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ID PMID Title PublicationDate abstract
9144507 Chloroquine inhibits processing of tumor necrosis factor in lipopolysaccharide-stimulated 1997 May 15 TNF, a potent immunoregulatory cytokine, is associated with inflammatory diseases such as rheumatoid arthritis, multiple sclerosis, and cerebral malaria when produced in excess. Antimalarial agents such as chloroquine and hydroxychloroquine have been used to treat some rheumatic diseases. Chloroquine was reported to inhibit production of TNF, although the underlying mechanism is poorly understood. In RAW 264.7 cells stimulated with LPS, addition of chloroquine at nontoxic concentrations did not inhibit induction of TNF mRNA and NF-kappaB activity. In the same cells, synthesis and steady state level of 26-kDa pro-TNF were also not significantly reduced by addition of chloroquine, while only small amount of 17-kDa mature TNF was detected in the medium. A pulse-chase experiment of pro-TNF produced in chloroquine-treated cells showed significant inhibition of processing of prohormone. Hydroxychloroquine showed similar inhibitory effect, whereas other lysosomal inhibitors such as ammonium chloride and methylamine had no effect on the production of TNF. Our results suggest that chloroquine inhibits production of TNF at the step of processing of membrane-bound pro-TNF to make soluble mature protein in a lysosome-independent manner.
9192179 Regulation of NF-kappa B and disease control: identification of a novel serine kinase and 1997 We have identified novel signal transduction cascades in activating NF-kappa B, as well as its pathogenetic roles in various disease processes. By applying the basic knowledge obtained through these studies, we hope to find new therapeutic measures against currently incurable diseases such as hematogenic cancer cell metastasis, rheumatoid arthritis, and AIDS. We also propose a novel strategy in screening effective inhibitors against transcription factors. Elucidation of the cis-regulatory element for expression of pathogenetic genes and identification of the responsible transcription factor will not only facilitate the study of pathogenesis but will also promote the development of effective therapy. Recognition of control mechanisms of the NF-kappa B activation pathway has explained the therapeutic efficacy of various compounds with different pharmacologic actions. A similar strategy may be applicable for other inducible transcription factors. From the medical point of view, one of the purposes of these approaches is to find small molecular weight compounds that can be administered orally and that are effective in controlling gene expression of pathogenetic genes.
19078482 Guidelines for Monitoring of NSAIDS: Who Listened? 2000 Oct The side effects of nonsteroidal anti-inflammatory drugs (NSAID) include problems involving peptic ulceration, renal function, and liver disease. Publications have stressed the need to monitor patients for these problems and the rheumatology community across the country has echoed these concerns in continuing education activities to physicians over the years. The American College of Rheumatology (ACR) disseminated recommendations for nonsteroidal anti-inflammatory drugs (NSAID) monitoring in rheumatoid arthritis (RA) patients. We used this as an example of expert opinion for monitoring of NSAID and compared it with the frequency of monitoring by primary care physicians using NSAID for various diseases. We asked whether the rheumatology community's efforts were successful over time to enhance NSAID monitoring by primary care physicians. Physicians across the United States, using a computerized medical record, allowed data to be extracted from their medical practices. Dates of NSAID prescriptions and laboratory test monitoring for any diagnosis were analyzed. Those tests included a CBC, hepatic panel, and renal tests. The frequency of baseline tests performed within 3 months before starting a NSAID by internists was 30% compared with 6% by family practitioners in private practice and 1% in academic family practice centers before publication of the ACR guideline. After dissemination of the guidelines in 1996, the frequency of baseline testing by these groups was lower. Follow-up monitoring within 3 months of starting a NSAID was also low (24, 3, and 2% respectively) and did not improve after ACR guideline publication. Publication and dissemination of the ACR guidelines, and other efforts, did not improve rates of monitoring. The rheumatology community needs to re-evaluate the effectiveness of programs that teach safe use of rheumatologic medications by primary care physicians.
