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

ID PMID Title PublicationDate abstract
7584949 Angiogenesis in cancer, vascular, rheumatoid and other disease. 1995 Jan Recent discoveries of endogenous negative regulators of angiogenesis, thrombospondin, angiostatin and glioma-derived angiogenesis inhibitory factor, all associated with neovascularized tumours, suggest a new paradigm of tumorigenesis. It is now helpful to think of the switch to the angiogenic phenotype as a net balance of positive and negative regulators of blood vessel growth. The extent to which the negative regulators are decreased during this switch may dictate whether a primary tumour grows rapidly or slowly and whether metastases grow at all.
1574313 Imaging temporomandibular joint abnormalities in patients with rheumatic disease. Comparis 1992 Apr The preoperative examination findings in the soft tissue and bone of 22 temporomandibular joints of 15 patients with rheumatic disease were compared with the diagnosis after TMJ surgery. Agreement was found in 15 joints with rheumatic involvement and in 4 with internal derangement. In 5 (with unsuccessful arthrotomography) of the 15 rheumatic joints, magnetic resonance imaging showed destruction of disks with soft-tissue replacement, corresponding to fibrous tissue/ankylosis observed at surgery. Bony fusions in 2 of these joints were depicted with computed tomography. In the remaining 10 joints, arthrotomography showed irregularly outlined small compartments corresponding to synovial proliferations observed during surgery. Similar arthrotomographic interpretation, however, was made in 2 of 3 temporomandibular joints with imaging-surgery disagreement; surgery showed fibrous adhesions. In the third joint with unsuccessful arthrotomography, magnetic resonance imaging showed internal derangement but no synovial proliferations that were surgically observed. As experienced with other joints, synovial proliferations (or fibrous adhesions) could not be depicted with magnetic resonance imaging. Thus, differentiation between internal derangement with and without rheumatic involvement could be impossible with both arthrotomography and unenhanced magnetic resonance imaging.
8713216 Vasculitic neuropathy: profile of twenty patients. 1995 Jul Twenty patients with vasculitic neuropathy were analyzed. Sixteen of the twenty presented with classic mononeuritis multiplex but four had distal, symmetrical, sensorimotor polyneuropathy. Though vasculitic neuropathy is classically associated with Collagen vascular syndromes like, polyarteritis nodosa, rheumatoid arthritis and systemic lupus erythematosis, only 13/20 of our patients had definitive Collagen vascular disease. A large proportion (7/20) had vasculitic neuropathy as the only clinical feature.
8886211 The appropriate use of NSAIDs in arthritic conditions. 1996 Sep Nonsteroidal anti-inflammatory drugs (NSAIDs) are an important component of therapy for many of the arthritides. They are of value in the treatment of rheumatoid arthritis (RA) and other arthritides with inflammatory characteristics and are frequently used to treat osteoarthritis (OA) when simple analgesics fail to provide relief. There is a great deal of interpatient variability with respect to response to NSAIDs; however, it is currently difficult to predict which patient will respond best to which drug. As a result, NSAID selection is based both on the medical history of the individual patient and the adverse-events profiles of the available agents. In general, patients on NSAIDs should be monitored closely for adverse events, particularly those patients with a history of, or risk factors for, gastrointestinal, renal, or hepatic disease. Use of the cytoprotective agent misoprostol is indicated in patients at high risk for gastrointestinal irritation. Although H2-antagonists in high dosages may be effective in the prophylaxis of gastropathy, there is some concern that use of these agents at usual dose levels may create a potential for adverse events by masking the pain associated with ongoing gastric erosive changes.
