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[(fluid in patients with RA)-283.2 (compared to those with OA)-283.2 (\(p <)]TJ
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[(0.01\) \(Figure 4\). )17.7 (These observations indicate that the reason)]TJ
0.2014 Tw T*
[(for this high concentration of )54.8 (AM might be secretion of)]TJ
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(vascular wall cells.)Tj
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[(However)39.7 (, the mechanism by which plasma and joint fluid)]TJ
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[(AM levels increase in patients with RA)-275.9 (remains unknown.)]TJ
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[(Several tissues including vessels secrete )54.8 (AM, and elevated)]TJ
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(AM could conceivably be caused by secretion from vascular)Tj
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[(cells in general. )17.8 (When we consider the results, in which )54.9 (AM)]TJ
0.2198 Tw T*
[(levels in the synovium of RA)-415 (patients were higher than)]TJ
-0.0022 Tw T*
[(those of OA)-192.9 (patients, we may assume that synovitis must be)]TJ
0.0081 Tw T*
[(one reason for the increased )54.8 (AM concentration in synovium)]TJ
0.0565 Tw T*
(and joint fluid, and may partially contribute to the increase)Tj
0.02499 Tw T*
[(in )54.8 (AM levels in plasma.)]TJ
0.09531 Tw 1.2 -1.2 Td
[(Our results indicate the possibility that )54.7 (AM participates)]TJ
0.0374 Tw -1.2 -1.2 Td
(in the pathophysiology of joint lesions in patients with RA.)Tj
-0.02071 Tw T*
[(T)69.9 (ogether with the fact that )54.8 (AM is known to inhibit the secre-)]TJ
0.2233 Tw T*
(tion of cytokines from several cell lines)Tj
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(2,15)Tj
-0.00011 Tc 0.2233 Tw 10 0 0 10 237.0434 497.1616 Tm
(, the findings)Tj
0.0705 Tw -18.3043 -1.2 Td
(seem to validate the assumption that production and secre-)Tj
0.0224 Tw T*
[(tion of )54.9 (AM in synovium are strongly correlated with antiin-)]TJ
0.11411 Tw T*
[(flammation in arthritis. )17.7 (Thus, the elevation of plasma )54.8 (AM)]TJ
0.2632 Tw T*
(levels may be related to the antiinflammatory response.)Tj
0 Tw T*
(Clementi, )Tj
/T1_1 1 Tf
0.10699 Tw 4.273 0 Td
(et al)Tj
/T1_0 1 Tf
2.2136 0 Td
[(investigated the antiinflammatory ef)17.7 (fect of)]TJ
-0.01241 Tw -6.4866 -1.2 Td
(AM in rats)Tj
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(3)Tj
-0.00011 Tc -0.01241 Tw 10 0 0 10 100.3226 425.1616 Tm
[(, finding that )54.8 (AM production in several cell lines)]TJ
0.09641 Tw -4.6323 -1.2 Td
(was strongly induced by stimulation of a group of inflam-)Tj
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(matory cytokines including interleukin 1 and tumor necrosis)Tj
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[(factor)19.6 (-)]TJ
/T1_2 1 Tf
0 Tc (\003)Tj
/T1_0 1 Tf
6.5 0 0 6.5 86.749 392.4616 Tm
(16)Tj
-0.00011 Tc 0.16949 Tw 10 0 0 10 93.249 389.1616 Tm
[(. It has also been reported that )54.9 (AM inhibits the)]TJ
0.0488 Tw -3.9249 -1.2 Td
(secretion of such cytokines in the Swiss 3T3 cell line)Tj
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(2)Tj
0.04871 Tw 10 0 0 10 274.0738 377.1616 Tm
(, and)Tj
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[(some studies reported that )54.8 (AM acted as a circulating vasoac-)]TJ
0.0807 Tw T*
(tive hormone in blood, and plays an antiinflammatory role)Tj
T*
(in the prevention of local infection and inflammation, thus)Tj
0.0766 Tw T*
(contributing to host defence systems)Tj
