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ID PMID Title PublicationDate abstract
11257151 Human parvovirus B19 infection in patients with systemic lupus erythematosus. 2001 Feb OBJECTIVE: The clinical significance of the presence of B19 DNA in patients with SLE was studied. METHODS: Sera from 72 patients with systemic lupus erythematosus (SLE), 23 patients with rheumatoid arthritis (RA), 18 patients with Sjögren's syndrome (SS), eight patients with Raynaud's phenomenon (RP), five patients with primary biliary cirrhosis (PBC), five patients with polymyositis (PM), four patients with erythema infectiosum (EI) and 22 normal controls were examined for parvovirus B19 (B19) infection by serological assays, nested PCR and Southern blotting. RESULTS: Parvovirus B19 DNA was detected in 17 of 72 patients with SLE and in three of four patients with EI, but not in patients with other systemic rheumatic diseases. Of the 17 patients with B19 DNA, only one had IgG anti-B19 antibody and two had IgM anti-B19 antibodies, whereas IgG and IgM anti-B19 antibodies were detected in 27 (49.1%) and 21 (38.2%) of 55 SLE patients without B19 DNA respectively. All sera from the patients with EI contained both IgG and IgM anti-B19 antibodies. B19 DNA was found more commonly in sera from SLE patients without anti-B19 antibodies than in those with anti-B19 antibodies (P<0.05). CONCLUSIONS: B19 infection in patients with SLE may be due to lack of anti-B19 antibodies because of either the immunocompromised nature of the host or the use of immunosuppressive drugs. There was a higher prevalence of hypocomplementaemia and RP in patients with parvovirus B19 viraemia than in those without parvovirus B19 viraemia.
11246666 Autoantibodies to receptor induced neoepitopes of fibrinolytic proteins in rheumatic and v 2001 Feb OBJECTIVE: Abnormal plasminogen activation has been implicated in vascular and rheumatic diseases. The development of an autoimmune response to neoepitopes of plasminogen and its activator (tissue-type plasminogen activator, t-PA) was explored in sera from patients with rheumatoid arthritis (RA, n = 30), Behcet's disease (n = 20), primary antiphospholipid syndrome (APS, n = 23), and idiopathic arterial (n = 33) or venous thrombosis (n = 16). METHODS: Sera diluted 1/50 were incubated with either plasminogen or t-PA bound to their natural receptors (immobilized fibrin or monocytic cells), and bound immunoglobulins were detected using a sheep peroxidase labeled anti-human Fab IgG. Controls included plates coated with fibrin or cells alone or plasminogen passively adsorbed to the plastic. Sera were considered positive when the absorbance at 405/490 nm was above the mean + 2 SD of normal sera. RESULTS: Reactivity of sera against plasminogen bound to cells (28%) or to fibrin (22%) was a predominant feature in patients with RA compared with other patient groups and controls. However, some patients with primary APS had reactivity against cell and fibrin bound plasminogen (9 and 13%, respectively). Autoantibodies against fibrin bound t-PA were detected in only 8% of patients with arterial or venous thrombosis. CONCLUSION: Conformational changes induced by molecular assembly of plasminogen on cell or fibrin surfaces result in the expression of neoepitopes recognized by autoantibodies. These autoantibodies could be markers of the proteolytic events associated with plasminogen activation in autoimmune diseases.
11237660 Overexpression of active TGF-beta-1 in the murine knee joint: evidence for synovial-layer- 2001 Feb OBJECTIVE: To investigate the impact of a prolonged and constant active TGF-beta expression by the synovial lining cells on cartilage and ligamentous joint structures in vivo. DESIGN: An adenoviral vector (AdTGF-beta1(223,225)) was used for the overexpression of active TGF-beta1 in knee joints of C57Bl/6 mice. RESULTS: It was found that physiological relevant levels of active TGF-beta1 produced by the synovial lining layer resulted in histopathological changes: hyperplasia of synovium and chondro-osteophyte formation at the so-called chondro-synovial junctions. No histological changes were seen after intra-articular injection of an empty control vector (AdDL70-3) or by overexpression of latent TGF-beta1 (AdTGF-beta1). The predominant site of TGF-beta production in osteoarthritis (OA) and rheumatoid arthritis (RA) is the synovial lining layer. To address the question whether the TGF-beta-induced changes were related to the expression site in the synovial lining, the synovial lining layer was depleted by local treatment with liposomes encapsulating clodronate. Depletion of the lining resulted in a dramatic change of TGF-beta1-induced pathology: markedly reduced chondro-osteophyte formation and increased accumulation of extracellular matrix in the synovium. CONCLUSION: This study shows that overexpression of active TGF-beta1 in the knee joint results in OA-like changes and suggests the synovial lining cells contribute to the chondro-osteophyte formation.