7516162 Expression of ICAM-R (ICAM-3), a novel counter-receptor for LFA-1, in rheumatoid and nonrh 1994 Jun OBJECTIVE: To study the distribution of intercellular adhesion molecule receptor (ICAM-R, or ICAM-3), a novel ligand for the leukointegrin lymphocyte function-associated antigen 1 (LFA-1), in normal and rheumatoid synovial membranes and to compare this with the distribution of ICAM-1, ICAM-2, vascular cell adhesion molecule 1 (VCAM-1), and endothelial leukocyte adhesion molecule 1 (ELAM-1). METHODS: We performed immunohistochemical analyses of frozen sections of normal and rheumatoid synovial tissue using monoclonal antibodies to the molecules examined. RESULTS: ICAM-1 staining was detectable on the vascular endothelium and the synovial lining cells of both normal and rheumatoid synovial membranes. A variable proportion of lymphocytes infiltrating rheumatoid tissues expressed ICAM-1, ICAM-2 staining was demonstrable in the vascular endothelium of both normal and inflamed tissues, the latter demonstrating a significantly higher proportion of positive vessels. ELAM-1 staining was not detectable in normal synovial membranes but was seen on the endothelium of a limited number of rheumatoid synovial vessels, usually close to the synovial lining cell layer. VCAM-1 staining was intense in both normal and rheumatoid synovial lining cells, but vascular staining was weak in both. In contrast, ICAM-R staining was not detected in association with any synovial blood vessels, but was widely expressed by lymphocytes and macrophages. Cells of the lining layer did not stain for ICAM-R. CONCLUSION: Although ICAM-R is a ligand for LFA-1 and shares considerable sequence homology with ICAM-1 and ICAM-2, it does not appear to be expressed by the endothelium of normal or inflamed synovial vessels. Intense expression of ICAM-R by rheumatoid synovial lymphocytes and macrophages suggests that it may play a role in processes requiring cell-cell contact, such as antigen presentation and homotypic aggregation.
8391786 Activation of neutrophils by soluble and insoluble immunoglobulin aggregates from synovial 1993 May OBJECTIVES: Previous work has shown that synovial fluid isolated from patients with active rheumatoid arthritis contains soluble (not sedimented by centrifugation at 11,600 g for two minutes) and insoluble (sedimented by centrifugation at 11,600 g for two minutes) immunoglobulin aggregates that are capable of activating reactive oxidant production by bloodstream neutrophils. The purpose of this study was to determine which of these types of immunoglobulin aggregates activated the secretion of reactive oxygen metabolites and granule enzymes from neutrophils. METHODS: Cell free synovial fluid (from patients with rheumatoid arthritis) was added to neutrophils isolated from blood of healthy controls that had been incubated in the presence and absence of granulocyte-macrophage colony stimulating factor (GM-CSF). Reactive oxidant production was measured by luminol chemiluminescence (which detects both intracellular and extracellular oxidant production) and by cytochrome c reduction (which measures superoxide secretion). RESULTS: The soluble aggregates only activated neutrophils that were previously primed, and activated a rapid and transient burst of reactive oxidant secretion. On the other hand, the insoluble aggregates activated primed and unprimed neutrophils with similar efficacy and most of the oxidants generated (especially in unprimed cells) were intracellular. The soluble aggregates, but not the insoluble aggregates, also activated the secretion of myeloperoxidase from neutrophils that had either been pretreated with cytochalasin B or primed with GM-CSF. CONCLUSION: It is thus proposed that these soluble immunoglobulin aggregates are responsible for activation of the release of tissue damaging granule enzymes and reactive oxidants from primed neutrophils within the rheumatoid joint.
8713902 Uncemented press-fit total hip arthroplasty using the Identifit custom-molding technique. 1996 Apr Fifty-three primary uncemented custom-molded Identifit (Depuy, Warsaw, IN) hip arthroplasties were evaluated prospectively at a mean follow-up period of 30 months. The custom technique provided the capability to reproduce the unique femoral offset, version, and height in each hip and to achieve high percentages of femoral canal fill. Surgical time for unilateral cases was a mean 153 minutes. Clinical results, however, were disappointing. Nine hips (17%) required stem revision for persistent thigh pain and limping. Of the remaining 44 hips, the mean Harris hip score was 83, and 20% experienced moderate to severe thigh pain and 50% had a limp. Radiographically, 65% of the stems had subsided and 27% had migrated into valgus. Survivorship analysis predicted an 80% stem survival rate at 43 months. A precise fit and fill of the femoral canal is not in itself sufficient for femoral implant stability in total hip arthroplasty surgery.
1402937 Long-term results and survivorship analysis of 89 total condylar knee prostheses. 1992 Sep The results of 89 total condylar I prostheses were assessed using both the Hospital for Special Surgery rating system and survivorship analysis. At an average follow-up period of 9.5 years (range, 5-15) 61 patients (72 knees) were available for clinical and radiographic evaluation. Thirty (41.5%) knees were rated as excellent, 29 (40.5%) good, 4 (5.5%) fair, and 6 (8.5%) poor. Three (4%) cases were considered failures because they needed a second operation. Loss of the postoperative alignment often associated with lateral instability was observed in 23 knees. Loosening of the tibial plateau occurred in two knees; in one of these a successful revision was performed. Survivorship analysis, using deep infection and aseptic loosening as end-point criteria, gave a 15-year probability of survival of 95%. These results confirm the validity of the total condylar prosthesis and the reliability of cementation in knee arthroplasty.
