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ID PMID Title PublicationDate abstract
9952027 Autoantibodies to transcriptional regulation proteins DEK and ALY in a patient with system 1999 Jan A human cDNA expression library that was used to investigate the nature of autoantigens recognized by the serum from a patient with systemic lupus erythematosus revealed the presence of antibodies directed against two transcriptional regulation protein: DEK, a site-specific 45 kD DNA binding protein, likely involved in signal transduction and transcriptional regulation, and a novel 28 kD protein that showed a 94% homology with murine ALY, a nuclear protein that plays a role in regulating the activity of TCRalpha enhancer complex. Whereas autoantibodies directed to epitopes on DEK are commonly found in patients with pauciarticular onset juvenile rheumatoid arthritis, autoantibodies against ALY have not been described and their occurrence has led to the cloning of the cDNA sequence of the first member of the human ALY family.
9864636 [Covering extensive soft tissue defects in infected knee endoprostheses by gastrocnemius f 1998 Nov Total knee arthroplasty has become a routine procedure in surgery. Deep infections have an incidence of 2-5%. Major risk factors are large prostheses, rheumatoid arthritis, diabetes mellitus and postoperative wound-healing complications. In large soft-tissue defects with skin necrosis, local wound care shows poor results, especially if loosening of the prosthesis and necrosis of the patellar ligament are evident. In these cases, no standard surgical therapy has been developed yet. Thus, we consider meticulous débridement with synovialectomy to be mandatory. Exchange of the prosthesis may be necessary. Soft-tissue coverage ought to be performed with a gastrocnemius muscle flap covered with a split-thickness skin graft. In the last three years, 11 patients with large soft-tissue defects and necrosis of the ligament were treated according to this concept. In all cases the muscle flap healed primarily and soft tissue coverage was excellent. Two patients who underwent single-stage removal and reimplantation of the prosthesis showed reinfections of the prosthesis. Reconstruction of the ligament was performed with the flap tendon. The patients with two-stage removal and reimplantation of the prosthesis and those who retained their implants had a good functional outcome. The gastrocnemius muscle flap provides easy and reliable soft-tissue reconstruction in large defects. In our patients a two-stage operation for reimplantation of the prosthesis was superior to a single-stage procedure. The reconstructed ligament should be reinforced with autologous material to prevent a secondary rupture. Early reconstruction with sufficient soft-tissue coverage and reconstruction of the ligament offers the patient the best chances of obtaining a good functional result and prevents arthrodesis or amputation. In addition, reconstructive surgery reduces the length of hospital stay and costs.
9684267 Immunonutrition: the role of omega-3 fatty acids. 1998 Jul The dietary fatty acids of the omega-3 series are rapidly incorporated into cell membranes and profoundly influence biological responses. These lipids influence membrane stability, membrane fluidity, cell mobility, the formation of receptors, binding of ligands to their receptors, activation of intracellular signaling pathways either directly or through the formation of eicosanoids, gene expression, and cell differentiation. In general, eicosanoids formed from the omega-3 fatty acids are much less potent in causing biological responses than those formed from the omega-6 fatty acids, including stimulation of cytokine production and inflammatory responses. In well-controlled clinical studies, consumption of omega-3 fatty acids has resulted in reduction of cardiovascular diseases including arrhythmias and hypertension, protection from renal disease, improvement in rheumatoid arthritis, improvement in inflammatory bowel diseases, reduced episodes of rejection, and protection from infection. The interactions between the omega-3 fatty acids and pharmacologic drugs that alter intracellular signaling pathways are only now being studied.
