700 cc of urine, and he was sent out on co-trimoxazole one double-strength tablet twice daily. The patient returned within several hours, again unable to void, and a Foley catheter was inserted draining 1100 cc of urine. The patient was admitted for further evaluation. Past history was notable for long-standing inflammatory arthritis treated with injectable gold, hydroxychloroquine and nonsteroidal anti-inflammatory agents. He had previously undergone left shoulder replacement and synovectomy of both knees. Diabetes mellitus was diagnosed 6 years earlier and treated with oral hypoglycemic agents. The patient denied any gastrointestinal complaints. Examination was notable for a temperature of 102.4 degreesF and obvious sequelae of long-standing rheumatoid arthritis. The abdomen was entirely benign, but rectal examination revealed an enlarged, nontender prostate. White blood cell count was 11,200/mm3. Urinalysis revealed 10-12 white blood cells per high power field and 15-20 red blood cells per high power field. Two blood cultures from admission grew Salmonella species sensitive to all antibiotics. Urine cultured at the time of admission remained sterile. The patient was treated initially with tobramycin and ciprofloxacin and was changed to ceftriaxone 1 g intravenously every 12 hr when the Salmonella was identified. Ultrasound examination confirmed an enlarged prostate but disclosed no ureteral or renal abnormalities. Intravenous pyelogram also revealed the enlarged prostate but was otherwise unremarkable. On the ninth hospital day a transurethral resection of the prostate (TURP) was performed with histologic evidence of abscesses containing acute inflammatory cells in the resected tissue. The tissue itself was culture negative. He gradually defervesced and completed a 14-day course of parenteral therapy. The patient did well for about 6 months at which point he developed anterior chest wall pain for which he applied a heating pad. A second degree burn developed which ulcerated and began to drain. Culture revealed Salmonella species with a similar sensitivity pattern as the previous isolate. Local care as well as courses of oral ciprofloxacin and chloramphenicol failed to eradicate the drainage. The patient underwent surgical excision of the sinus tract 11 months after the initial bacteremia. Surgical specimens again grew Salmonella. Unfortunately, neither this nor the previous chest wall isolate was saved for further analysis. The area continued to drain and bone scan was consistent with osteomyelitis of the left sixth rib. Ceftriaxone 2 g intravenously per day was begun. The following month (16 months after the initial bacteremia) the patient underwent extensive debridement of the anterior chest wall with removal of the sixth and seventh ribs, and closure via a pectoralis myocutaneous flap. Forty-eight hours postoperatively, the patient suffered an acute myocardial infarction and expired. Postmortem revealed severe coronary artery disease. No additional focus of Salmonella infection was found.
11407688 The combination of tumor necrosis factor alpha blockade with interleukin-1 and interleukin 2001 Jun OBJECTIVE: Anti-tumor necrosis factor a (anti-TNFalpha) therapy has shown efficacy in the treatment of rheumatoid arthritis (RA). Since interleukin-1 (IL-1), TNFalpha, and IL-17 have many additive and/or synergistic effects in vitro, we tested whether their combined inhibition by soluble receptors would lead to an enhanced effect on ex vivo models of synovial inflammation and bone destruction. METHODS: RA synovium and bone explants were cultured for 7 days in the presence of 1 microg/ml soluble TNFalpha receptor (STNFR; as in current therapy), type II soluble IL-1 receptor (sIL-1RII), or sIL-17R either alone or in combination. Their effects on the production of IL-6 and the release of C-telopeptide of type I collagen (CTX), a marker of type I collagen destruction, were measured by enzyme-linked immunosorbent assay. RESULTS: In synovium, each soluble receptor alone decreased IL-6 production and CTX release by approximately 35% and approximately 55%, respectively. The combination of all 3 receptors was more effective, inhibiting IL-6 production and collagen degradation by up to 70%. Neither sIL-17R, sIL-1RII, or sTNFR alone had no effect (or an effect of <20% inhibition) on IL-6 production in 18%, 33%, and 22%, respectively, of the samples. In bone, sIL-17R, sIL-1RII, and sTNFR decreased IL-6 production by 23%, 50%, and 37%, respectively, while the combination decreased IL-6 production by 75%. A 50% inhibition of CTX release was obtained with sIL-1RII for 63% of the samples versus 38% of the samples with either sTNFR or sIL-17R. However, the combination of all 3 receptors was not more potent than sIL-1RII alone. CONCLUSION: The inhibitory effect of sTNFR on IL-6 production and collagen degradation in RA synovium and bone was increased in combination with sIL-17R and sIL-1RII. These results support the concept of combination therapy, which may increase the percentage of responding patients as well as the degree of individual patient response.
