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ID PMID Title PublicationDate abstract
16571614 Lymphoid interstitial pneumonia: clinical features, associations and prognosis. 2006 Aug Lymphoid interstitial pneumonia (LIP) is rare and its clinical course incompletely described. The aim of this study was to examine the clinical features, associations and prognosis of surgical lung biopsy-proven LIP. The study group consisted of 15 subjects encountered over a 14-yr period. The majority of subjects were females (n = 11) and the mean age was 47 yrs (range 17-78 yrs). Underlying systemic immune disorders were frequent, including Sjögren's syndrome (n = 8), rheumatoid arthritis, systemic lupus erythematosus, polymyositis, common variable immunodeficiency and dysproteinaemia. Only three patients were classified as "idiopathic". Presenting symptoms were dominated by dyspnoea and cough. Restrictive physiology, reduced diffusion capacity (62.5+/-18.4% predicted) and bronchoalveolar lavage lymphocytosis (30.5+/-29.1% pred) were noted. Thirteen patients received corticosteroid therapy. Of the nine whose response could be assessed, four showed clinical improvement and four were stable. Overall, median survival was 11.5 yrs. Of the seven patients who died, respiratory problems were the primary cause of death in three. Conversion to lymphoma was not identified. In conclusion, histopathological lymphoid interstitial pneumonia is commonly associated with immune system dysregulation, with idiopathic lymphoid interstitial pneumonia being extremely rare. Clinical stability or improvement with corticosteroids can be expected; however, survival remains impaired.
16511916 Quinacrine but not chloroquine inhibits PMA induced upregulation of matrix metalloproteina 2006 Mar OBJECTIVE: Macrophages play an important role in rheumatoid arthritis (RA). RA is a disease characterized by the successive accumulation of leukocytes resulting in subsequent destruction of affected joints. Activation of matrix metalloproteinases (MMP) is essential for many physiological as well as many pathological events owing to the essential role of MMP in cell migration. We analyzed the effectiveness of quinacrine as an inhibitor of MMP activation in leukocytes and investigated the mode of action. METHODS: Leukocytes were isolated and treated with quinacrine with or without phorbol myristic acetate (PMA). ELISA and RT-PCR were used to monitor production of MMP-1, MMP-2, MMP-3, and MMP-8 at the mRNA and protein level. RESULTS: Quinacrine suppressed PMA induced MMP-1 release in mononuclear cells (MNC) in a dose- and time-dependent manner. RT-PCR showed that quinacrine downregulated induced as well as noninduced steady-state mRNA levels of MMP-1, MMP-2, and MMP-8, but had no effect on MMP-3. The observed inhibition was not due to effects of quinacrine on phospholipase A2 (PLA2) activity. Adding exogenous arachidonic acid to reconstitute the blocked PLA2 signaling pathways did not result in restoration of PMA induced mRNA transcription. CONCLUSION: Inhibition of MMP by quinacrine might, in part, account for its reported immunosuppressive action. Synthesizing more potent derivatives of quinacrine may be a means of suppressing undesired MMP activation.
16459351 Alterations in the phenotype and function of immune cells in ovariectomy-induced osteopeni 2006 Apr BACKGROUND: Within the last few years, much evidence has been presented on the involvement of the immune system in certain types of bone loss, such as activated T cells in rheumatoid arthritis and in periodontitis. Estrogen deficiency induces bone loss; however, how this deficiency affects the immune system has not been sufficiently studied. METHODS: To evaluate the effects of estrogen withdrawal on the status and functionality of the immune system, mice were ovariectomized or sham-operated, and 5 weeks after surgery, when osteopenia had developed, several parameters were analysed in spleen and in bone marrow. We analysed bone turnover, cell phenotype by flow cytometry, cell function by cell proliferation assays, and the expression of several genes related to the process. RESULTS: Five weeks after ovariectomy, augmented osteoclastogenesis persisted in the bone marrow. In addition, the ovariectomized mice had more B-cells and CD3+ T-cells expressing the receptor activator of NF-kappaB ligand (CD3+/RANKL+). The ovariectomized mice had lower serum alkaline phosphatase activity, a normal amount of T cells, lower percentages of CD11b+ and CD51+ cells in the bone marrow, and a lower serum interferon-gamma level compared with sham-operated controls. CONCLUSIONS: The data suggest that, 5 weeks after ovariectomy, bone turnover remains imbalanced, with increased osteoclastogenesis and a decreased rate of bone formation. Moreover, there is an increase in B-cell formation, with normal and decreased percentages of T cells and myelomonocytic cells (CD11b+), respectively, in the bone marrow. Decreased serum interferon-gamma levels could be involved in the increased osteoclastogenesis found in the present work.