9649424 Direct link between cytokine activity and a catalytic site for macrophage migration inhibi 1998 Jul 1 Macrophage migration inhibitory factor (MIF) is a secreted protein that activates macrophages, neutrophils and T cells, and is implicated in sepsis, adult respiratory distress syndrome and rheumatoid arthritis. The mechanism of MIF function, however, is unknown. The three-dimensional structure of MIF is unlike that of any other cytokine, but bears striking resemblance to three microbial enzymes, two of which possess an N-terminal proline that serves as a catalytic base. Human MIF also possesses an N-terminal proline (Pro-1) that is invariant among all known homologues. Multiple sequence alignment of these MIF homologues reveals additional invariant residues that span the entire polypeptide but are in close proximity to the N-terminal proline in the folded protein. We find that p-hydroxyphenylpyruvate, a catalytic substrate of MIF, binds to the N-terminal region and interacts with Pro-1. Mutation of Pro-1 to a glycine substantially reduces the catalytic and cytokine activity of MIF. We suggest that the underlying biological activity of MIF may be based on an enzymatic reaction. The identification of the active site should facilitate the development of structure-based inhibitors.
9617577 Diurnal rhythms of pro-inflammatory cytokines: regulation by plasma cortisol and therapeut 1998 Apr Clinical features of certain immuno-inflammatory disorders such as rheumatoid arthritis and asthma exhibit diurnal fluctuation, which could be related to diurnal rhythmicity of pro-inflammatory cytokine production. To investigate the latter, the authors performed measurements of lipopolysaccharide (LPS)-stimulated whole blood, interferon gamma (IFN-gamma), tumour necrosis factor alpha (TNF-alpha), interleukin 1 (IL-1) and IL-12 production in 13 healthy volunteers over 24 h. These cytokines exhibited distinct diurnal rhythms that peaked in the early morning and were inversely related to the rhythm of plasma cortisol. Elevation of plasma cortisol within the physiological range by administration of cortisone acetate, 25 mg at 21.00, markedly suppressed IFN-gamma, TNF-alpha, IL-1 and IL-12 production, but not the later early morning rise of endogenous plasma cortisol. Suppression of cytokine production was temporally dissociated from changes in numbers of circulating mononuclear cells. Regulation of pro-inflammatory cytokine production by plasma cortisol has potential therapeutic implications. In contrast to standard schedules, a small, late evening, dose of glucocorticoid to suppress the diurnal increase in pro-inflammatory cytokine production could alleviate early morning inflammatory symptoms and minimize side-effects.
9477594 [Sex hormones and osteoporosis: a physiological perspective for prevention and therapy]. 1997 Oct Estrogen deficiency is the main cause of post-menopausal osteoporosis and hormone replacement therapy is consensually regarded as the first line choice for its prevention. Hormone-replacement has also been shown to prevent bone loss associated with rheumatoid arthritis (RA) and corticotherapy. The rationale for its use in RA is reinforced by evidence of beneficial effects on disease activity. Estrogens also have bone-protective effects in males. C-19 progestagens seem to potentiate the skeletal effects of estrogens whereas C-21 derivatives appear to have no significant influence. Progestagens may be particularly useful in the prevention of steroid-induced osteopenia. Testosterone is an effective treatment for male osteoporosis associated with hypogonadism and is also promising in the treatment of osteoporosis in aged eugonadal males. The association of this hormone potentiates the effects of estrogens on bone mineral density in post-menopausal women. However, anabolic androgens have been preferred in this condition, due to a lower androgenizing effect. They represent a valid therapeutic alternative, particularly in cases of cortical osteoporosis with low bone turnover and in the aged and frail. In general, the different modalities of hormonal therapy clearly deserve a higher degree of preference in the treatment and prevention of osteoporosis than common present practice in our country. It is time to reassess this matter, clear unfounded fears and reinforce the physiological and scientific foundations of our therapeutic options for osteoporosis.