11217588 Prevalence of carpal tunnel syndrome and median mononeuropathy among dentists. 2001 Feb BACKGROUND: The authors undertook a study to determine the prevalence in dentists of abnormal sensory nerve conduction and/or symptoms of carpal tunnel syndrome, or CTS, the most common nerve entrapment syndrome. METHODS: In a cross-sectional study, dentists (n = 1,079) were screened during the American Dental Association's Annual Health Screening Program in 1997 and 1998 by means of standard electrodiagnostic measures in the dominant hand and a self-reported symptom questionnaire. The authors diagnosed a median mononeuropathy from a 0.5- or 0.8-millisecond, or ms, prolongation of the median sensory-evoked peak latency compared to the ulnar latency. They diagnosed CTS if the subject also had accompanying symptoms of numbness, tingling or pain. RESULTS: Thirteen percent of screened dentists were diagnosed with a median mononeuropathy (using a 0.5-ms prolongation as the criterion), but only 32 percent of these had symptoms consistent with CTS (4.8 percent overall). When the 0.8-ms prolongation was used as the electrodiagnostic criterion, only 2.9 percent (overall) were diagnosed with CTS. People with diabetes, rheumatoid arthritis and obesity were more likely to have a median mononeuropathy. CONCLUSIONS: The prevalence of symptoms consistent with CTS in the dominant hand among dentists was higher than the prevalence in the general population. However, when electrodiagnostic confirmation is added, the prevalence of CTS was nearly the same as that among the general population. CLINICAL IMPLICATIONS: Early recognition of CTS can lead to more effective management. Education regarding ergonomic risk factors can be an effective preventive measure.
11138330 The effects of low-dose methotrexate on thymidylate synthetase activity in human periphera 2000 Nov OBJECTIVE: Methotrexate (MTX) in low doses is widely used in the treatment of rheumatoid arthritis (RA) and it is not known whether its effects are due to immunosuppressive and/or anti-inflammatory actions. High concentrations of MTX inhibit the activity of thymidylate synthetase (TS) and dihydrofolate reductase essential for DNA synthesis. This study investigated the effects of low-dose MTX on TS activity and proliferation in human peripheral blood mononuclear cells (PBMC). METHODS: The MTX concentrations in our experiments were chosen according to the plasma concentrations measured in 8 RA patients treated with MTX. The effect of MTX on TS activity and DNA synthesis were measured in stimulated normal PBMC and in PBMC obtained from 6 RA patients treated with oral MTX before and 2 hours after intake of their weekly MTX dose. The effect of MTX on the TS mRNA concentration was also investigated in order to elucidate its effect on TS production. RESULTS: Low-dose MTX significantly inhibited TS activity and the proliferation of stimulated PBMC independent of the mode of activation. Interestingly, the concentration of TS mRNA in normal PBMC was upregulated by the presence of MTX. Finally, there was no difference between TS activity measured before and after MTX intake in 6 RA patients on long-term MTX treatment. CONCLUSION: We show that low concentrations of MTX inhibit TS activity in vitro. An in vivo effect cannot, however, be proven given our study design. The role of these in vitro findings is discussed, particularly in relation to the in vivo effects of MTX.