8517075 [Value of arthrosonography of the shoulder in rheumatologic diagnosis. Examination techniq 1993 Mar The sonographic examination of the shoulder has established itself in the diagnostic spectrum of the imaging methods. Especially the results of the rotator cuff have contributed to the fact, that arthrosonography is now indisputable for the shoulder examination. In this paper another scan--the examination through the fossa axillaris--is added to the standard ones, to find the early changes of the shoulder capsule in order to receive efficient results in discovering the omarthritis.
8197491 Visual function and long-term chloroquine treatment. 1994 Jan Ophthalmic examinations and selected tests of visual function were performed on 64 patients with rheumatoid arthritis who had received daily doses of 200 mg chloroquine sulphate for periods ranging from 3 to 11 months. Visual fields were determined by Humphrey automated perimetry and Amsler grids and a further battery of four tests of macular function (visual evoked potentials, critical flicker fusion threshold, Cambridge contrast sensitivity and the macular dazzle test) were administered. No case of retinal pigmentary abnormalities plus visual loss was found, but 2 patients were advised to cease chloroquine therapy on the basis of funduscopic findings. A small group of patients with relatively poor scores on one or more tests had normal visual fields and ophthalmic findings. There were no significant partial correlations between test results and the cumulative dose of chloroquine. These results support the opinion that currently recommended doses of chloroquine pose a minimal risk of retinal toxicity.
7837159 Performance of online biomedical databases in rheumatology. 1994 Oct OBJECTIVE: To compare the performance of MEDLINE, EMBASE, and BIOSIS in selected rheumatology topics. METHODS: Online literature searches were conducted with regard to the epidemiology of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and ankylosing spondylitis (AS), as well as for 3 specific questions representing clinical, clinical/laboratory, and therapeutic topics in rheumatology. Total number of citations retrieved, type and language of publication, percentage of contribution from rheumatology journals, and degree of overlap among the databases were recorded. Publications retrieved for the 3 specific questions were also graded for relevance. RESULTS: For 1991, each online biomedical database (OBD) retrieved more than 1,100 citations for RA, over 600 for SLE, and over 110 for AS. For the epidemiology subtopic, fewer than 25% of the citations were retrieved by more than one of the databases. About 3/4 of the citations obtained for the specific search questions were retrieved by a single database. No major differences were observed among databases in relation to number of relevance of citations retrieved. Over 60% of the papers assessed had low relevance in relation to the topic of the search. Efficiency was estimated as the percentage of all relevant citations retrieved by each OBD. Results varied according to the topic, but in most cases each database retrieved at least 50% of the relevant citations. About 45% of the citations retrieved for the 3 search questions were published in nonrheumatology journals. CONCLUSION: No database was superior in all respects. The majority of the citations were retrieved by a single database. A high percentage of the articles retrieved were not relevant, implying low specificity. If a comprehensive online search in rheumatology is required, 2 or more databases should be utilized.