9548078 HLA-DRB1*0405 is the predominant allele in Brazilian patients with Vogt-Koyanagi-Harada di 1998 Mar Vogt-Koyanagi-Harada (VKH) disease is a rare disorder affecting pigmented structures especially the eye and is the main cause of autoimmune non-infectious uveitis in the Brazilian population. The autoimmune target is believed to be the melanocyte. A strong association of VKH disease with HLA-DR4 in the Japanese population is well known. The same association, albeit with lower relative risks has been found in other populations. A secondary association to HLA-DR1 involving a sequence linked with susceptibility to Rheumatoid Arthritis has also been described. VKH disease is more common in non-Caucasian populations. Brazilian patients of varying ethnic origins have been typed for HLA class II antigens. Several of the features found in other population samples are present. Over half of the patients typed HLA-DR4 (20/37) and typing with sequence-specific oligonucleotides disclosed predominance of the DRB1*0405 allele with a relative risk of 11.76 over the general population. In addition, HLA-DR1 and DQ4 were also present, in patients both positive and negative for HLA-DR4. These results suggest that, as in other autoimmune diseases, multiple overlapping susceptibility factors encoded by the MHC complex contribute to the overall susceptibility for the disease, the major factor however, being the presence of the DRB1*0405 allele.
9528261 [Characteristics of medical institutions visited by patients with intractable diseases--an 1998 Jan The Research Committee of Epidemiology of Intractable Diseases (Ministry of Health and Welfare, Japan) conducted a nationwide survey of 34 intractable diseases. Each of 47 prefectural governments reported information on all patients with the diseases who received financial aid for the disease from April 1992 to March 1993. Information collected on each patient included the identification number, sex, age, the code of the municipality where the patient lived, and the medical institution and department where the patient was being treated. Out of 247, 726 patients whose information was reported by prefectural governments, we analysed data of 208,945 patients whose medical institutions were reported. The results can be summarized as follows: 1) Aged patients and children who were less than ten years old tended to visit medical institutions located in their neighborhoods and be treated in small hospitals or clinics. 2) The proportion of patients who visited hospitals with 200 beds or more was 77 percent. 3) Patients with the diseases resulting in physical disabilities such as SMON and malignant rheumatoid arthritis tended to visit clinics. Patients with skin diseases as pemphigus, epidermolysis bullosa and pustular psoriasis tended to be treated in university hospitals. 4) Many patients living in prefectures near large cities such as Tokyo and Ishikawa visited medical institutions in the large cities. 5) The proportion of patients who visited university hospitals decreased during the eight years from 1984 to 1992. However, a quarter of these patients visited university hospitals.
9484795 Involvement of leukotriene B4 in murine dermatitis models. 1998 Feb 1 Leukotriene B4 (LTB4) is a product of the 5-lipoxygenase pathway of arachidonic acid (AA) metabolism. LTB4 is a potent chemotactic factor for neutrophils and has been postulated to play an important role in a variety of pathological conditions including rheumatoid arthritis, psoriasis, and inflammatory bowel disease. To investigate the role of LTB4 in dermatitis, we used S-(4-dimethylaminobenzyl)-N-[(2S)-3-mercapto-2-methylpropionyl]-L- cysteine (SA6541), a potent leukotriene A4 (LTA4) hydrolase inhibitor. SA6541 inhibited LTB4 production with an IC50 value of 270 nM in vitro. 5-Hydroperoxyeicosatetraenoic acid (5-HPETE) or AA injection induced LTB4 production and neutrophil influx in mouse ear. SA6541 inhibited 5-HPETE- and AA-induced LTB4 production and neutrophil influx in mouse ear when administered orally at a dose of 50 mg/kg. SA6541 also inhibited 5-HPETE-induced prostaglandin E2 (PGE2) production, probably by an indirect effect through the inhibition of LTB4 production. These results suggest that LTB4 may be important in the pathogenesis of dermatitides such as psoriasis.