11107554 [Novel extracorporeal granulocyte apheresis column inhibits myocardial reperfusion injury: 2000 Nov OBJECTIVES: Leukocyte infiltration is very important in myocardial ischemia/reperfusion injury. A new extracorporeal circulation therapy using a granulocyte-apheresis column (G-1) has recently been proved to be effective and safe in patients with rheumatoid arthritis and with ulcerative colitis. This study investigated whether this therapy would reduce myocardial ischemia/reperfusion injury. METHODS: Rabbits were subjected to 30 min ischemia followed by 180 min reperfusion with no treatment (control group: n = 12); or treated with extracorporeal blood circulation (2 ml/min) passing through the G-1 (G-1 group: n = 12), or sham column (sham group: n = 12). Infarct size was determined by tetrazolium staining and expressed as a percentage of the area at risk. RESULTS: Infarct size in the G-1 group (15.9 +/- 3.4%) was significantly (p < 0.01) smaller than in the control (34.7 +/- 3.9%) and sham (35.2 +/- 4.1%) groups. Granulocyte emigration into the ischemic myocardium assessed by histopathological score was significantly (p < 0.01) less in the G-1 group (0.58 +/- 0.17) than in the sham group (1.42 +/- 0.26). There was a significant (r = 0.78, p < 0.0001) positive correlation between this score and infarct size. Flow cytometry showed alterations in the adhesion molecule expression on granulocytes during the passage through the G-1, but not sham, columns as a low L-selectin and high Mac-1 form, which is associated with the inability to home to the inflamed site. CONCLUSIONS: Extracorporeal circulation with the G-1 column, a newly-developed clinically applicable therapy, appears to reduce infarct size at least in part by limiting the emigration capacity of granulocytes into the ischemic myocardium.
11070441 Antonovsky's sense of coherence: trait or state? 2000 Nov BACKGROUND: The aim of this study was first to analyze the stability of Antonovsky's Sense of Coherence (SOC) as a measure of a person's world view over time; secondly, to investigate its relationship with depression and anxiety. METHODS: Data from two longitudinal studies were used: a study of severely injured accident victims (n = 96), and a study of patients suffering from rheumatoid arthritis (RA, n = 60). The 13 items short version of the SOC scale and measures of depression and anxiety (Symptom Checklist, Hospital Anxiety and Depression Scale) were administered repeatedly over 6-12 months in both studies. RESULTS: In the sample of accident victims, a significant decrease in the SOC mean score was observed during the first half year after the accident. During the same time period, symptoms of anxiety and depression decreased significantly. In the second half year after the accident, SOC as well as measures of psychopathology remained stable. RA patients showed high stability of SOC and measures of anxiety and depression over time. In both samples, between-time correlations of SOC scores were high (r > or = 0. 70, p<0.01), indicating a high test-retest stability of SOC. Furthermore, in both samples, significant negative correlations of a moderate to high degree (r = -0.28 to -0.73, p<0.01) were found between SOC and measures of anxiety and depression. CONCLUSIONS: SOC can be seen as a relatively stable (trait) measure. However, traumatic events such as life-threatening accidents may change a person's world view and thus their SOC, even if psychiatric symptoms abate. This suggests that SOC is not merely a proxy measure of psychopathology, but rather a partially independent, general measure of a person's world view.
11060755 Novel strategies for the treatment of osteoarthritis. 2000 Jul Osteoarthritis is a worldwide heterogeneous group of conditions that leads to joint symptoms, which are associated with defective integrity of articular cartilage, in addition to related changes in the underlying bone at the joint margins. The prevalence of the disease after the age of 65 years, is about 60% in men and 70% in women. The aetiology of osteoarthritis is multifactorial, with the end result being mechanical joint failure and varying degrees of loss of joint function. The pathophysiological events associated with osteoarthritis are beginning to be understood. Essential inflammatory cytokines, such as IL-1beta and TNF-alpha, are involved initiating a vicious cycle of catabolic and degradative events in cartilage, mediated by metalloproteinases, which degrade cartilage extracellular matrix. The role of inflammation in the pathophysiology and progression of early osteoarthritis is supported further by the observation that C-reactive protein levels are raised in women with early knee osteoarthritis and higher levels predict those whose disease will progress. The synovium from osteoarthritis joints stains for IL-1beta and TNF-alpha. Nitric oxide, which exerts pro-inflammatory effects, is released during inflammation. Cartilage from patients with rheumatoid arthritis and osteoarthritis spontaneously produces nitric oxide in vitro. In experimental osteoarthritis, nitric oxide induces chondrocyte apoptosis, thus contributing to cartilage degradation. Hence unregulated nitric oxide production in humans plays a part in the pathophysiology of the disease. These recent observations suggest that therapy can now be targeted at specific sites of pathophysiological pathways involved in the pathogenesis of osteoarthritis. The novel strategies under consideration for the treatment of osteoarthritis can be divided into five main areas. These are COX-2 inhibitors, nitric oxide synthesis inhibitors and anti-oxidants, chondrocyte and bone growth promoters, metalloproteinase and cytokine inhibitors and gene therapy.