16357732 Prevalence of abuse in fibromyalgia and other rheumatic disorders at a specialized clinic 2005 Jun BACKGROUND: The importance of past adverse experiences is increasingly recognized in patients with rheumatic disease. OBJECTIVE: The objective of this study was to study the association of physical, verbal, and sexual abuse in patients with rheumatic disorders as compared with healthy volunteers. METHODS: In this case-control study, 500 new patients attending an outpatient rheumatic clinic were interviewed from September 1, 1999, to August 31, 2001. A total of 187 patients with 3 diagnoses were selected: 58 had fibromyalgia (FM), 74 rheumatoid arthritis (RA), and 55 patients with soft tissue rheumatic disease (STRD). All selected patients were asked to complete a questionnaire designed to obtain information regarding demographics and history of verbal, physical, and sexual abuse. A group of 187 healthy control subjects were also included, matched for sex and age. RESULTS: The prevalence of abuse was significantly more common in the rheumatic disease group than in the control group (48.1% versus 15%, P < 0.001). The prevalence of abuse among the groups was as follows: 70.7% of patients with FM reported abuse (24.3% verbal, 60.9% physical, and 14.8% sexual), 35.1% of patients with RA had a history of abuse (42.3% verbal, 30.7% physical, and 0% sexual), whereas 41.8% of patients with STRD reported abuse (43.4% verbal, 43.4% physical, and 0% sexual). When comparing the 3 groups, patients with FM showed a higher prevalence of abuse (P < 0.05). The abuse was usually longstanding (range, 1-10 years), and most abusers were close family members. CONCLUSION: Abuse, both physical and psychologic, was significantly increased in our rheumatic disease population, especially in patients with FM. Further studies are needed to fully establish its role. Questions about abuse may provide important information relative to care of our patients.
16308731 The inhibition of angiogenesis by antisense oligonucleotides to clusterin. 2005 Angiogenesis is a primary disease target in ocular retinopathy and a secondary target in numerous other angiogenic diseases such as cancer, rheumatoid arthritis and psoriasis. Clinical trials using antiangiogenic antisense oligonucleotides (aso's) for the treatment of ocular disorders or cancer are well advanced. Clusterin aso's are currently under investigation for the treatment of prostate cancer. We have investigated the antiangiogenic properties of clusterin aso's using a capillary cell (HUVEC) viability assay. In this study we included aso's to known apoptosis modulators (bcl-2, bcl-xl and survivin) which were previously identified in HUVEC's. We have also studied the effect of clusterin aso's on angiogenesis using an in vitro, matrigel assay and on HUVEC apoptosis using an ELISA DNA fragmentation assay. Clusterin, bcl-2, bcl-xl and survivin aso's were all found to inhibit HUVEC growth. The apoptosis-inducing drugs paclitaxel, camptothecin and doxorubicin were also found to inhibit HUVEC proliferation. Combinations of aso's with these drugs demonstrated a minor additive but not synergistic inhibitory effect on HUVEC proliferation. Clusterin aso's were found to strongly inhibit angiogenesis and induce high levels of apoptosis in HUVECs. In cancer cells the prosurvival protein clusterin may protect the cells from apoptosis-inducing agents so that the clusterin aso's may act as chemosensitization agents. These data demonstrate a strong antiangiogenic action of clusterin aso's, that is not necessarily related to any chemosensitization effect of this agent.