9469557 Cataract patients in a defined Swedish population 1986-1990. VIII. Postoperative astigmati 1997 Oct PURPOSE: Cataract surgery is often followed by a certain amount of astigmatism that changes in the postoperative period. However, there are large variations in both size and changes of the postoperative astigmatism. I have analysed the variations and the influence of different explanatory variables on the postoperative astigmatism. METHODS: Data for all patients undergoing cataract surgery from 1986 up to and including 1990 in the Lund Health Care District were prospectively recorded. Except for cases operated on with both keratoplasty and cataract, all cases were included in the study. The different explanatory variables considered included sex, age, preoperative axial length, preoperative average keratometry, preoperative intraocular pressure, glaucoma history, diabetes history, uveitis history (including both anterior and posterior uveitis), and a history of rheumatoid arthritis. RESULTS: Besides age and sex, several variables significantly influenced the development of size and/or change in the postoperative astigmatism. They were preoperative astigmatism (polar value), preoperative intraocular pressure, and whether or not the cataract patient had an insulin dependent diabetes. Phacoemulsification as extraction mode, the location of the incision, complications at surgery, and whether or not a sphincterotomy was performed also influenced the two parameters of astigmatism. It was also important whether or not the operation was performed by a high volume surgeon. CONCLUSION: In this material, the most important predisposing factors for rapid changes in the postoperative astigmatism were large preoperative astigmatism (polar value), young age, low preoperative intraocular pressure, if an ECCE were chosen as the extraction type, and the surgeon. The same variables and, in addition, if the location of the incision was anterior to the limbus were the most important explanatory variables in generating an early, large with-the-rule astigmatism.
9467192 Orthopedic pathology of the lower extremities: scintigraphic evaluation in the thigh, knee 1998 Jan Radionuclide imaging (RI) of the osseous and nonosseous structures of the thigh, knee, and leg provide important diagnostic and prognostic information upon which the orthopedic surgeon can base treatment planning and management decisions. 99mTc-MDP scintigraphy is essential in overuse injuries such as stress fractures and shin splints. RI is important in assessing complications of trauma. It is the only imaging modality able to assess the magnitude of physeal stimulus caused by femoral fractures and to predict a favorable or unfavorable outcome of leg length by semiquantitative analysis; SPECT imaging can detect and locate decreased metabolism associated with posttraumatic closure of the physeal plate to predict growth arrest and deformities. Three-phase bone imaging (TPBI) is essential to differentiate hypervascular from avascular nonunions and follow delayed union. In osteonecrosis of the knee, bone scintigraphy precedes radiography changes even in stage l of the disease. 99mTc-MDP and 99mTc-HIG imaging are powerful tools in determining the outcomes of osteoarthritis and rheumatoid arthritis, respectively. Bone scintigraphy can also detect chronic ligament and acute and chronic meniscal lesions. The combined use of TPBI, gallium-67 citrate imaging, and indium-111 or 99mTc-HMPAO labeled leukocytes is important to diagnose and differentiate acute from chronic osteomyelitis, and to detect infected knee prostheses. Thallium-201 chloride imaging and 99mTc-sestamibi imaging have an important role in the assessment of tumor response to chemotherapy and in the quantification of tumor viability.
9309196 Approaches to the management of systemic lupus erythematosus. 1997 Sep Systemic lupus erythematosus is a difficult disease to study with a variable disease course characterized by exacerbations and remissions. A variety of biologic agents are under investigation as potential treatments for systemic lupus erythematosus, either in murine disease models or in clinical trials. These products are designed to specifically interfere with the following immunologic processes: T-cell activation and T-cell-B-cell collaboration, production of anti-dsDNA antibodies, deposition of anti-dsDNA antibody complexes, complement activation, and deposition, and cytokine activation and modulation. More aggressive interventions include gene therapy and stem-cell transplantation. Recently developed immunomodulators have been studied in patients with systemic lupus erythematosus 2'-Chlorodeoxyadenosine, mycophenolate mofetil, and leflunomide. Additional innovative pharmaceutical treatments include the mild androgen dehydroepiandrosterone, estrogen antagonists, including tamoxifen and selective estrogen receptor modulators, and the prolactin inhibitor bromocriptine. Other promising pharmaceutical interventions include products designed to inhibit synthesis of the proinflammatory mediators: prostaglandins, leukotrienes, and nitric oxide. Although previously regarded as an indication to be avoided in the development of new therapeutics, enthusiasm for studying systemic lupus erythematosus in clinical trials now exists. A variety of biologic and pharmaceutical agents offer promise as potential therapies. As with rheumatoid arthritis, development of these products will benefit from active involvement of rheumatologists and efforts to develop international consensus regarding trial methodology and outcome measures.