10983733 Potential novel uses of thalidomide: focus on palliative care. 2000 Aug Thalidomide, after being banned from the market in the early 1960s because of the worldwide teratogenesis disaster, is currently being rediscovered because of its multiple therapeutic effects in various serious diseases and symptoms. Original studies examined the anxiolytic, mild hypnotic, anti-emetic and adjuvant analgesic properties of this drug. Subsequently, thalidomide was found to be highly effective in managing the cutaneous manifestations of leprosy (erythema nodosum leprosum) and even to be superior to aspirin (acetylsalicylic acid) in controlling leprosy-associated fever. Recent research shows promising results with thalidomide in patients with progressive bodyweight loss related to advanced cancer and HIV infection. Thalidomide therapy of diseases such as tuberculosis, sarcoidosis, aphthous ulcers in HIV syndrome and Behcet's disease, rheumatoid arthritis, multiple myeloma, graft-versus-host disease, pyoderma gangrenosum, inflammatory bowel disease, Sjögren's syndrome, lupus erythematosus and a variety of solid tumours is currently being explored. Furthermore, in preliminary studies, thalidomide has been found to be effective in several syndromes related to advanced cancer, such as the cancer cachexia syndrome, chronic nausea, insomnia, profuse sweating and pain. Whether thalidomide has a therapeutic effect on neoplastic fever has yet to be elucidated. These intriguing features make the use of the drug potentially attractive for palliative care. In addition, by a distinct mechanism of action compared with most other drugs, thalidomide offers the possibility of combined treatment with other agents with non-overlapping toxicities. The mechanism of action of thalidomide is probably based on the suppression of tumour necrosis factor-alpha and the modulation of interleukins. However, it is not possible to identify a single dominant mechanism, since the action of cytokines and the effect of thalidomide appear to be complex. This review article discusses the original uses and teratogenic effects of thalidomide within its historical context and, linking recent research at the molecular level with clinical findings, aims to provide the reader with insight into the current understanding of its biological actions, toxicities and potential benefits.
10918514 Preclinical development of keliximab, a Primatized anti-CD4 monoclonal antibody, in human 2000 Apr The preclinical safety assessment of biopharmaceuticals necessitates that studies be conducted in species in which the products are pharmacologically active. Monoclonal antibodies are a promising class of biopharmaceuticals for many disease indications; however, by design, these agents tend to have limited species cross-reactivity and tend to only be active in primates. Keliximab is a human-cynomolgus monkey chimeric (Primatized) monoclonal antibody with specificity for human and chimpanzee CD4. In order to conduct a comprehensive preclinical safety assessment of this antibody to support chronic treatment of rheumatoid arthritis in patients, a human CD4 transgenic mouse was used for chronic and reproductive toxicity studies and for genotoxic studies. In addition, immunotoxicity studies were conducted in these mice with Candida albicans, Pneumocystis carinii and B16 melanoma cells to assess the effects of keliximab on host resistance to infection and immunosurveillance to neoplasia. The results of these studies found keliximab to be well tolerated with the only effects observed being related to its pharmacologic activity on CD4+ T lymphocytes. The use of transgenic mice expressing human proteins provides a useful alternative to studies in chimpanzees with biopharmaceutical agents having limited species cross-reactivity.