16295817 Vitamin D: important for prevention of osteoporosis, cardiovascular heart disease, type 1 2005 Oct Vitamin D is very important for overall health and wellbeing. A major source of vitamin D comes from exposure to sunlight. Measurement of 25-hydroxyvitamin D in the blood and not 1,25-dihydroxyvitamin D is used to determine vitamin D status. A blood level of 25-hydroxyvitamin D of at least 20 ng/mL is considered to be vitamin D sufficient. Vitamin D deficiency increases the risk of many common cancers, multiple sclerosis, rheumatoid arthritis, hypertension, cardiovascular heart disease, and type I diabetes.
16206366 Standardized assessment of adverse events in rheumatology clinical trials: summary of the 2005 Oct A presentation, demonstration, and discussion of recently developed adverse event instruments were the topics for the OMERACT 7 Drug Safety Module. The module began with a plenary introducing the needs and challenges of adverse event ascertainment. It was followed by a review of module work from previous OMERACT meetings on a prototype coding instrument (Rheumatology Common Toxicity Criteria), then a brief description of the process behind the recently developed patient self-report and investigator report adverse event instruments. These current instruments are designed for use in controlled trials although they could be used in other settings. The instruments rely primarily on patient self-reporting using a checklist, which the investigator then folds into a parallel structured but more medically sophisticated instrument. In pilot testing, this innovative dual-use system has shown reliability and acceptability, while preserving validity. A "stakeholder panel" of representatives from 8 sectors followed--patient, nurse investigator, regulator, clinician scientist, industry, OMERACT, global public health/WHO, and Cochrane Collaboration--for their perspectives on the needs, challenges, and potential ways forward for adverse event ascertainment and reporting in clinical trials. At the breakout session small focus groups participated in hands-on interactive testing of one of 3 versions of the instruments, which differ in degree of comprehensiveness. Each focus group had a participatory patient with rheumatoid arthritis. At a second plenary there was group feedback by rapporteurs and presentation of results from pilot studies of iterative testing of validity, reliability, and feasibility of the instruments. During plenary discussion a frequent suggestion for improvement was to refine the process so that event ascertainment could be done entirely using the patient instrument with minimal input from the investigator at the visit, if patient-investigator agreement was high. Most found the patient checklist attractive, particularly if the patient instrument was shown to be reliable and valid. Finally, a future research agenda was discussed.
16206357 Longitudinal analysis of a pediatric rheumatology clinic population. 2005 Oct OBJECTIVE: To analyze a prospectively maintained pediatric rheumatology clinic disease registry. METHODS: A total of 3269 consecutive referrals to the Pediatric Rheumatology Clinic, University of Saskatchewan, during the period 1981-2004 were analyzed. RESULTS: Among 3269 patients, a diagnosis was established in 2098 (64.2%). Within this group, 72 subjects (3.4%) were determined to be healthy. Of the remaining 2026 diagnosed patients (62.0% of the total population), 1032 (50.9%) had a rheumatic disease and 994 (49.1%) a nonrheumatic disease. A diagnosis was not established in 1171 patients (35.8%). Among the 1032 patients with a rheumatic disease, 326 (31.6%) had juvenile rheumatoid arthritis (JRA), 360 (34.9%) a spondyloarthropathy (SpA), and 225 (21.8%) a collagen vascular/connective tissue rheumatic disease. The remaining 121 patients with a rheumatic disease (11.7%) had a variety of other conditions. Of the 994 nonrheumatic disease patients, 37 (3.7%) with ocular inflammatory conditions had been referred to exclude an associated rheumatic disease. The remaining group of 957 patients comprised 345 (36.1%) with an orthopedic, mechanical or traumatic condition, 231 (24.1%) had an infection, 45 (4.7%) a hematologic or neoplastic disease, and 336 (35.1%) a variety of other conditions. Current clinic point prevalences for JRA, SpA, and collagen vascular diseases are 35.0, 16.9 and 17.7/100,000, respectively. The mean annual clinic referral incidences of JRA, SpA, and collagen vascular/connective tissue diseases were, respectively, 4.7, 5.2, and 1.7/100,000 children. CONCLUSION: Disease registries help establish the frequencies and spectrum of childhood rheumatic diseases and the role of pediatric rheumatology programs in evaluating and caring for children with a wide variety of conditions. Longitudinal disease registries aid in characterizing clinical, epidemiologic, and demographic features of childhood rheumatic diseases.