10929893 Who needs prophylaxis of nonsteroidal anti-inflammatory drug-induced ulcers and what is op 2000 Jun Nonsteroidal anti-inflammatory drugs (NSAIDs) are used successfully by many patients for the treatment of the signs and symptoms of arthritis, and other painful and inflammatory disorders. However, traditional nonselective NSAIDs that inhibit COX-1 and COX-2 lead to a state of propensity for gastric and duodenal ulcer disease and ulcer complications. The point prevalence of endoscopic ulcers ranges from 14 to 44% of patients using NSAIDs. Moreover, it is estimated that 1.46-1.90% of chronic NSAID users develop serious upper gastrointestinal (UGI) toxicity annually, most notably UGI bleeding, gastric/duodenal obstruction or ulcer perforation. In the USA, it has been estimated that 107,000 hospitalisations and 16,500 deaths occur annually related to the use of nonselective NSAIDs. Because these ulcer complications are often not heralded by chronic symptoms of dyspepsia, symptoms alone are not sufficient to guide long-term management of NSAID-related toxicity. Instead, prophylactic and preventive therapies are recommended in patients at above-average and high risk. Epidemiological data have identified that patients with a past history of ulcer disease, past history of UGI bleeding, greater age, concomitant corticosteroid use, and those who use higher doses and multiple NSAIDs fall into this category. Other risk factors of lesser importance have also been identified. A controversial issue remains regarding the possible increased risk of NSAID-associated ulcers and ulcer complications in patients who are infected with Helicobacter pylori. Prophylactic therapies have been evaluated primarily in randomised clinical trials, with the rate of endoscopic ulcers as the primary endpoint. It is assumed, but not proven, that these endoscopic ulcer rates are surrogate markers for gastrointestinal toxicity and are predictive of the rate of significant UGI adverse events. In the only outcomes trial to date, it was reported that misoprostol (200 microg 4 times daily) caused an approximately 50% reduction in serious UGI adverse events in a large 6-month trial involving rheumatoid arthritis patients. In parallel, this approximates the 50% reduction of endoscopic ulcers seen in randomised controlled trials using misoprostol. While H2 receptor antagonists are ineffective agents at traditional doses, proton pump inhibitors have been clearly shown to reduce the rate of endoscopic ulcers in several trials. In fact, the efficacy approximates to the efficacy seen with misoprostol. Beyond efficacy and in practical terms, the choice of optimal prophylaxis should take into consideration patient compliance, patient satisfaction, side-effects and cost.