10908574 The acute myeloid leukemia-associated protein, DEK, forms a splicing-dependent interaction 2000 Jul 24 DEK is an approximately 45-kD phosphoprotein that is fused to the nucleoporin CAN as a result of a (6;9) chromosomal translocation in a subset of acute myeloid leukemias (AMLs). It has also been identified as an autoimmune antigen in juvenile rheumatoid arthritis and other rheumatic diseases. Despite the association of DEK with several human diseases, its function is not known. In this study, we demonstrate that DEK, together with SR proteins, associates with the SRm160 splicing coactivator in vitro. DEK is recruited to splicing factor-containing nuclear speckles upon concentration of SRm160 in these structures, indicating that DEK and SRm160 associate in vivo. We further demonstrate that DEK associates with splicing complexes through interactions mediated by SR proteins. Significantly, DEK remains bound to the exon-product RNA after splicing, and this association requires the prior formation of a spliceosome. Thus, DEK is a candidate factor for controlling postsplicing steps in gene expression that are influenced by the prior removal of an intron from pre-mRNA.
10732430 The impact of new technologies on vaccines. 1999 Nov Vast changes are taking place in vaccinology consequent to the introduction of new technologies. Amongst the vaccines included in the Expanded Programme of Immunization (EPI), the pertussis vaccine has been replaced by acellular purified fractions devoid of side-effects. Non-pathogenic but immunogenic mutants of tetanus and diptheria toxins are likely to replace the toxoids. An effective vaccine against hepatitis B prepared by recombinant technology is in large-scale use. Conjugated vaccines against Haemophilus influenzae b, S. pneumococcus and meningococcus are now available, as also vaccines against mumps, rubella and measles. Combination vaccines have been devised to limit the number of injections. Vaccine delivery systems have been developed to deliver multiple doses of the vaccine at a single contact point. A genetically-engineered oral vaccine for typhoid imparts better and longer duration of immunity. Oral vaccines for cholera and other enteric infections are under clinical trials. The nose as a route for immunization is showing promise for mucosal immunity and for anti-inflammatory experimental vaccines against multiple sclerosis and insulin-dependent diabetes mellitus. The range of vaccines has expanded to include pathogens resident in the body such as Helicobacter pylori (duodenal ulcer), S. mutans (dental caries), and human papilloma virus (carcinoma of the cervix). An important progress is the recognition that DNA alone can constitute the vaccines, inducing both humoral and cell-mediated immune responses. A large number of DNA vaccines have been made and shown interesting results in experimental animals. Live recombinant vaccines against rabies and rinderpest have proven to be highly effective for controlling these infections in the field, and those for AIDS are under clinical trial. Potent adjuvants have added to the efficacy of the vaccines. New technologies have emerged to 'humanize' mouse monoclonals by genetic engineering and express these efficiently in plants. These recombinant antibodies are opening out an era of highly specific and safe therapeutic interventions. Human recombinant antibodies would be invaluable for treating patients with terminal tetanus and rabies. Antibodies are already in use for treatment of cancer, rheumatoid arthritis and allergies. An advantage of preformed antibodies directed at a defined target and given in adequate amounts is the certainty of efficacy in every recipient, in contrast to vaccines, where the quality and quantum of immune response varies from individual to individual.
10685807 Impaired expression of IgA Fc receptors (CD89) by blood phagocytic cells in ankylosing spo 2000 Feb OBJECTIVE: Expression of IgA Fc receptors (CD89, FcalphaR) and their occupancy by endogenous IgA were studied on blood monocytes and neutrophits to determine if FcalphaR defects could account for enhanced serum IgA and IgA-IC commonly found in patients with ankylosing spondylitis (AS). METHODS: Peripheral blood samples were obtained from 34 patients with AS, 15 patients with rheumatoid arthritis, and 34 healthy individuals. Cell surface FcalphaR was analyzed using a quantitative flow cytometry method in which blood cells were stained with anti-FcalphaR monoclonal antibodies recognizing epitopes outside the IgA binding site and with F(ab')2 fragments of anti-IgA antibodies. Modulation of cell surface FcalphaR was evaluated after incubation of blood cells at 37 degrees C in absence of plasma. Biochemical characterization of iodinated FcalphaR molecules was determined by immunoprecipitation and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). RESULTS: FcaR expression was significantly decreased on monocytes and neutrophils in patients with AS compared to control groups. FcalphaR levels were inversely correlated with serum IgA, suggesting its negative regulatory role. Modulation experiments resulted in rapid and higher FcalphaR upregulation in AS than in controls, indicating that these molecules were downregulated only at the cell surface. Moreover, analysis of the surface iodinated FcalphaR molecules by SDS-PAGE revealed higher Mr (60-90 kDa) in AS than controls (55-75 kDa), also suggesting an altered glycosylation. Analysis of receptor occupancy revealed high levels of endogenous IgA bound to monocytes and neutrophils in patients with AS, pointing to a saturation of IgA Fc receptors. CONCLUSION: We observed impaired expression of FcalphaR in patients with AS that is characterized by a downregulation process associated with post-translational alterations and enhanced binding of endogenous IgA. These alterations might lead to a defective blood clearance by FcalphaR resulting in the enhancement of IgA and IgA-IC in AS patients. Decreased FcalphaR expression represents a new marker for this disease.