16193357 Development and reliability of a standard rating system for outcome measurement of foot an 2005 Sep BACKGROUND: This study evaluated the validity and inter- and intraclinician reliability of (1) the Japanese Society of Surgery of the Foot (JSSF) standard rating system for four sites [ankle-hindfoot (AH), midfoot (MF), hallux (HL), and lesser toe (LT)] and the rheumatoid arthritis (RA) foot and ankle scale and (2) the Japanese Orthopaedic Association's foot rating scale (JOA scale). METHODS: Clinicians from the same institute independently evaluated participating patients from their institute by two evaluations at a 1- to 4-week interval. Statistical evaluation was as follows. (1) The intraclass correlation coefficient (ICC) was calculated from data collected from at least two examinations of each patient by at least two evaluating clinicians (Data A). (2) Total scores for the two evaluations were determined from the distribution of differences in data between the two evaluations (Data B); each item was evaluated by determining Cohen's coefficient of agreement. (3) The relation between patient satisfaction and total score was investigated only for patients who underwent surgery (Data C). Spearman's rank correlation coefficient was obtained. RESULTS: Participants were 65 clinicians and 610 patients, including those with disorders of the AH (313), MF (47), HL (153), and LT (50) and those with RA (47). From Data A, the ICC was high for AH and HL by JSSF scales and for AH, MF, and LT by the JOA scale. From Data B, the coefficient showed high validity for both scales for AH, with almost no difference between the two scales; the validity for HL was higher with the JOA scale than with the JSSF scale. From Data C, correlations were significant between patient satisfaction and outcome for AH and HL by the JSSF scales and for AH, HL, and LT by the JOA scale. CONCLUSIONS: The validity of both scales was high. Clinical evaluation of the therapeutic results using these scales would be highly reliable.
16131817 TP53 gene mutation, an unfavorable prognostic factor for malignant lymphomas in autoimmune 2005 OBJECTIVES: To investigate whether mutations of the TP53 tumor suppressor gene are associated with a poor prognosis in lymphoproliferative disorders (LPD) developing in patients with a history of autoimmune disease (AID). METHODS: Fifty patients, 15 males and 35 females ranging in age from 23 to 83 (median, 61) years, were examined. Rheumatoid arthritis (21 cases) is the commonest type of AID followed by systemic lupus erythematosus (10), dermatomyositis (9), progressive systemic sclerosis (4), and autoimmune hemolytic anemia (6). The interval between the diagnosis of AID and LPD ranged from 1 to 660 months (mean 42 months). Histological, immunohistological, and in situ hybridization studies revealed that 37 tumors were B cell lymphomas and 13 were T cell lymphomas with the Epstein-Barr virus genome present in the tumor cells in 24% of cases. Stage of disease was I in 15 cases, II in 5, III in 9, and IV in 21. RESULTS: Polymerase chain reaction-single strand conformation polymorphism followed by direct sequencing revealed TP53 mutations in 45.9% of B cell and 53.8% of T cell lymphomas. The follow-up study revealed an unfavorable prognosis in cases with mutations compared with those without: the 1-year survival rate was 43.5 and 73.0% in B cell and 16.7 and 50% in T cell lymphoma, respectively. CONCLUSIONS: The occurrence of a TP53 mutation is an unfavorable prognostic factor not only in B cell but also in T cell LPD in AID.