20478142 [Longterm results of poldi hip replacement.]. 1999 The authors evaluated 124 patients operated on by means of cemented Poldi THR in the period 1980-1986 on average 14,2 years after the primary implantation (12,2-18,0). Average age of patients was 55 years (in the range of 33 to 75). Pre-operative diagnosis was osteoarthritis in 78 cases and rheumatoid arthritis in 46 patients. All patients had normal anatomical relations. The implants applied included a 49 mm polyethylene cup and a bananashaped CoCr polished stem with 32 mm head with the use of 1st generation method of cementing. Harris Hip Score averaged prior to the surgery 49 (19-52) and after the surgery 68 (49-98). In 59 patients Harris Hip Score was above 70 points. In total, 10 revision surgeries were performed of which 9 due to aseptic loosening (the cup - 6times, the cup and the stem - twice, the stem - once) and 1 due to septic loosening. There were 23 cases of evident loosening of the cup (of which 8 symptomatic and 15 asymptomatic one) and 8 probable. The number of potential operations of the cup is 46 and that of the stem 11. Combined prevalence of revision surgeries accomplished and potential is 54 (43,5 %) in case of the cup and 14 (11,2 %) in case of the stem. The survival rate after 14 years is 81,5 % in the acetabular cup and 95,2 % in case of the stem. Authors found out an increased number of THR failure after 12 years due to aseptic loosening of the acetabular cup. After the Kaplan-Maier curve the survival rate of THR after 4 years is 99 %, after 8 years 97 %, after 10 years 94 %, after 12 years 91 % and after 15 years 76 %. Linear polyethylene wear of the cup is on average 0,14 mm annually, and the volumetric one amounts to 189 cubic mm annually. Key words: THR, longterm results.
11809002 Thalidomide: new indications? 2001 Dec Thalidomide, which was developed as a nonbarbiturate sedative agent, was taken off the market in 1961 after it was linked to a spate of major birth defects. Gradually, thalidomide was reintroduced for the treatment of a few skin diseases including leprous erythema nodosum, severe mucosal ulcers (e.g., associated with HIV infection or Behçet's disease), lymphocytic skin infiltrations, cutaneous lupus erythematosus, and chronic graft-versus-host disease. Recent reports of original pharmacological properties including modulation of cytokine production (mainly reduced TNF-alpha production) and inhibition of angiogenesis have led to the suggestion that thalidomide may be useful in some inflammatory and neoplastic conditions. Several open-label studies and case reports have described the effects of thalidomide in Crohn's disease, rheumatoid arthritis, ankylosing spondylarthritis, systemic sclerosis, and a few other systemic disorders. In these indications, minor but dose-limiting side effects were apparently common. Thalidomide analogs with better acceptability profiles are under evaluation. The anti-angiogenic effects of thalidomide may make this compound valuable as single-drug therapy or as an adjunct to chemotherapy in patients with cancer, particularly those with metastases or multiple myeloma. This possibility requires further evaluation.
11765223 Lung cancer associated with several connective tissue diseases: with a review of literatur 2001 Nov The association between connective tissue disease (CTD) and malignancy has been an area of debate. Whether this relation is casual or causal, it would seem that the importance of their possible relationship is twofold. The purpose of this study is to describe the clinical features of lung cancer associated with several CTDs. Patients with CTD associated with lung cancer were retrospectively evaluated. A review of the clinical features of 153 reported cases from 1944 to the present was conducted. There were 82 females and 71 males, with a median age of 58. Histological types of lung cancer were as follows, bronchioloalveolar cell carcinoma (39 cases), adenocarcinoma (36), squamous cell carcinoma (28), small cell lung cancer (27), large cell carcinoma (6), others (8), and unknown (10). There was a relationship between smoking and development of lung cancer in patients with rheumatoid arthritis (RA) and polymyositis/dermatomyositis (PM/DM). The majority of patients with progressive systemic sclerosis (PSS) who developed lung cancer were female, with underlying interstitial fibrosis, and most tumors were of bronchioloalveolar cell or adenocarcinoma cell type. Patient characteristics were significantly different among the various groups of CTD associated with lung cancer.