1633634 HLA molecules in autoimmune diseases. 1992 Jun The association of certain autoimmune diseases with HLA molecules is being refined through the use of sequence-specific oligonucleotide probes and amino acid sequencing, together with continuing elucidation of the functional features of HLA molecules derived from the milestone description by Bjorkman of the HLA molecular structure. The association of insulin-dependent diabetes mellitus and HLA began with weak associations of Class I antigens (B8 and B15) and progressed to Class II antigens (DR3 and DR4), then to subtypes of DR4 (Dw4, 10, and 14), and now to DQ molecules including the absence of aspartic acid at position 57 of the DQ beta chain and the presence of arginine at position 52 of the DQ alpha chain. In rheumatoid arthritis (RA) the HLA antigen association remains with certain Class II molecules of the DR series (DR4 and DR1) that share amino acid sequences with a restricted number of other DR antigens seen in RA, as well as a segment of the gp 110 protein of the Epstein-Barr virus. Although ankylosing spondylitis has a strong association with the Class I antigen B27, that association is not explained by any of the B27 subtypes defined by monoclonal antibodies, by the eight variable amino acids in B27 subtypes, or by the two unique amino acids on B27. The remarkable antibody cross-reactivity among lymphocytes bearing B27, a synthetic peptide sequence (63-84) of B27, and the 188-193 sequence of K. pneumoniae nitrogenase has provided strong support for molecular mimicry being an important mechanism in the association of HLA molecules with disease.(ABSTRACT TRUNCATED AT 250 WORDS)
8495280 Cellular regulatory mechanisms that may underlie the effects of corticosteroids on bone. 1993 May The overall effects of corticosteroids on the skeleton are dependent on many factors including dose, duration of exposure to the steroid, steroid type and species. Some effects are indirect and are brought about by changes in, for example, parathyroid hormone secretion and intestinal calcium absorption, while others may result from cellular responses within the microenvironment of bone itself. Explants of trabecular bone are commonly used to study glucocorticoid effects in vitro, though it is often difficult to be certain that in vitro results directly reflect in vivo activity. Corticosteroids are dual inhibitors of cyclo-oxygenase and lipo-oxygenase, and may exert effects via inhibition of eicosanoid synthesis. They can also inhibit synthesis of cytokines, such as interleukin-1, which stimulate bone resorption and remodelling, by monocytes and macrophages. The production of cytokines and growth factors by bone cells themselves and the expression of their receptors may also be influenced by corticosteroids. Examples of corticosteroid-induced inhibition of synthesis include tumour necrosis factor and interleukin-6, and such effects may be important in explaining therapeutic actions of corticosteroids (e.g. in myeloma). Although it is not yet clear why different glucocorticoids have different effects, a number of factors determine the overall effect of a steroid. These include steroid metabolism and tissue distribution, selective effects on cytokine production, and tissue differences in gene transcription.
8882301 Clinical pharmacokinetics of low-dose pulse methotrexate in rheumatoid arthritis. 1996 Mar Low-dose pulse methotrexate has emerged as one of the most frequently used slow-acting, symptom-modifying antirheumatic drugs in patients with rheumatoid arthritis (RA) because of its favourable risk-benefit profile. Methotrexate is a weak bicarboxylic acid structurally related to folic acid. The most widely used methods for the analysis of methotrexate are immunoassays, particularly fluorescence polarisation immunoassay. After oral administration, the drug is rapidly but incompletely absorbed. Since food does not significantly affect the bioavailability of oral methotrexate in adult patients, the drug may be taken regardless of meals. There is a marked interindividual variability in the extent of absorption of oral methotrexate. Conversely, the intraindividual variability is moderate even over a long time period. Intramuscular and subcutaneous injections of methotrexate result in comparable pharmacokinetics, suggesting that these routes of administration are interchangeable. A mean protein binding to serum albumin of 42 to 57% is usually reported. Again, the unbound fraction exhibits a large interindividual variability. The steady-state volume of distribution is approximately 1 L/kg. Methotrexate distributes to extravascular compartments, including synovial fluid, and to different tissues, especially kidney, liver and joint tissues. Finally, the drug is transported into cells, mainly by a carrier-mediated active transport process. Methotrexate is partly oxidised by hepatic aldehyde oxidase to 7-hydroxymethotrexate. This main, circulating metabolite is over 90% bound to serum albumin. Both methotrexate and 7-hydroxy-methotrexate may be converted to polyglutamyl derivatives which are selectively retained in cells. Methotrexate is mainly excreted by the kidney as intact drug regardless of the route of administration. The drug is filtered by the glomeruli, and then undergoes both secretion and reabsorption processes within the tubule. These processes are differentially saturable, resulting in possible nonlinear elimination pharmacokinetics. The usually reported mean values for the elimination half-life and the total body clearance of methotrexate are 5 to 8 hours and 4.8 to 7.8 L/h, respectively. A positive correlation between methotrexate clearance and creatinine clearance has been found by some authors. Finally, the pharmacokinetics of low-dose methotrexate appears to be highly variable and largely unpredictable even in patients with normal renal and hepatic function. Furthermore, studies in patients with juvenile rheumatoid arthritis provide evidence of age-dependent pharmacokinetics of the drug. These features must be considered when judging the individual clinical response to methotrexate therapy. Various drugs currently used in RA may interact with methotrexate. Aspirin might affect methotrexate disposition to a greater extent than other nonsteroidal anti-inflammatory drugs without causing greater toxicity. Corticosteroids do not interfere with the pharmacokinetics of methotrexate, whereas chloroquine may reduce the gastrointestinal absorption of the drug. Folates, especially folic acid, have been shown to reduce the adverse effects of methotrexate without compromising its efficacy in RA. Finally, both trimethoprim-sulfamethoxazole (cotrimoxazole) and probenecid lead to increased toxicity of methotrexate, and hence should be avoided in patients receiving these drugs. A relationship between oral dosage and efficacy has been found in the range 5 to 20mg methotrexate weekly. The plateau of efficacy is attained at approximately 10 mg/m2/week in most patients. No clear relationship between pharmacokinetic parameters and clinical response has been demonstrated. Overall, the dosage must be individualised because of interindividual variability in the dose-response curve. This variability is probably related, at least in part, to the wide interindividual variability in the disposition of the drug.