16129918 In vivo effects of high-dose methotrexate on bone remodeling in rats. 2005 Jul Methotrexatae (MTX) is a folate antagonist. MTX osteopathy is well recognized to accompany a high-dose therapy with this drug for the treatment of childhood malignancy. Clinical tests also show that low-dose MTX used in the treatment of rheumatoid arthritis may impair bone formation in a population already predisposed to osteoporosis. However, results of clinical tests are hard to interpret, as it is necessary to take into account malignancy-induced changes in the osseous tissue, long-term immobility and concurrent administration of glucocorticosteroids. We conducted in vivo tests to evaluate the effects of oral and intramuscular administration of high dose of MTX on bone remodeling processes in rats. Effects of MTX on the processes of bone remodeling were evaluated by assessing macrometric and histomorphometric parameters as well as mechanical properties of the femur. The tests were carried out on male Wistar rats. Animals were divided into four groups, composed of 7 animals each: Control group (0.9% NaCl solution), MTX-1 po group (MTX at the dose of 1 mg/kg po daily for 10 days: every day for the first five days, and after an 18-day interval, every day for five days), MTX-1 im group (MTX at the dose of 1 mg/kg im daily for 10 days: every day for the first five days, and after an 18-day interval, every day for five days), MTX-5 im group (MTX at the dose 5 mg/kg im daily for 2 days a week for the period of four weeks). Changes in bone remodeling were examined 4 weeks after the first MTX administration. These results show that MTX administered intramuscularly at high doses inhibited the formation and mineralization of new osseous matrix and impaired mechanical properties of the femoral bone, whereas its oral administration had no effect on bone remodeling in rats.
16045902 Expression and regulation of murine macrophage angiopoietin-2. 2005 Apr Our understanding of angiogenesis has increased significantly in the past few years with the discovery of angiopoietins (Ang). Specifically, Ang2 has been associated with pathologic as well as normal vascularization. While previous studies have shown that a major source of Ang2 has been endothelial cells and tumor cells, we reasoned that macrophages would also have the ability to express angiopoietins, specifically Ang2, due to that cell's role in wound healing, tumor angiogenesis, and a number of non-oncological diseases, such as rheumatoid arthritis and psoriasis. In this study, murine macrophages constitutively expressed both transcripts and protein for Ang2 but not Ang1 or Ang3. The secretion of Ang2 was enhanced by treatment with lipopolysaccharide, interferon-gamma, prostaglandin E2 and other cyclic AMP-elevating agents, as well as vascular endothelial growth factor (VEGF). Cyclic AMP-dependent protein kinase (PKA) played a major role in this enhancement since the PKA inhibitor, H89, blocked secretion of Ang2. Since stimulation of the PKA pathway can lead to macrophage production of VEGF, it is possible that enhancement of Ang2 production by macrophages may be due to autocrine responsiveness to VEGF. Adding anti-VEGF antibodies to the supernatants of stimulated macrophages blocked secretion of Ang2. This study is the first to show murine macrophage production of Ang2 and to provide evidence that it can be regulated. Understanding the regulation of macrophage Ang2 production is especially important in an effort to target the pathologic role of macrophages while preserving their role in immunity and homeostasis.