11753240 [Somatostatin receptors in immune system cells]. 2001 Sep Many hormones and some neuropeptides and neurotransmitters play a key role in regulating numerous lymphoid cell functions. In particular, somatostatin (ss), substance P (sp) and vasoactive intestinal polypeptide (vip) appear to be involved in numerous regulating mechanisms of cell activities in the immune system under both physiological and pathological conditions. ss may be produced by lymphoid cells and accessories as part of the immune system. The distribution of somatostatin receptors (ssr) in the normal human thymus has prompted the hypothesis that ss, and probably other neuropeptides, may play an important role in cell homeostasis in this organ, as well as being one of the processes that regulates the maturation of T lymphocytes. The advent of molecular biology has showed a variable expression of ssr on the various T and B cell lines or lines deriving from lymphoma/ leukemia and human myeloma. Using autoradiographic studies, ssr have been predominantly found in lymphoblastic areas of lymphoma, which represent the active part of the tumour. The expression of ssR has been found in vivo and in vitro, also in pathological sites in patients with autoimmune and granulomatous diseases like rheumatoid arthritis and sarcoidosis.
11711037 Ovariectomy aggravates convulsions and hippocampal gamma-aminobutyric acid inhibition indu 2001 Nov 2 The possible cyclosporin A application for rheumatoid arthritis that develops preferentially in middle-aged women raises concerns about adverse effects of cyclosporin A, including neurotoxicity in patients with climacterium. The present study was aimed at elucidating the effect of cyclosporin A on the convulsive activity and gamma-aminobutyric acid (GABA) neural activity of the hippocampus in ovariectomized rats, as a menopause/climacterium model. Ovariectomy markedly aggravated the effect of repeated administration of cyclosporin A (40 mg/kg, once a day for 5 or 6 days), convulsions and reduction of the basal GABA levels and aminooxyacetic acid-evoked GABA accumulation. These aggravations were blocked by estradiol replacement. The present findings demonstrated that ovariectomy increased the susceptibility to cyclosporin A-induced convulsions by accelerating an inhibitory action of cyclosporin A on GABA neural activity in the hippocampus, this being blocked by estrogen replacement. Menopause/climacterium is, therefore, included in the risk factors for cyclosporin A-induced neurotoxicity and this risk is lowered by estrogen replacement therapy.
11555615 Production of soluble human alpha3-fucosyltransferase (FucT VII) by membrane targeting and 2001 Sep The rational design of fucosyltransferase (FucT VII) inhibitors as potential medication in the treatment of rheumatoid arthritis requires the three-dimensional structure of this member of the glycosyltransferase family. Structure determination by X-ray diffraction analysis needs purified, soluble enzyme protein. For this purpose we developed a novel method for the high-yield production of soluble FucT VII by in vivo proteolysis. To obtain a soluble form of FucT VII a mammalian expression construct was made encoding an N-terminal portion of FucT VI (amino acids 1-63) fused with the stem region and catalytic domain of FucT VII (amino acids 39-342). Chinese hamster ovary cells stably transfected with this construct produced FucT activity in the supernatant, which has the same catalytic properties as wild-type FucT VII. This soluble form of FucT VII can be obtained in high amounts (1 mg/L) and can be efficiently purified by GDP-hexanolamine affinity chromatography. In conclusion, it was demonstrated that the intrinsic properties of FucT VII could be transferred to secreted FucT VII constructs, which may open possibilities for production of soluble forms of other members of the glycosyltransferase family as well.
11541781 Protein crystal growth and the International Space Station. 1999 May Protein structural information plays a key role in understanding biological structure-function relationships and in the development of new pharmaceuticals for both chronic and infectious diseases. The Center for Macromolecular Crystallography (CMC) has devoted considerable effort studying the fundamental processes involved in macromolecular crystal growth both in a 1-g and microgravity environment. Results from experiments performed on more than 35 U.S. space shuttle flights have clearly indicated that microgravity can provide a beneficial environment for macromolecular crystal growth. This research has led to the development of a new generation of pharmaceuticals that are currently in preclinical or clinical trials for diseases such as cutaneous T-cell lymphoma, psoriasis, rheumatoid arthritis, AIDS, influenza, stroke and other cardiovascular complications. The International Space Station (ISS) provides an opportunity to have complete crystallographic capability on orbit, which was previously not possible with the space shuttle orbiter. As envisioned, the x-ray Crystallography Facility (XCF) will be a complete facility for growing protein crystals; selecting, harvesting, and mounting sample crystals for x-ray diffraction; cryo-freezing mounted crystals if necessary; performing x-ray diffraction studies; and downlinking the data for use by crystallographers on the ground. Other advantages of such a facility include crystal characterization so that iterations in the crystal growth conditions can be made, thereby optimizing the final crystals produced in a three month interval on the ISS.