9290140 A phantom for evaluating bone mineral density of the hand by dual-energy x-ray absorptiome 1997 Aug Dual-energy x-ray absorptiometry (DXA) is a precise, widely used method for measuring bone mineral density (BMD), usually of the lumbar spine and femoral neck. Recent developments, such as a lower x-ray tube current and pixel by pixel analysis, enable smaller bones and thinner tissues volumes, as in the hand, to be measured. Measurements of hand bone mineral content (BMC) and BMD could be useful in assessing disease severity in early rheumatoid arthritis and in monitoring disease progression and response to therapeutic intervention. A phantom is required for evaluating the software, measuring long-term precision and comparing with other DXA methods. This note describes the design and evaluation of a hand phantom for use on a Lunar DPX-L dual-energy x-ray absorptiometer. The phantom consists of three sections representing the metacarpals, and proximal and distal phalanges, using aluminum and Perspex as the bone and lean tissue equivalents respectively. The BMD of the three sections is approximately 1.0, 0.6 and 0.3 g cm-2. The phantom demonstrates limitations in the potential accuracy of BMD determination at low densities using the Small Animal Software on the Lunar DPX-L. Improved recognition of low-density regions was obtained with the Lunar EXPERT with precision values of 0.9, 1.1 and 2.0% for the three sections of the phantom respectively.
9164978 Expression of IFN-inducible protein-10 in chronic hepatitis. 1997 Jun 1 Chemokines such as IFN-inducible protein-10 (IP-10) and JE/monocyte chemotactic protein-1 (MCP-1) are induced in the murine liver in a tissue-specific manner. We examined whether IP-10 and MCP-1 are pathologically involved in chronic hepatitis. Whereas the serum levels of IP-10 and MCP-1 in patients with chronic persistent hepatitis C were elevated compared with those in normal volunteers, both chemokine levels were further significantly higher in patients with the active form (chronic active hepatitis (CAH)). The elevated IP-10 level was not a general phenomenon of inflammation, because it was not seen in patients with rheumatoid arthritis, whereas MCP-1 levels were elevated to the same extent in both patient groups. Better responsiveness to IFN therapy in CAH was related to lesser grades of necroinflammatory activity and was predicted by the lower IP-10 and higher MCP-1 levels. IP-10 levels in patients cured by IFN therapy decreased to the levels in normal volunteers, while the MCP-1 levels only slightly decreased. Serum levels of both chemokines in patients who were not cured remained unchanged after IFN therapy. In situ hybridization analysis of CAH revealed that IP-10 mRNA was expressed mainly in hepatocytes around intralobular focal and periportal piecemeal necrosis, while some MCP-1 mRNA was expressed in some sinusoidal cells. These results suggested that IP-10 plays a specific role in the intralobular accumulation of mononuclear cells and/or the death of hepatocytes in chronic hepatitis.
9128418 [Immunohistochemical study of myofibroblast and S-100 protein positive cells in interstiti 1997 Feb Immunohistochemical study was carried out in patients with collagen vascular disease associated with interstitial pneumonia. The subjects were 16 patients, consisting of seven rheumatoid arthritis (RA), five dermatomyositis (DM) and four progressive systemic sclerosis (PSS), in whom the pathological findings were consistent with usual interstitial pneumonia. Immunohistochemical examinations were performed by the ABC method using antibodies to vimentin (vim), alpha-smooth muscle actin (alpha-SMA), and S-100 protein. In fibrosis associated with RA, proliferation of alpha-SMA-positive myofibroblasts was widely observed in all subjects. Myofibroblasts were present also in patients with DM and PSS, but not as notable as in those with RA. Proliferation of vim-positive fibroblasts was observed in patients with idiopathic pulmonary fibrosis (IPF). Diverse S-100 protein positive cells appeared in patients with acute exacerbations of RA, especially when associated with bronchiolitis obliterans organizing pneumonia (BOOP) pattern. S-100 protein positive cells were observed occasionally also in patients with DM and PSS, but they markedly decreased in number, compared to those with RA. They were generally hard to detect in lungs of patients with IPF. These findings suggest that interstitial pneumonia associated with collagen vascular disease can be fairly clearly differentiated from IPF each other, based on the degree of proliferation of myofibroblasts and on the presence of S-100 protein positive cells in number.