16039551 Chemically modified tetracyclines induce apoptosis in cultured mast cells. 2005 Oct Chemically modified tetracyclines are a group of non-antimicrobial tetracycline derivatives, which possess antiinflammatory, anticollagenolytic and antiproliferative properties. Here we studied the effects of four different chemically modified tetracyclines (CMT-1, CMT-3, CMT-8 and CMT-308) on proliferation and viability of cultured mouse and human mast cells. All studied CMTs (25 microM) effectively inhibited the viability and proliferation of human mast cell line (HMC-1) cells and mouse bone marrow derived mast cells (mBMMCs), as judged by trypan blue exclusion and by incorporation of [(3)H]thymidine. The antiproliferative effect of CMTs was not dependent on the stimulating growth factor, i.e. CMTs inhibited both IL-3 and c-kit ligand-induced proliferation of mBMMCs. The reduced viability of mast cells was due to induction of apoptosis, as indicated by the increased amount of apoptotic nucleosomes and the appearance of TUNEL positive cells in the presence of CMTs. The induction of apoptosis was further confirmed by showing that CMT-3 induces activation of caspase-3 and caspase-9 in HMC-1 cells. Additionally, CMT-3 induced downregulation of the expression of antiapoptotic Bcl-2 protein in HMC-1 cells. Compared to doxycycline, the antiproliferative and proapoptotic effects of different CMTs were clearly more pronounced. Of the studied CMTs, CMT-3 and CMT-8 appeared to be the most potent inhibitors of mast cell proliferation and survival. The present results show that CMTs have an antiproliferative and proapoptotic effect on both malignant and non-malignant mast cells. In conclusion, CMTs could offer a novel means to treat disorders with inappropriate expansion of mast cells, such as rheumatoid arthritis and systemic mast cell diseases.
16012780 Catabolism of native and oxidized low density lipoproteins: in vivo insights from small an 2005 Dec The human organism is exposed to numerous processes that generate reactive oxygen species (ROS). ROS may directly or indirectly cause oxidative modification and damage of proteins. Protein oxidation is regarded as a crucial event in the pathogenesis of various diseases ranging from rheumatoid arthritis to Alzheimer's disease and atherosclerosis. As a representative example, oxidation of low density lipoprotein (LDL) is regarded as a crucial event in atherogenesis. Data concerning the role of circulating oxidized LDL (oxLDL) in the development and outcome of diseases are scarce. One reason for this is the shortage of methods for direct assessment of the metabolic fate of circulating oxLDL in vivo. We present an improved methodology based on the radiolabelling of apoB-100 of native LDL (nLDL) and oxLDL, respectively, with the positron emitter fluorine-18 ((18)F) by conjugation with N-succinimidyl-4-[(18)F]fluorobenzoate ([(18)F]SFB). Radiolabelling of both nLDL and oxLDL using [(18)F]SFB causes neither additional oxidative structural modifications of LDL lipids and proteins nor alteration of their biological activity and functionality, respectively, in vitro. The method was further evaluated with respect to the radiopharmacological properties of both [(18)F]fluorobenzoylated nLDL and oxLDL by biodistribution studies in male Wistar rats. The metabolic fate of [(18)F]fluorobenzoylated nLDL and oxLDL in rats in vivo was further delineated by dynamic positron emission tomography (PET) using a dedicated small animal tomograph (spatial resolution of 2 mm). From this study we conclude that the use of [(18)F]FB-labelled LDL particles is an attractive alternative to, e.g., LDL iodination methods, and is of value to characterize and to discriminate the kinetics and the metabolic fate of nLDL and oxLDL in small animals in vivo.
15983634 [The role of anti-nucleosome antibodies in systemic lupus erythematosus. Results of a stud 2005 Apr OBJECTIVE: The aim of our study was to investigate the prevalence and the disease specificity of anti-nucleosome antibodies in systemic lupus erythematosus and their association with disease activity and renal involvement. METHODS: Anti-nucleosome antibodies were measured by ELISA in the sera of patients with systemic lupus erythematosus (SLE) (47), rheumatoid arthritis (RA) (22), mixed connective tissue disease (MCTD) (19), systemic sclerosis (SSc) (11) and Sjögren's syndrome (SS) (10). Anti-dsDNA antibodies were measured by IIF on Crithidia luciliae. In the patients with SLE serum levels of C3 and C4 complement components were also measured. Sera of 22 healthy individuals were assayed as controls. SLE activity was evaluated by the ECLAM score. RESULTS: Anti-nucleosome antibodies were found in 40 patients with SLE (85.1%), in 10 with RA (45.4%), in 8 with MCTD (42.1%), in 4 with SSc (36.3%), in 1 with SS (10%) and in none of the healthy controls. Anti-dsDNA antibodies were found in 23 patients with SLE and were absent in the patients with other CTD and in controls. All the patients with SLE and renal involvement were positive both for anti-dsDNA antibodies and anti-nucleosome antibodies. No significant correlation was observed between anti-nucleosome antibodies and disease activity and renal involvement. CONCLUSION: Anti-nucleosome antibodies are present in a high percentage of the patients with SLE but they don't seem to be specific markers of the disease. Our data don't support a clear correlation between anti-nucleosome antibodies and disease activity and renal involvement.