11446385 Etanercept reduces hyperalgesia in experimental painful neuropathy. 2001 Jun Etanercept, a recombinant tumor necrosis factor receptor (p75)-Fc fusion protein competitively inhibits tumor necrosis factor-alpha (TNF). Etanercept has been successfully used in patients with rheumatoid arthritis, where it reduces pain and inflammation. Because locally produced proinflammatory cytokines play a role in pain after nerve injury, we investigated whether etanercept can reduce pain and hyperalgesia in an animal model of painful neuropathy, the chronic constriction injury of the sciatic nerve. C57BL/6 mice received etanercept or sham treatment by local near-nerve injection to the injured nerve or by systemic application. Treatment with etanercept reduced thermal hyperalgesia and mechanical allodynia significantly in both modes of application. The effect of etanercept was present in animals that were treated from the time of surgery and in those that were treated from day 6, when hyperalgesia was already present. These results suggest the potential of etanercept as a treatment option for patients with neuropathic pain.
11361190 Osteoporosis with low dose corticosteroids: contribution of underlying disease effects and 2001 May OBJECTIVE: Corticosteroid use is associated with rapid bone loss, but the effect of low dose corticosteroids (CS) remains controversial and the extent to which increased fracture risk relates to quantitative effects, as reflected by change in bone mineral density (BMD), or to qualitative effects due to altered microarchitecture is unclear. Moreover the contribution of the underlying disease, for which CS are used, confounds the assessment of CS effects on bone. Our aim was to examine these effects of CS on bone. METHODS: We measured BMD, quantitative ultrasound (US), and clinical and radiological disease indices in 76 patients with rheumatoid arthritis (RA) treated with or without low dose CS. Disease effects were quantitated using the Health Assessment Questionnaire and radiological scores. RESULTS: BMD and US measures were significantly reduced in RA patients compared to age matched controls. Low dose CS use was associated with a further small but nonsignificant reduction in BMD, and US measures did not further discriminate CS effects on bone. Radiological score was an independent predictor of US measures, suggesting that in RA, calcaneal bone may reflect both systemic and local disease effects. CONCLUSION: US did not appear to discriminate effects of low dose CS on bone better than BMD. However, underlying RA disease effects on bone are detectable by US. Quantitative US should be investigated for its utility in assessing disease activity or progress in RA.
11354547 NF-kappaB activation in sarcoidosis. 2001 Mar BACKGROUND AND AIM: Sarcoidosis is an inflammatory disorder of unknown origin. The nuclear regulatory factor-kappaB (NF-kappaB) appears to play a key role in immune and inflammatory processes such as asthma, rheumatoid arthritis and inflammatory bowel disease. We hypothesized that NF-kappaB activation might be involved in the pathological process of sarcoidosis. METHODS: Twelve sarcoidosis patients, biopsy proven, and five healthy control subjects, all nonsmokers, were studied. Blood samples were taken and routinely analysed for several parameters including the serum angiotensin converting enzyme (sACE) level. Mononuclear cells were isolated from these patients in order to quantify the NF-kappaB contents in the nuclear extract of the mononuclear cells. RESULTS: Mononuclear cells NF-kappaB expressed per mg protein were twice as high in both untreated (n = 5) and treated (n = 7) patients with sarcoidosis compared to the control subjects (p < 0.001). In contrast, the sACE level appeared to be low in the treated patients compared to the untreated patients (p < 0.01). CONCLUSIONS: These results indicate that the inflammation in sarcoidosis is associated with NF-kappaB activation. Moreover, the suppression of the activated NF-kappaB response by glucocorticoids seems less successful than the suppression of the sACE activity. Future studies should focus on the clinical relevance of this observation and establish the possible therapeutic consequences of the increased NF-kappaB activation in sarcoidosis.