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(4,17)Tj
-0.00011 Tc 0.0766 Tw 10 0 0 10 214.509 329.1616 Tm
(. From these obser-)Tj
0.0159 Tw -16.0509 -1.2 Td
[(vations, we speculate that )54.8 (AM may play a role in the patho-)]TJ
0.09019 Tw T*
(physiology of inflammation as well as in the regulation of)Tj
0.02499 Tw T*
(joint disorders.)Tj
0.2048 Tw 1.2 -1.22 Td
(Synovitis inevitably plays a role in the destruction of)Tj
0.1183 Tw -1.2 -1.22 Td
[(joint surface, so we measured the concentration of )54.8 (AM in)]TJ
0.0311 Tw 0 -1.22 TD
[(articular cartilage. )17.7 (W)79.9 (e found the )54.8 (AM concentration in carti-)]TJ
0.01669 Tw T*
[(lage was lower than that of other tissues. )17.7 (While the concen-)]TJ
0.1152 Tw T*
[(tration of )54.8 (AM in normal human articular cartilage has not)]TJ
0.0199 Tc 0.3649 Tw T*
(been determined, an immunohistochemical study has)Tj
-0.00011 Tc 0.03889 Tw T*
(reported that normal human articular chondrocytes produce)Tj
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(AM)Tj
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(18)Tj
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[(. No statistically significant dif)17.7 (ference was found in)]TJ
0.10291 Tw -2.2608 -1.22 Td
[(the articular cartilage concentration of )54.8 (AM in RA)-298.1 (and OA)]TJ
0.043 Tw T*
[(patients \(Figure 5\). )17.8 (W)79.9 (e therefore speculate that this may be)]TJ
0.1918 Tw T*
(because our samples consisted of endstage arthritis, with)Tj
-0.03529 Tw T*
[(advanced degeneration and dif)17.7 (ferentiation of the cartilage. )54.9 (A)]TJ
0.1606 Tw T*
[(thorough investigation of the role )54.8 (AM in cartilage patho-)]TJ
0.02499 Tw T*
[(physiology is necessary)64.8 (.)]TJ
0.1308 Tw 1.2 -1.2 Td
[(W)79.9 (e observed that plasma )54.8 (AM concentration in patients)]TJ
0.0423 Tw -1.2 -1.2 Td
[(with RA)-237.5 (is higher than that of healthy controls, and plasma)]TJ
0.13229 Tw 0 -1.2 TD
[(AM and plasma CRP)-345.6 (levels were found to be well corre-)]TJ
0.0071 Tw T*
[(lated. Our data suggest that plasma )54.7 (AM levels increase with)]TJ
0.0744 Tw 26.4 63.88 Td
[(the activity of RA. )17.7 (W)79.9 (e conclude that )54.8 (AM probably plays a)]TJ
0.1306 Tw T*
(part in the regulation of the inflammatory process of RA,)Tj
0.0587 Tw T*
(and its plasma and/or joint fluid levels could be used as an)Tj
0.02499 Tw T*
(index of the degree of RA.)Tj
/T1_3 1 Tf
0 Tw 0 -2.4 TD
(REFERENCES)Tj
/T1_0 1 Tf
0.02499 Tw 8 0 0 8 325 643.1616 Tm
[(1.)-875.1 (Kitamura K, Kangawa K, Kawamoto M, et al. )54.8 (Adrenomedullin: a)]TJ
1.675 -1.25 Td
(novel hypotensive peptide isolated from human pheochromocy-)Tj
0 -1.25 TD
(toma. Biochem Biophys Res Commun 1993;192:553-60.)Tj
-1.675 -1.25 Td
[(2.)-875.1 (Isumi )36.8 (Y)128.9 (,)-0.1 ( Kubo )54.8 (A, Katafuchi )17.7 (T)74 (, Kangawa K, Minamino N.)]TJ
1.675 -1.25 Td
(Adrenomedullin suppresses interleukin-1 beta-induced tumor)Tj
T*
[(necrosis factor)19.7 (-alpha production in Swiss 3T3 cells. FEBS Lett)]TJ
0 Tc 0 Tw T*
[(1999;463:1)36.9 (10-4.)]TJ
-0.00011 Tc 0.02499 Tw -1.675 -1.25 Td
[(3.)-875.1 (Clementi G, Caruso )54.8 (A, Cutuli )17.7 (VM, Prato )54.8 (A, Mangano NG, )54.8 (Amico-)]TJ
1.675 -1.25 Td
[(Roxas M. )54.8 (Antiinflammatory activity of adrenomedullin in the acetic)]TJ
T*
(acid peritonitis in rats. Life Sci 1999;65:PL203-8.)Tj
-1.675 -1.2625 Td
[(4.)-875.1 (Ueda S, Nishio K, Minamino N, et al. Increased plasma levels of)]TJ
1.675 -1.2625 Td
(adrenomedullin in patients with systemic inflammatory response)Tj
0 -1.2625 TD