15903040 [Large variation in indications for internal fixation or arthroplasty in displaced femoral 2005 Apr 30 OBJECTIVE: To describe the treatment protocols for displaced femoral neck fractures in all 8 university hospitals (UH) and 12 general hospitals (GH). DESIGN: Descriptive; questionnaire. METHOD: Questionnaires were distributed to general surgeons who also perform traumatology surgery. They were requested to give succinct answers to questions about local protocol for the maximum permissible time interval between hip trauma and operation, indications for internal fixation and arthroplasty, operative technique and postoperative degree of weight-bearing in patients over 60 years of age with a displaced femoral neck fracture. RESULTS: Internal fixation and arthroplasty were performed within 24 and 48 hours respectively in 95% of all hospitals. A biological upper age limit of between 65 and 80 years old was the most commonly quoted indication for internal fixation in 70% of all hospitals. In 83% of GH dementia was considered an indication for arthroplasty as opposed to 0% in UH. Poor bone quality, immobility, comminution and inadequate reduction were incidentally quoted indications for arthroplasty. Rheumatoid arthritis, arthrosis and pathological fracture were contra-indications for internal fixation in all hospitals. Operative techniques for internal fixation and arthroplasty were similar in both UH and GH. After internal fixation, full weight-bearing was recommended in all UH and partial weight-bearing in 7 (58%) of GH. Following arthroplasty all protocols prescribed full weight-bearing. CONCLUSION: The variation in indications for internal fixation or arthroplasty reflects the lack of studies that demonstrate clearly which patient can be treated optimally with which treatment modality. There were few differences in the operative techniques of internal fixation and arthroplasty between the hospitals.
15848021 Influence of co-administrated sinomenine on pharmacokinetic fate of paeoniflorin in unrest 2005 May 13 Paeonia lactiflora Pall. (Ranunculaceae) root and Sinomenium acutum Rehder and Wilson (Menispermaceae) stem are two herbs widely used in Chinese medicine to treat rheumatoid arthritis. While, in theory, either herb could be used alone, in practice, Chinese medicine practitioners prescribe them together. Studies on pharmacokinetic interaction between the active constituents of these two herbs (paeoniflorin and sinomenine, respectively) provide empirical evidence to support their clinical practice. A single dose of paeoniflorin (150 mg/kg) alone and with sinomenine hydrochloride (90 mg/kg) was administered by gastric gavage to unrestrained conscious male Sprague-Dawley rats (n=5 or 6, 240-270 [corrected] g). Blood samples were collected periodically via a jugular vein before and after dosing from 10 min to 12 h. A high-performance liquid chromatographic (HPLC) assay was developed to determine the plasma concentrations of paeoniflorin. Non-compartmental pharmacokinetic profiles were constructed by using the software PK Solutions 2.0. The pharmacokinetic parameters were compared using unpaired Student t-test. After co-administration of sinomenine, the peak plasma concentration of paeoniflorin was elevated (P<0.01), the peak time was delayed (P<0.01), the AUC(0-t) was increased (P<0.001), the mean residence time (MRT) was prolonged (P<0.01), the C(L) was decreased (P<0.01) and the V(d) was reduced (P<0.05). These results indicate that sinomenine hydrochloride at 90 mg/kg significantly improved the bioavailability of paeoniflorin in rats.