9419440 Treatment of autoimmune diseases through manipulation of antigen presentation. 1997 In rheumatoid arthritis, HLA-DR alleles associated with elevated relative risk share a common sequence in the third hypervariable domain of the major histocompatibility complex class II molecule (MHC II). Immunization of mice with a peptide vaccine comprised of the appropriate MHC II sequence in adjuvant blocked the onset and reduced the relapse rate of experimental autoimmune encephalomyelitis (EAE). A phase I clinical trial testing a single injection of a third hypervariable domain peptide from the HLA-DRB1*0401 sequence in alum adjuvant showed that the vaccine is well tolerated and generates an anti-HLA-DR antibody response in approximately 25% of the treated patients. A phase II trial testing multiple boosts is in progress. In a more antigen-specific approach, solubilized MHC II molecules loaded with an autoantigenic peptide are injected intravenously to induce unresponsiveness by the binding of the T-cell receptor (TCR) in the absence of costimulation. Appropriate soluble MHC II:autoantigenic peptide complexes inhibit the recall antigen proliferative response of T clones or draining lymph node cells, and reduce the progression of EAE and experimental autoimmune myasthenia gravis (EAMG). A test of a soluble HLA-DR2:myelin basic protein (MBP) complex in multiple sclerosis is progressing in phase I.
9071509 Immune ablation and hematopoietic stem cell rescue for severe autoimmune diseases (SADS). 1997 In addition to our center (Northwestern University, Chicago), several institutions in the United States (Fred Hutchinson Cancer Center, University of California at Los Angeles, and Medical College of Wisconsin) and Europe are activating protocols to transplant patients with SADS. In this age of cost-effectiveness, it will be difficult to arrange third-party reimbursement for a hematopoietic stem cell transplant that may lead to medical charges of between $100,000 and $200,000. However, the cost of standard medical care for patients with SADS is not trivial. Dialysis for an SLE patient with renal failure costs $40,000 per year, while the medical resources required to care for a patient with progressive multiple sclerosis may exceed $35,000 per year. Unique BMT regimen-related toxicities may occur, including intracranial hemorrhage in the SLE or rheumatoid arthritis patient who has vasculitis; acute neurologic decompensation in patients with multiple sclerosis, especially if the conditioning regimen contains neurotoxic agents that cross a compromised blood-brain barrier; respiratory failure in patients with myasthenia gravis; and increased renal or pulmonary toxicity in patients with scleroderma and parenchymal fibrosis. Scleroderma-associated gastrointestinal dysmotility and bacterial overgrowth may also lead to greater fungal and bacterial infections [76]. BMT is currently considered appropriate therapy for patients with chronic-phase Chronic myelogenous leukemia (CML) and indolent lymphomas who otherwise have a relatively long life expectancy of 5 and 10 years, respectively. The roughly similar long survival but greater functional impairment of patients with SADS may justify consideration of immune ablation and hematopoietic stem cell rescue.
19078345 Pustulotic arthro-osteitis report of a case successfully treated with laser-assisted arthr 1999 Feb A 61-year-old man with palmoplantar pustulosis had pain and swelling persisting in his left knee for more than 3 years. The rheumatoid factor and HLA B 27 antigen were absent. Plain radiographs of the knee revealed no abnormalities despite the persistent synovitis. The bone scintigraphy showed increased uptake in the manubriosternal joint as well as in the knee. Eventually, the patient underwent arthroscopic synovectomy assisted with a holmium: YAG laser. No postoperative complications such as hemarthrosis were noted. The patient was pain free with full range of motion of the knee 22 months after surgery. Peripheral arthritis associated with palmoplantar pustulosis is usually transient. This unique case suggests that laser-assisted arthroscopic synovectomy would be a useful therapeutic option for persistent severe synovitis resistant to conservative treatment in pustulotic arthro-osteitis.