8869665 Folate and homocysteine status and haemolysis in patients treated with sulphasalazine for 1996 Aug In an attempt to estimate the frequency of folate deficiency and haemolysis in a group of 25 outpatients with arthritis treated with sulphasalazine (SASP), haematological measurements, including plasma total homocysteine (tHcy) which is a sensitive marker of folate deficiency, serum folate (S-folate), erythrocyte (RBC) folate, S-cobalamin and routine indices of haemolysis were performed. No patient had been taking folate-containing vitamins for at least 8 weeks prior to the study. Compared to a group of 72 healthy hospital staff, the median plasma tHcy was significantly higher in the patient group (8.8 mumol 1(-1) vs. 6.8 mumol 1(-1); p = 0.003). Five patients (20%) had plasma tHcy levels that exceeded the upper normal limit of plasma tHcy (median+2 SD of the reference group). Median S-folate was significantly lower in the patient group (6.0 nmol 1(-1) vs. 8.5 nmol 1(-1); p < 0.001), and 11 (44%) patients had depressed S-folate. Only three (12%) patients had RBC folate values below the reference interval. There was no difference in the levels of RBC folate between the two groups. A comparison of S-cobalamin levels in the two groups disclosed a significantly lower level in the patient group. However, no patient had cobalamin deficiency as assessed by S-cobalamin and S-methylmalonate measurements. Thus, it is unlikely that any patient had increased plasma tHcy due to cobalamin deficiency. Of 24 patients having a HbA1c measurement performed, 12 (50%) had decreased levels indicating chronic haemolysis. Only seven (28%) patients had reticulocytosis. HbA1c was positively correlated to haptoglobin levels (r = 0.77; p < 0.001) and negatively correlated to the percentage of reticulocytes (r = -0.50; p = 0.02). The percentage of reticulocytes was negatively correlated to haptoglobin levels (r = -0.42; p = 0.04). The chronic haemolysis of the patients' blood due to SASP might explain the similar RBC folate values in the two groups because of a relatively higher folate content of young erythrocytes. In conclusion, our results support previous findings of folate deficiency and haemolysis occurring in a considerable fraction of patients receiving treatment with SASP. Measurements of plasma tHcy suggest that a substantial number of patients may have folate deficiency at the tissue level.
7728393 Peptide transporter genes (TAP) polymorphisms and genetic susceptibility to rheumatoid art 1995 Mar The association of rheumatoid arthritis (RA) with HLA-DRB1 alleles indicates that at least one RA susceptibility gene is linked to the HLA class II region. Transporter associated with protein processing (TAP) genes, which lie upstream of the HLA-structural genes, may also contribute to disease susceptibility. We investigated polymorphisms of the peptide transporter genes, TAP 1 and TAP 2, by PCR-ASO hybridization techniques in 82 RA patients and 66 control individuals. Although there was a suggestion of linkage between some TAP polymorphisms and RA, these seem to be dependent on HLA-DRB1*04, since these positive associations disappeared when HLA-DRB1*04 positive RA patients and controls were compared. Furthermore, no particular TAP allele or haplotype was associated with any clinical or immunological subgroup of RA. We conclude that the TAP genes do not have a major influence on susceptibility to RA in the European Caucasian population.