10479465 Health benefits of docosahexaenoic acid (DHA). 1999 Sep Docosahexaenoic acid (DHA) is essential for the growth and functional development of the brain in infants. DHA is also required for maintenance of normal brain function in adults. The inclusion of plentiful DHA in the diet improves learning ability, whereas deficiencies of DHA are associated with deficits in learning. DHA is taken up by the brain in preference to other fatty acids. The turnover of DHA in the brain is very fast, more so than is generally realized. The visual acuity of healthy, full-term, formula-fed infants is increased when their formula includes DHA. During the last 50 years, many infants have been fed formula diets lacking DHA and other omega-3 fatty acids. DHA deficiencies are associated with foetal alcohol syndrome, attention deficit hyperactivity disorder, cystic fibrosis, phenylketonuria, unipolar depression, aggressive hostility, and adrenoleukodystrophy. Decreases in DHA in the brain are associated with cognitive decline during aging and with onset of sporadic Alzheimer disease. The leading cause of death in western nations is cardiovascular disease. Epidemiological studies have shown a strong correlation between fish consumption and reduction in sudden death from myocardial infarction. The reduction is approximately 50% with 200 mg day(-1)of DHA from fish. DHA is the active component in fish. Not only does fish oil reduce triglycerides in the blood and decrease thrombosis, but it also prevents cardiac arrhythmias. The association of DHA deficiency with depression is the reason for the robust positive correlation between depression and myocardial infarction. Patients with cardiovascular disease or Type II diabetes are often advised to adopt a low-fat diet with a high proportion of carbohydrate. A study with women shows that this type of diet increases plasma triglycerides and the severity of Type II diabetes and coronary heart disease. DHA is present in fatty fish (salmon, tuna, mackerel) and mother's milk. DHA is present at low levels in meat and eggs, but is not usually present in infant formulas. EPA, another long-chain n-3 fatty acid, is also present in fatty fish. The shorter chain n-3 fatty acid, alpha-linolenic acid, is not converted very well to DHA in man. These longchain n-3 fatty acids (also known as omega-3 fatty acids) are now becoming available in some foods, especially infant formula and eggs in Europe and Japan. Fish oil decreases the proliferation of tumour cells, whereas arachidonic acid, a longchain n-6 fatty acid, increases their proliferation. These opposite effects are also seen with inflammation, particularly with rheumatoid arthritis, and with asthma. DHA has a positive effect on diseases such as hypertension, arthritis, atherosclerosis, depression, adult-onset diabetes mellitus, myocardial infarction, thrombosis, and some cancers.
9486409 Modulation of proinflammatory cytokine production in tumour necrosis factor-alpha (TNF-alp 1998 Feb TNF-alpha is one of the major proinflammatory cytokines involved in the pathogenesis of chronic inflammatory joint disease, in human rheumatoid arthritis as well as in murine models of this disease. It was previously described that a highly destructive chronic spontaneous inflammatory arthritis develops in mice expressing a human TNF-alpha transgene modified with the 3' untranslated region of beta-globin. The present study investigates in this mouse model the effects of the anti-inflammatory cytokines IL-4, IL-10 and IL-13 administered in vivo on proinflammatory cytokine expression. Groups of TNF-alpha-transgenic mice were engrafted with xenogeneic transfected Chinese hamster ovary (CHO) fibroblasts secreting murine IL-4, IL-10 or IL-13. In vivo treatments consisted of 3 or 4 weekly engraftments, starting when the mice were 4weeks old. Control groups of transgenic mice were engrafted with beta-galactosidase gene-transfected CHO cells or injected with medium. A significant decreased expression of TNF-alpha transgene, endogenous mouse TNF-alpha and IL-1 mRNA was observed in splenocytes of mice treated for 3 or 4 weeks with CHO/IL-4 and CHO/IL-13, and, to a lesser extent, with CHO/IL-10, compared with controls. Finally, attenuation of histological scores of arthritides was statistically significant only in the group of CHO/IL-4-treated mice after 3weeks of treatment (P<0.05), and was not significant in any other group. These results show that IL-4, IL-10 or IL-13, administered by gene therapy, can decrease the mRNA steady state levels of both endogenous and transgenic cytokines in human TNF-alpha transgenic mice. In addition, IL-4 can slightly attenuate the development of arthritides in this model.