10593942 Molecular cloning of a zinc finger autoantigen transiently associated with interphase nucl 1999 Dec 17 We have cloned a novel human autoimmune antigen in a patient suffering from rheumatoid arthritis with high levels of antibodies to the nucleolus organizer regions. Initially the human autoimmune serum was used to select a cDNA of 317 amino acids from a hamster expression library. Using the hamster DNA as a probe, we isolated the human homologous cDNA of 320 amino acids. Human and hamster polypeptides share a 95% amino acid homology. The deduced 36-kDa protein contains a putative amino-terminal NLS signal, nine cysteine-X-X-cysteine motifs highly conserved, and a carboxyl-terminal poly acidic region. Several homologous expressed sequence tags have been identified in data bases suggesting that orthologous proteins are present throughout evolution from worms to humans. A Drosophila expressed sequence tag was further completely sequenced for a full-length protein with 60% amino acid identity to the human homologue. Northern blot analysis revealed that this novel protein is widely distributed in human tissues with significantly higher expression levels in heart and skeletal muscle. Specific antibodies to the recombinant protein and transfection experiments demonstrated by immunofluorescence the localization of the protein predominantly but not exclusively to the nucleolus of interphase mammalian cells. In actinomycin D-treated cells the protein remains associated with the nucleolus but is not segregated, like other ribosomal factors such as upstream binding factor. In mitosis the protein was found to be associated with centromeres and concentrated at the midbody in cytokinesis. Transient distribution of this evolutionarily conserved zinc finger nucleolar autoantigen to the mitotic centromeres may provide the means for several aspects of cell cycle control and transcriptional regulation.
10579830 Discovery of novel non-peptide CCR1 receptor antagonists. 1999 Nov 4 Ligands for the CCR1 receptor (MIP-1alpha and RANTES) have been implicated in a number of chronic inflammatory diseases, most notably multiple sclerosis and rheumatoid arthritis. Because these ligands share a common receptor, CCR1, we sought to discover antagonists for this receptor as an approach to treating these disorders. A novel series of 4-hydroxypiperidines has been discovered by high throughput screening (HTS) which potently inhibits the binding of MIP-1alpha and RANTES to the recombinant human CCR1 chemokine receptor. The structure-activity relationships of various segments of this template are described as the initial HTS lead 1 was optimized synthetically to the highly potent receptor antagonist 6s. This compound has been shown to have at least 200-fold selectivity for inhibition of CCR1 over other human 7-TM receptors, including other chemokine receptors. In addition, data obtained from in vitro functional assays demonstrate the functional antagonism of compound 6s and structurally related analogues against the CCR1 receptor in a concentration dependent manner. The discovery and optimization of potent and selective CCR1 receptor antagonists represented by compound 6s potentially represent a novel approach to the treatment of chronic inflammatory diseases.