8611303 Identification of a mobile intracardiac rheumatoid nodule mimicking an atrial myxoma. 1995 Nov Cardiovascular involvement occurs in 30% to 50% of patients with rheumatoid arthritis and typically presents as nonspecific inflammation or fibrosis of cardiac structures or as nodules embedded in the various cardiac tissues. This case report describes a unique pedunculated, mobile left atrial rheumatoid nodule prolapsing through the mitral valve plane and mimicking an atrial myxoma. A brief discussion of intracardiac rheumatoid nodules and their potential significance follows.
8126990 [Analysis of factors for the development of pulmonary tuberculosis in persons with collage 1994 Feb Recently, the annual reduction in the incidence rate of tuberculosis has slowed in Japan. One reason for this trend is believed to be due to an increase in the number of immunocompromised hosts. In our department, we discovered 10 cases of pulmonary tuberculosis among 962 cases of collagenosis, and have analyzed the factors for the development of pulmonary tuberculosis in these patients. A total of 29 patients wer involved in the study: 22 with systemic lupus erythematosus (SLE) (active disease, 10; inactive disease, 12) and having no pulmonary complications, and seven with pulmonary tuberculosis and no concomitant diseases. Our findings were as follows: 1. Seven of the 10 patients with pulmonary tuberculosis also suffered from SLE. 2. Nine of the 10 patients had been treated with a corticosteroid or immunosuppressant. 3. Serum CH50 and erythrocyte sedimentation rate (ESR) were valuable indicators for diagnosing pulmonary tuberculosis in the patients with SLE. 4. Patients with SLE and pulmonary tuberculosis tended to show lymphopenia in peripheral blood, which was further enhanced by prolonged use of steroids. 5. Miliary tuberculosis rather than pulmonary tuberculosis tended to develop in elderly patients, and required longer hospitalization.
1536666 Comparison of auranofin, methotrexate, and the combination of both in the treatment of rhe 1992 Mar OBJECTIVE: To compare the relative safety and efficacy of auranofin (AUR), methotrexate (MTX), and the combination of both in the treatment of active rheumatoid arthritis (RA). METHODS: Three hundred thirty-five patients with active RA were entered into a 48-week, prospective, controlled, double-blind, multicenter trial and were randomly assigned to 1 of 3 treatment groups. RESULTS: Two hundred eleven patients completed the trial. No remissions were seen, and there were no statistically significant differences among the treatment groups in the clinical or laboratory variables measured. Patients taking AUR alone had a slower onset of response than did patients taking MTX alone or in combination. Withdrawals because of adverse drug reactions were slightly more common for those taking combination therapy, but the differences were not statistically significant. Withdrawals because of lack of response were more common for single-drug therapy, with the difference between AUR and the combination reaching statistical significance. No unexpected adverse drug effects were identified, and all reactions resolved without sequelae. CONCLUSION: Except for fewer withdrawals because of lack of response, combination therapy did not demonstrate any advantage in efficacy over single-drug treatment within the time frame of the study.
8785263 The pathophysiology of angiogenesis. 1995 The formation of new capillary blood vessels, a process termed "angiogenesis", is one of the most pervasive and fundamentally essential biological processes encountered in mammalian organizations. Angiogenesis is an important event in a variety of physiological settings, such as embryonic development, chronic inflammation, and wound repair. It is a process that is tightly regulated in both time and space. Angiogenesis is driven by a cocktail of growth factors and pro-angiogenic cytokines and is tempered by an equally diverse group of inhibitors of neovascularization. Angiogenesis is also central to the etiology and pathogenesis of a number of pathological processes that include, among others, solid tumors, diseases of the eye, and chronic inflammatory disorders such as rheumatoid arthritis, psoriasis, and periodontitis. Based on recent work from several laboratories, it is now eminently clear that most if not all angiogenesis and vasoproliferative-dependent disease processes are not only a consequence of the unrestricted production of normal or aberrant forms of pro-angiogenic mediators but also the result of a relative deficiency in angiogenic-inhibitory molecules. In this review, I will describe how these multifunctional mediator systems function to coordinate and regulate the angiogenic response, and how disruption in the molecular controls that regulate the production of pro-angiogenic and angiostatic mediators leads to aberrant angiogenesis and disease. The implications of these findings in the development of novel therapeutic strategies for the treatment of diseases characterized by disregulated angiogenesis will also be discussed.