15781326 Hydroxamate-based peptide inhibitors of matrix metalloprotease 2. 2005 Mar There is major interest in designing inhibitors for matrix metalloproteinase 2 (MMP-2, gelatinase A) since this enzyme is known to be involved in pathological processes such as tumor invasion or rheumatoid arthritis. The majority of MMP-2 inhibitor candidate drugs block the active site of MMP-2 by binding to its catalytic Zn2+ ion through a chelating (hydroxamate, sulphonate etc.) group. Despite the general interest in designing MMP-2 inhibitors, the results with many of the drug candidates were disappointing, their failure was usually explained by cross-reactions with other MMPs. One way to enhance MMP-2 selectivity is to design inhibitors that interact with both the active site and exosites such as the fibronectin type II (FN2) domains of the enzyme. In the present work, we have examined the inhibitory potential and MMP-2 selectivity of hydroxamates of three groups of peptides known to bind to the collagen-binding FN2 domains of MMP-2. The first type of peptides consisted of collagen-like (Pro-Pro-Gly)(n) repeats, peptides of the second group were identified from a random 15-mer phage display library based on their binding to immobilized FN2 domains of MMP-2. A hydroxamate of peptide p33-42, known to bind to the third FN2 domain of MMP-2 has also been tested. Our studies have shown that these compounds inhibited MMP-2 with IC50 values of 10-100 microM. The fact that their inhibitory potential was nearly identical for MMP-2del, a recombinant version of MMP-2 that lacks the FN2 domains, suggests that inhibition is not mediated by their binding to FN2 domains. It seems likely that the failure to exploit interaction with the FN2 domains is due to the fact that the FN2 domains and the catalytic domain of MMP-2 tumble independently, therefore only a tiny fraction of the conformational isomers can bind peptide hydroxamates via both the active site and the FN2 domain(s).
15776786 Focus on: biologics that affect therapeutic agents in dermatology. 2005 Mar Tumor necrosis factor (TNF)-alpha is one of the oldest known cytokines in human physiology. It is involved in both normal and pathologic states. Virtually every cell and organ in the body are affected by TNF-alpha. Though TNF-alpha is usually involved in inflammation as a normal host defense response, when overproduced, it can become pathologic and affect almost every organ system. In this article, we address the role of TNF-alpha in diseases such as rheumatoid arthritis, Crohn's disease, psoriasis, and ankylosing spondylitis as well as the drugs used to modulate TNF-alpha. Specifically, we look at the structure, mechanism of action, and clinical use for etanercept, infliximab, and adalimumab. Historically, we also review the drug lenercept, another TNF-alpha modulator. These drugs offer alternative effective treatments to rheumatologic and dermatologic diseases without as many of the toxic side effects of some of the traditional therapies. The traditional agents target TNF-alpha in addition to several other modes of action (disease modifying anti-rheumatic drugs [DMARDS] such as cyclosporine and methotrexate) (Table 1). Though TNF-alpha immunomodulation seems to be a very effective, promising treatment in several TNF-alpha mediated disease processes, long-term studies need to be performed to assess the risk-benefit ratio of using these drugs over an extended period of time.
15564720 The biology of CD20 and its potential as a target for mAb therapy. 2005 CD20 is a 33-37 kDa, non-glycosylated phosphoprotein expressed on the surface of almost all normal and malignant B cells. It is also the target for rituximab, the most effective anti-cancer monoclonal antibody developed to date. Rituximab has now been given to over 300,000 lymphoma patients in the last decade and interestingly is now being explored for use in other disorders, such as autoimmune conditions including rheumatoid arthritis and systemic lupus erythematosus. Despite the success in immunotherapy, knowledge about the biology of CD20 is still relatively scarce, partly because it has no known natural ligand and CD20 knockout mice display an almost normal phenotype. However, interesting insight has come from work showing that CD20 is resident in lipid raft domains of the plasma membrane where it probably functions as a store-operated calcium channel following ligation of the B cell receptor for antigen. In the current review, these and data relating to its activity as a therapeutic target will be discussed in depth. It is clear that a greater understanding of CD20 biology and the effector mechanisms, such as antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity and growth regulation, which operate with anti-CD20 mAb in vivo will allow more efficient exploitation of CD20 as a therapeutic target.