10501785 Validation of the simple calculated osteoporosis risk estimation (SCORE) for patient selec 1999 Bone densitometry using dual energy X-ray absorptiometry (DXA) is the 'gold standard' for osteoporosis diagnosis. However, mass screening for osteoporosis has not been recommended, and no consensus has been reached regarding specific targeted screening programs. Recently, the Simple Calculated Osteoporosis Risk Estimation (SCORE) was developed to identify postmenopausal women likely to have low BMD (< or > -2.0 SD of the young adult normal), who may be selected for DXA testing. This instrument uses a case-selective approach to screen for osteoporosis by summing a score based on: age, race, rheumatoid arthritis, history of nontraumatic fracture over 45 years of age, estrogen use, and weight. In our study, SCORE was validated using 398 postmenopausal women at least 45 years of age residing within 50 km of Toronto, Ontario, Canada (one of 9 centers of the Canadian Multicentre Osteoporosis Study, a national population-based study). At the recommended threshold of 6, SCORE had a sensitivity of 90%, specificity of 32% and a positive predictive value of 64%. From receiver operating characteristic (ROC) analysis, no threshold identified SCORE as a useful instrument in our population; area under the ROC curve was 0. 71. Specificity of the SCORE is poor; at the recommended threshold of 6, 68% of those with normal bone mineral density (BMD) would be selected for bone densitometry. Development and validation of SCORE by Lydick and colleagues may have been confounded by the nature of the study sample; sampling from specialty clinics; and by the choice of outcome, combining data from different DXA machines, and using only data from the femoral neck to identify low BMD. A simple and effective approach to select patients for bone densitometry has yet to be established.
10442582 The influence of growth hormone (GH) deficiency and GH replacement on quality of life in G 1999 The total absence of hormones such as cortisol or thyroxine causes death within weeks. Lack of estrogen or testosterone is followed by infertility and impaired sexual functioning. Relative deficiencies of almost all classical hormones have a substantial impact on quality of life (QOL). However, in contrast to virtually all aspects of metabolism, QOL is difficult to measure. Only recently have tests been developed to assess general QOL, whereas specific tests address those aspects of QOL affected only in specific situations or disease states. For example, in rheumatoid arthritis and other chronic disabling diseases, the use of measures of QOL to assess treatment modalities is almost routine. In diseases with overt metabolic disturbances attention is generally focused on changes in metabolic parameters and the issue of QOL is neglected. Although very few practising endocrinologists will not support the idea that they specialize in improving QOL, its assessment in patients with endocrinological disorders began only recently--in patients with growth hormone (GH) deficiency only 10 years ago. It became apparent that GH deficiency in adult life is unmistakably followed by changes in parameters that determine QOL. In adults with childhood-onset GH deficiency, the unemployment rate is higher and the marriage rate lower than in the general population. Another symbol of success in life, the possession of a driver's licence, is less frequently attained by these patients. Most patients with adult-onset GH deficiency score unfavourably in questionnaires such as the Nottingham Health Profile. GH substitution is now available on a scale large enough to enable studies to be made of the effects on QOL in adults. The first studies were reported in 1989. However, only in the last few years have studies appeared in which sufficient number of patients and sufficient length of treatment were reported to allow a more objective judgement of the effectiveness of GH substitution. Although there is still room for improvement in the methods used to assess the effects of GH treatment on QOL in GH-deficient adults, there is now little doubt as to its beneficial effect.
10402073 Oxidative stress in systemic lupus erythematosus and allied conditions with vascular invol 1999 Jun OBJECTIVE: To evaluate the occurrence and clinical significance of lipid peroxidation (oxidative stress) in rheumatic diseases characterized by vascular involvement. PATIENTS AND METHODS: Plasma 8-epi-PGF2alpha (oxidative stress marker) was measured by gas chromatography-mass spectrometry in 36 patients with systemic lupus erythematosus (SLE), 13 with systemic sclerosis (SSc), 13 with systemic vasculitis [Wegener's granulomatosis (WG), n = 4; Churg Strauss syndrome (CSS), n = 3; Behcet syndrome, n = 6], 12 with rheumatoid arthritis (RA) and in 23 healthy controls (n = 23). RESULTS: 8-epi-PGF2alpha levels were higher in patients with SLE (P = 0.007), SSc (P < 0.001) and vasculitis (P = 0.001) than in controls. In SLE, a positive Coombs' test and arterial hypertension independently predicted 8-epi-PGF2alpha concentrations (P = 0.004 and P = 0.001, respectively). SLE patients not taking prednisolone showed higher 8-epi-PGF2alpha concentrations than SLE patients on prednisolone (P = 0.02). In the latter group, a dose response relationship was noted between 8-epi-PGF2alpha and steroid dosage (r = 0.6, P = 0.0003). In WG and CSS, 8-epi-PGF2alpha concentrations correlated with disease activity (r = 0.8, P = 0.01) and were higher than in patients with Behcet disease (P = 0.003). CONCLUSIONS: Oxidative stress may be pathogenetically relevant in some autoimmune rheumatic diseases with vascular involvement. Amelioration of some clinical manifestations of these diseases may be envisaged by targeting lipid peroxidation with dietary or pharmacological antioxidants.