9620225 Expression of type IV collagenase correlates with the expression of vascular endothelial g 1997 Tumor growth and metastasis are angiogenesis-dependent processes initiated and regulated by a number of cytokines. Vascular endothelial growth factor (VEGF) is a potent angiogenic protein with a selective mitogenic effect on vascular endothelial cells, known to be involved in physiological (embryogenesis) and pathophysiological (rheumatoid arthritis, tumor) angiogenesis. An increased expression of matrix metalloproteinase type IV collagenase has been reported in invading endothelial cells in vitro and in malignant cells, degrading structures of the basement membranes in various human malignancies. In the present study we investigated the expression of the genes for type IV collagenase and vascular endothelial growth factor (VEGF) in 40 cases of primary non-small-cell lung cancer (NSCLC). Specimens were immunostained by an antibody directed against VEGF and mRNA transcripts of VEGF and type IV collagenase were localized by non-radioactive in situ hybridization. VEGF mRNA was detected in 33 neoplasms, while in 23 cases transcripts of the type IV collagenase gene were visualized by digoxigenin-labeled cDNA probes. Transcripts of both mRNAs were detected in malignant cells. Furthermore, anti-VEGF immunostaining was present in newly formed microvessels close to the atypical cells, and mRNA of type IV collagenase was present in stromal cells adjacent to the tumor. A statistically significant correlation was found between the expression of type IV collagenase and VEGF (P = 0.0061). These data suggest a double role for type IV collagenase in the metastatic process of NSCLC: (1) facilitating the invasion of tumor cells by the proteolytic cleavage of the basement membrane and (2) similarly supporting the endothelial cell invasion essential for tumor angiogenesis. Furthermore, our findings sustain the hypothesis that metastatic spread and angiogenesis are associated with a clonal expansion of highly angiogenic and invasive tumor cell clones.
11055820 COX-2-Specific inhibitors--the emergence of a new class of analgesic and anti-inflammatory 2000 The prostaglandin series of bioactive compounds is formed by the interaction of two distinct but related enzymes, cyclo-oxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). COX-1 is a constitutive form which is present mainly in the gastric mucosa, kidney and platelets. COX-2 is mainly an inducible form, although also to some extent present constitutively in the CNS, the juxtaglomerular apparatus of the kidney and in the placenta during late gestation. Both isoforms contribute to the inflammatory process, but COX-2 is of considerable therapeutic interest as it is induced, resulting in an enhanced formation of prostaglandins, during acute as well as chronic inflammation. Conventional NSAIDs inhibit both isoforms to a similar extent and in an approximately equal dose and concentration range. The two recently developed and clinically available selective COX-2 inhibitors, celecoxib and rofecoxib, are about 100-1000 times more selective on the COX-2 than on the COX-1 isoform. In Europe rofecoxib is today indicated for the symptoms and signs of osteoarthritis, whereas celecoxib is indicated for both osteoarthritis and rheumatoid arthritis. The major clinical interest of these drugs has been related to the lower incidence of gastrointestinal bleeding which, with the conventional COX-1/COX-2 agents has been a source of hospitalisation, disablement and death, especially in the elderly. Clinical trials have convincingly demonstrated that celecoxib and rofecoxib in clinical use induce very few gastrointestinal complications compared to conventional and non-selective NSAIDs. However, the well known contraindications for NSAIDs, such as late pregnancy, aspirin-induced asthma, congestive heart failure and renal dysfunction, will so far apply also to the COX-2 inhibitors. Compared to the traditional and non-selective NSAIDs, COX-2 inhibitors may provide an insight into additional therapeutic areas, such as gastrointestinal cancer and dementia, where the potential relevance to COX-2 mechanisms are currently being explored and clinical trials being performed. With the rapid clinical acceptance of celecoxib and rofecoxib, knowledge about their clinical usefulness in various inflammatory disease states and pain disorders is increasing. For the many patients suffering from such conditions, the selective COX-2 inhibitors are likely to become a significant addition to the therapeutic arsenal of analgesic and anti-inflammatory drugs.