11284357 [Manubriosternal dislocation caused by indirect flexion-compression trauma. A case report 2001 Mar Manubriosternal dislocation caused by indirect flexion-compression trauma is an extremely rare condition. Two forms of manubriosternal luxation are distinguished: in type I the sternum is dislocated posterior and in type II anterior to the manubrium. Direct or indirect trauma may cause manubriosternal dislocation. Mode of injury in direct trauma is mostly a head-on collition in a motor accident resulting either in type I or type II luxation. The unusual origin of manubriosternal dislocation by indirect trauma is put down to flexion-compression injuries of the thoracic spine and results in a type II dislocation. Predisposition to manubriosternal dislocation by indirect trauma consists in rheumatoid arthritis or extreme forms of kyphosis. Outcome of many patients treated conservatively after initial reposition with adhesive tape, symptomatic pain therapy, cryotherapy and prohibition of any physical training over several weeks is subluxation or complete luxation of the manubriosternal joint. This condition may lead to chronic pain, periarticular calcification with ankylosis and progredient deformation. Lacking a controlled study for treatment of manubriosternal dislocation a standard therapeutic regime could not be established yet. In the literature only a few case-reports of patients undergoing operative therapy are published. We report a type II dislocation of the manubriosternal joint caused by indirect flexion-compression trauma. We achieved a very good long-term result using a 8-hole 1/3 tubular plate for fixation of the manubriosternal joint after reposition.
11111126 CD3+, CD4-, CD8-, TCR alpha beta-, TCR gamma delta+ granular lymphocyte proliferative diso 2000 Granular lymphocyte-proliferative disorder is characterized by a proliferation of large granular lymphocytes (LGLs). It is often associated with neutropenia, rheumatoid arthritis (RA), and pure red cell aplasia (PRCA). Phenotypic analysis has demonstrated that in most cases, the LGLs show a clonal rearrangement of the TCR alpha beta rearrangement. We are reporting a patient with TCR gamma delta LGL proliferation without clinical findings and lymphocytosis. The patient showed an expansion of the CD3+, CD16+, CD56+, and CD57+ LGL populations which involved coexpression of TCR gamma delta with TCR J gamma and J delta 1 gene rearrangement. Autoimmune manifestations, including RA and PRCA, have not appeared and the results of laboratory examinations have not changed for 1 year after the diagnosis.
11032099 Significant upper gastrointestinal events associated with conventional NSAID versus celeco 2000 Oct Despite their substantial clinical benefits in the management of rheumatoid arthritis, osteoarthritis, pain, and other musculoskeletal complaints, conventional nonsteroidal antiinflammatory drugs (NSAID) are associated with significant toxicities that can frequently limit their use. The most common and noteworthy adverse effects of NSAID are gastrointestinal (GI), and range from dyspeptic symptoms to ulcers and serious ulcer complications. The upper GI toxicities associated with the use of conventional NSAID led to the search for medications that were as clinically effective as these agents, but with a significantly improved GI safety profile. It is now known that the constitutively expressed isoenzyme cyclooxygenase (COX)-1 catalyzes the synthesis of prostanoids that help to regulate normal physiologic processes, including GI mucosa protection, whereas the inducible isoenzyme COX-2 leads to the generation of prostaglandins that mediate inflammation, pain, and fever. This knowledge has led to the development of new compounds that, at therapeutic concentrations, inhibit COX-2 without affecting COX-1. The first COX-2 targeted agent approved by the US Food and Drug Administration (FDA) was celecoxib. This article reviews the risks of GI complications associated with conventional NSAID use and compares these risks with that of the new COX-2 specific inhibitor celecoxib.