19078358 Azathioprine hepatotoxicity is uncommon in patients with Rheumatic diseases. 1999 Apr At present, there is no consensus regarding the utility of liver enzyme monitoring in rheumatology patients undergoing treatment with azathioprine (AZA). To further investigate this issue, we retrospectively reviewed for current or past use of AZA all patient records in our Disease Modifying Antirheumatic Drug (DMARD) clinic from May 1986 through September 1996. Information available from individual DMARD charts included AZA data (dates initiated, dose, indication for changing dose or stopping AZA), co-administered DMARDs, and aspartate aminotransferase (AST) serum values. In patients followed in the clinic through February 1994, serum alkaline phosphatase (AP) values additionally were available. Published reports of AZA hepatotoxicity in rheumatoid arthritis (RA) patients were found by a MEDLINE search, supplemented by a manual search of reference lists.We screened 429 patient records, and all patients who had received AZA at any time during the study period (n = 56) were identified for further review. The mean daily AZA dose was 96 mg (median = 100 mg/ day, range = 25-200 mg/day). All of the 56 patients had undergone routine periodic monitoring of serum AST while taking AZA (mean interval = 26 days); 30 of these patients additionally underwent monitoring of serum AP (mean interval = 24 days). Twenty-three (41%) of the patients had at least one episode of an abnormally elevated serum AST and/or AP while taking AZA. Only 1 of these 2 laboratory values was abnormal in 12 patients. The average time from AZA initiation to first appearance of an abnormal AST and/or AP value was 27 days (range = 7-62 days). During observation alone, all abnormal laboratory test results became normalized in 20 of 23 patients (87%) during the study period. There were no interventions in response to an abnormal laboratory value, and no patient experienced an adverse clinical outcome attributable to AZA hepatotoxicity during the 10-year study period.AZA use for rheumatic conditions may be associated with elevations in both the serum AST and/or AP values. Most of these elevations were transient, and none were clinically significant in our patient population. This study supports current American College of Rheumatology guidelines, which do not recommend routine periodic monitoring with liver enzyme tests in RA patients taking AZA. Furthermore, this study suggests that the utility of the baseline liver enzyme test in these patients is not well established.
9918235 Mechanism of immunosuppression of the antirheumatic herb TWHf in human T cells. 1999 Jan OBJECTIVE: To investigate the immunosuppressive mechanism of Tripterygium wilfordii Hook-F (TWHf) in human T cells. TWHf, a traditional Chinese medicinal herb for rheumatoid arthritis, has been shown to inhibit the function of immune effector cells such as neutrophils, macrophages, and B lymphocytes. METHODS: T cell survival was evaluated with trypan blue exclusion assay, morphologic changes with Wright's stain, the induction of endonuclease activity with DNA fragmentation assay, and the subdiploid DNA content with flow cytometry. T cell activation was measured with interleukin 2 (IL-2) ELISA and the expression of several surface molecules with flow cytometry. RESULTS: At high dosages, TWHf caused inhibition of T cell proliferation and this mechanism was mediated through the induction of apoptosis. TWHf, in noncytotoxic dosages, was as potent as cyclosporin A and more potent than prednisolone and cyclophosphamide in inhibiting IL-2 production from activated T cells. TWHf also inhibited both phorbol 12-myristate 13-acetate induced IL-2Ralpha expression and ionomycin induced CD40 ligand expression. TWHf did not reverse downregulated expression of CD3 and CD4 by phorbol ester stimulation. CONCLUSION: This is the first evidence that the immunosuppressive mechanism of TWHf in T cells was mediated through both downregulation of T cell receptor signaling pathway and induction of cellular apoptosis, which is defective in autoimmune diseases.