9528991 Inhibitory effect of glucocorticoid for osteoblast apoptosis induced by activated peripher 1998 Apr Recent studies suggest a protective effect of glucocorticoid against progression of bone erosion and periarticular osteoporosis in patients with rheumatoid arthritis (RA), although this steroid hormone itself is believed to increase bone loss. To understand the antagonistic effect of glucocorticoid for osteopenic process in RA patients, we examined the effect of dexamethasone on Fas-mediated apoptosis of cultured human osteoblasts induced by either anti-Fas IgM or activated peripheral blood mononuclear cells (PBMC). Human osteoblastic cell line MG63 and primary osteoblast-like cells obtained from biopsy specimens were used in this study. PBMC isolated from healthy donors were cultured with or without recombinant interleukin-2 (rIL-2) followed by 12-O-tetradecanoyl-phorbol 13-acetate (PMA) with ionomycin in the presence or absence of dexamethasone. Fas was functionally expressed on MG63 and primary osteoblast-like cells, and treatment of these cells with dexamethasone affected neither Fas expression nor anti-Fas IgM-induced apoptosis. Activated PBMC expressing membrane-type Fas ligand (mFasL) efficiently killed both MG63 and primary osteoblasts-like cells, and the addition of human Fas chimeric protein (hFas-Fc) significantly diminished the cytotoxicity, indicating that interactions between mFasL of activated PBMC and Fas on human osteoblasts induce apoptosis of the latter. Although dexamethasone did not affect apoptosis of MG63 and primary osteoblast-like cells induced by anti-Fas IgM, treatment of activated PBMC with dexamethasone markedly inhibited both mFasL expression and cytotoxicity of these cells against human osteoblasts, suggesting that dexamethasone preferentially acts not on osteoblasts but PBMC. Cultured supernatants from activated PBMC induced apoptosis of human osteoblasts and the addition of hFas-Fc also inhibited the cytotoxicity of the supernatants. In addition, soluble form FasL (sFasL) was detected in the supernatants of activated PBMC. Furthermore, both the cytotoxicity and sFasL concentration of cultured supernatants of activated PBMC incubated with dexamethasone was significantly lower than that in the absence of dexamethasone. Our data suggest that glucocorticoid suppresses the apoptotic process of osteoblasts by inhibiting the expression of both mFasL and sFasL derived from activated PBMC, mediating a protective effect against periarticular bone loss and bone erosion in inflammatory arthritis such as RA.
11268330 Immunoablation followed by autologous hematopoietic stem cell infusion for the treatment o 2000 Nov BACKGROUND AND OBJECTIVES: The aim of this study was to evaluate the tolerability and effectiveness of a non-myeloablative conditioning regimen followed by autologous hematopoietic stem cell infusion for the treatment of severe autoimmune diseases. DESIGN AND METHODS: From 1996 patients with severe autoimmune disease not responsive to conventional immunosuppressive treatment were selected. The patients' blood or marrow cells were harvested after incubation with vincristine and methylprednisolone. Two different immunoablative conditioning regimens were employed. The first used cyclophosphamide (2500 mg/m2 in one day) and antilymphocyte globulin (ALG) (15 vials/m2 in three days) and the second used fludarabine (300 mg/m2 in two courses of 5 days) plus ALG (25 vials/m2 in 5 days). RESULTS: Nineteen patients (14 female, 5 male) with severe autoimmune diseases were treated. Nine had a rheumatologic disorder (5 juvenile chronic arthritis, 1 rheumatoid arthritis, 1 systemic vasculitis, 1 Sjögren's syndrome, 1 Behçt's disease), 4 a neurologic disorder (3 multiple sclerosis, 1 myasthenia), 3 a haematologic disease (2 pure red cell aplasia, 1 autoimmune thrombocytopenia), 2 had a gastrointestinal disease (1 Crohn's disease, 1 autoimmune enteropathy) and 1 had a multiple autoimmune disorder. There was no regimen-related toxicity and no opportunistic infections occurred. Ninety percent of the patients improved and/or had a complete remission after the procedure. Fifty percent of the subjects went into complete or partial remission after a median follow-up of 15 months (range 3-25) while 50% relapsed after a median follow-up of 11 months, (range 6-16). The incidence of relapse in the group treated with fludarabine was lower (30%). INTERPRETATION AND CONCLUSIONS: A non-myeloablative conditioning regimen was able to induce persistent remission in some patients with severe autoimmune diseases. There was no mortality or morbidity related to the procedure. The extent of remission does, however, remain to be established.