10967026 Influence of nucleotide polymorphisms in the CCR2 gene and the CCR5 promoter on the expres 2000 Sep Polymorphisms in the CCR2 gene (CCR2-64I) and the CCR5 promoter (pCCR5-59029G) have been correlated with slower HIV-1 disease progression. How these polymorphisms influence the rate of AIDS progression has remained unclear. We have therefore investigated whether these nucleotide polymorphisms will reduce the expression levels of surface CCR5 and CXCR4, and thus lead to slower AIDS progression. For this, a cohort of Chinese volunteers in Taiwan was subjected to the determination of CCR2 and pCCR5 genotypes followed by analysis of the surface CCR5 and CXCR4 expression on five cell types derived from peripheral blood mononuclear cells by flow cytometry. Several significant associations were detected between genotypes and expression levels of the proteins. The most important finding was that an increased number of CD4(+) cells expressing CCR5 correlated with pCCR5-59029A homozygosity without the interference of both the CCR2-64 and the CCR5 delta 32 (deleted 32 bp) mutations (P: = 0.0453), which is consistent with the previous data on the association of the genotype to AIDS progression. Since different genetic polymorphisms co-exist in human beings, the rate of AIDS progression as well as the risk of rheumatoid arthritis may be governed by the interplay of the array of nucleotide changes and their affected proteins.
10936476 Phagocytes and oxidative stress. 2000 Jul Neutrophils and other phagocytes manufacture O(2)(-) (superoxide) by the one-electron reduction of oxygen at the expense of NADPH. Most of the O(2)(-) reacts with itself to form H(2)O(2) (hydrogen peroxide). From these agents a large number of highly reactive microbicidal oxidants are formed, including HOCl (hypochlorous acid), which is produced by the myeloperoxidase-catalyzed oxidation of Cl(-) by H(2)O(2); OH(*) (hydroxyl radical), produced by the reduction of H(2)O(2) by Fe(++) or Cu(+); ONOO(-) (peroxynitrite), formed by the reaction between O(2)(-) and NO(*); and many others. These reactive oxidants are manufactured for the purpose of killing invading microorganisms, but they also inflict damage on nearby tissues, and are thought to be of pathogenic significance in a large number of diseases. Included among these are emphysema, acute respiratory distress syndrome, atherosclerosis, reperfusion injury, malignancy and rheumatoid arthritis.
10843756 Expression of soluble CD137 correlates with activation-induced cell death of lymphocytes. 2000 Jun CD137 is a member of the tumour necrosis factor receptor family which delivers a potent co-stimulatory signal to T lymphocytes. Soluble forms of CD137 (sCD137) can be found at enhanced levels in sera of patients with rheumatoid arthritis. Here we show that expression of sCD137 lags behind that of membrane-bound CD137 (mCD137) by about 24 h. In fully activated lymphocytes, time of maximum increase and level of expression of sCD137 were at day 2 and 3, respectively. Expression of sCD137 in lymphocytes requires strong activation, and levels of sCD137 correlate negatively with lymphocyte proliferation and positively with the degree of activation-induced cell death caused by mitogen overstimulation. Since activation of lymphocytes through membrane-bound CD137 delivers a potent stimulatory signal, sCD137 may provide a negative control mechanism for immune responses.
10844522 Inhibition of cyclin A gene expression in human B cells by an immunosuppressant mizoribine 2000 Jun Mizoribine has been shown to have beneficial effects in the treatment of rheumatoid arthritis and lupus nephritis, in which abnormal B cell functions are involved. Previous studies demonstrated that mizoribine directly suppresses the function of human B cells. The current study explored in detail the mechanism of the suppression of human B cell responses by mizoribine at the molecular level. Highly purified peripheral blood B cells obtained from normal healthy individuals were stimulated with Staphylococcus aureus Cowan I (SAC) plus IL-2 in the presence or absence of mizoribine or methotrexate for 48 h to 72 h. The expression of cyclin A mRNA was determined by semiquantitative reverse transcriptase-polymerase chain reaction followed by Southern hybridization. Although at pharmacologically attainable concentrations both mizoribine and methotrexate suppressed the production of IgM of SAC-activated B cells, mizoribine, but not methotrexate, decreased the expression of cyclin A protein as well as mRNA in B cells stimulated with SAC + IL-2. Of note, mizoribine facilitated the degradation of cyclin A mRNA in the presence of actinomycin D, indicating that mizoribine shortens the stability of cyclin A mRNA. The results indicate that mizoribine suppresses the expression of cyclin A mRNA in human B cells by down-regulating its stability, and thus down-regulates their responses.