11037891 Nucleosomes are major T and B cell autoantigens in systemic lupus erythematosus. 2000 Oct OBJECTIVE: Double-stranded DNA (dsDNA) is a well-known target of autoantibodies in systemic lupus erythematosus (SLE). The majority of these autoantibodies are of the IgG isotype and show affinity maturation, both of which are known hallmarks of T cell help. T cell responses to autoantigens, including DNA, have been reported only incidentally in SLE patients. Nevertheless, in murine SLE, naked DNA and complexed DNA (nucleosomes) are known to be recognized by T cells. This study aimed to characterize the antinucleosome response and its clinical impact on human SLE. METHODS: Nucleosomes were prepared from chicken erythrocytes. Sera from SLE and control patients were investigated by enzyme-linked immunosorbent assay (ELISA) for nucleosome-specific antibody responses. Peripheral blood mononuclear cells (PBMC) from SLE and control patients were analyzed by a kinetic T cell proliferation assay. PBMC were subsequently analyzed for nucleosome-specific T cell proliferation. RESULTS: Of 136 SLE patients, 56% were seropositive for antinucleosome antibodies. In contrast, only 3% of 309 control patients (with rheumatoid arthritis, mixed connective tissue disease, undifferentiated connective tissue disease, Lyme borreliosis, scleroderma, Sjögren's syndrome, ulcerative colitis, hepatitis B virus infection, or human immunodeficiency virus infection) were seropositive. Thus, the antinucleosome ELISA had a sensitivity of 56%, a specificity of 97%, and a diagnostic confidence of 90% when applied to SLE. It was therefore superior to an anti-DNA ELISA that demonstrated a 69% diagnostic confidence in the same population. Antinucleosome reactivity in SLE patients correlated significantly with disease activity (P < 0.0001), nephritis (P < 0.002), and psychosis (P < 0.02). When proliferation assays were applied, 14 of 26 SLE patients (54%) were positive for nucleosome-specific T cells that proliferated in response to their cognate antigen. A suppressed response was elicited in 3 SLE patients (12%); in these patients, the PBMC response to nucleosomes was lower than the proliferation of PBMC in the presence of culture medium only. PBMC from the remaining 9 SLE patients (35%) were nonresponsive to nucleosomes in either way. Responding, nonresponding, and suppressed populations differed from each other significantly (P < 0.0001). None of the PBMC from 7 healthy donors and 10 control patients could be stimulated with nucleosomal antigens. CONCLUSION: We present evidence that nucleosomes are major autoantigens in human SLE and that antinucleosomal antibodies are highly specific for the disease. The antinucleosome ELISA has been shown to be superior to the anti-dsDNA ELISA and may thus be a significantly better tool for diagnosing SLE. Nucleosome-specific T cells in SLE patients may help B cells class switch to IgG and undergo affinity maturation.
10779796 Ley/H: an endothelial-selective, cytokine-inducible, angiogenic mediator. 2000 May 1 Endothelial cells (ECs) are key participants in angiogenic processes that characterize tumor growth, wound repair, and inflammatory diseases, such as human rheumatoid arthritis (RA). We and others have shown that EC molecules, such as soluble E-selectin, mediate angiogenesis. Here we describe an EC molecule, Lewisy-6/H-5-2 glycoconjugate (Ley/H), that shares some structural features with the soluble E-selectin ligand, sialyl Lewisx (sialyl Lex). One of the main previously recognized functions of Lewisy is as a blood group glycoconjugate. Here we show that Ley/H is rapidly cytokine inducible, up-regulated in RA synovial tissue, where it is cell-bound, and up-regulated in the soluble form in angiogenic RA compared with nonangiogenic osteoarthritic joint fluid. Soluble Ley/H also has a novel function, for it is a potent angiogenic mediator in both in vitro and in vivo bioassays. These results suggest a novel paradigm of soluble blood group Ags as mediators of angiogenic responses and suggest new targets for therapy of diseases, such as RA, that are characterized by persistent neovascularization.