[(syndrome. )54.8 (Am J Respir Crit Care Med 1999;160:132-6.)]TJ
-1.675 -1.2625 Td
[(5.)-875.1 (Y)110.8 (udoh K, Matsuno H, Kimura )17.7 (T)74 (. Plasma adrenomedullin in)]TJ
1.675 -1.2625 Td
(rheumatoid arthritis compared with other rheumatic diseases.)Tj
T*
(Arthritis Rheum 1999;42:1297-8.)Tj
-1.675 -1.2625 Td
[(6.)-875.1 (Evereklioglu C, )36.8 (Y)110.8 (urekli M, Er H, et al. Increased plasma)]TJ
1.675 -1.2625 Td
[(adrenomedullin levels in patients with Behcet\325)54.8 (s disease.)]TJ
T*
(Dermatology 2000;201:312-5.)Tj
-1.675 -1.2625 Td
[(7.)-875.1 (Ohta H, )17.7 (T)69.9 (suji )17.7 (T)74 (,)-0.1 ( )54.8 (Asai S, et al. One-step direct assay for mature-type)]TJ
1.675 -1.2625 Td
(adrenomedullin with monoclonal antibodies. Clin Chem)Tj
0 Tc 0 Tw T*
(1999;45:244-51.)Tj
-0.00011 Tc 0.02499 Tw -1.675 -1.2625 Td
[(8.)-875.1 (Kitamura K, Ichiki )36.8 (Y)128.9 (,)-0.1 ( )17.7 (T)69.9 (anaka M, et al. Immunoreactive)]TJ
1.675 -1.2625 Td
(adrenomedullin in human plasma. FEBS Lett 1994;341:288-90.)Tj
-1.675 -1.2875 Td
[(9.)-875.1 (Kellgren JH, Lawrence JL. Osteoarthritis and disc degeneration in)]TJ
0 Tc 1.675 -1.2875 Td
[(an urban population. )54.8 (Ann Rheum Dis 1958;17:388-97.)]TJ
-0.00011 Tc -2.175 -1.2875 Td
[(10.)-875.1 (Ishimitsu )17.7 (T)74 (, Nishikimi )17.7 (T)74 (, Saito )36.8 (Y)128.9 (, et al. Plasma levels of)]TJ
2.175 -1.2875 Td
(adrenomedullin, a newly identified hypotensive peptide, in patients)Tj
0 -1.2875 TD
(with hypertension and renal failure. J Clin Invest 1994;94:2158-61.)Tj
-2.1381 -1.2875 Td
[(1)36.8 (1)-0.1 (.)-875.1 (Nishikimi )17.7 (T)74 (, Saito )36.8 (Y)128.9 (, Kitamura K, et al. Increased plasma levels of)]TJ
2.1381 -1.2875 Td
[(adrenomedullin in patients with heart failure. J )54.8 (Am Coll Cardiol)]TJ
0 Tc 0 Tw T*
(1995;26:1424-31.)Tj
-0.00011 Tc 0.02499 Tw -2.175 -1.2875 Td
[(12.)-875.1 (Kobayashi K, Kitamura K, Hirayama N, et al. Increased plasma)]TJ
2.175 -1.2875 Td
[(adrenomedullin in acute myocardial infarction. )54.8 (Am Heart J)]TJ
0 Tc 0 Tw T*
(1996;131:676-80.)Tj
-0.00011 Tc 0.02499 Tw -2.175 -1.2875 Td
[(13.)-875.1 (Ohta H, )17.7 (T)69.9 (suji )17.7 (T)74 (,)-0.1 ( )54.8 (Asai S, et al. )54.8 (A)-220.1 (simple immunoradiometric assay)]TJ
2.175 -1.2875 Td
(for measuring the entire molecules of adrenomedullin in human)Tj
0 Tc T*
[(plasma. Clin Chim )54.8 (Acta 1999;287:131\32043.)]TJ
-0.00011 Tc -2.175 -1.2875 Td
[(14.)-875.1 (Kitamura K, Kato J, Kawamoto M, et al. )17.7 (The intermediate form of)]TJ
2.175 -1.2875 Td
(glycine-extended adrenomedullin is the major circulating molecular)Tj
T*
(form in human plasma. Biochem Biophys Res Commun)Tj
0 Tc 0 Tw T*
(1998;244:551-5.)Tj
-0.00011 Tc 0.02499 Tw -2.175 -1.2875 Td
[(15.)-875.1 (Kamoi H, Kanazawa H, Hirata K, Kurihara N, )36.7 (Y)99.8 (ano )36.8 (Y)128.9 (, Otani S.)]TJ
2.175 -1.2875 Td
(Adrenomedullin inhibits the secretion of cytokine-induced)Tj
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[(neutrophil chemoattractant, a member of the interleukin-8 family)64.8 (,)]TJ
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(from rat alveolar macrophages. Biochem Biophys Res Commun)Tj
0 Tc 0 Tw T*
[(1995;21)36.9 (1:1031-5.)]TJ
-0.00011 Tc 0.02499 Tw -2.175 -1.2875 Td
[(16.)-875.1 (Hofbauer KH, Schoof E, Kurtz )54.8 (A, Sandner P)110.7 (. Inflammatory)]TJ
2.175 -1.2875 Td
(cytokines stimulate adrenomedullin expression through nitric)Tj
T*
(oxide-dependent and -independent pathways. Hypertension)Tj
0 Tc 0 Tw T*
(2002;39:161-7.)Tj
-0.00011 Tc 0.02499 Tw -2.175 -1.275 Td
[(17.)-875.1 (Elsasser )17.7 (TH, Kahl S. )54.8 (Adrenomedullin has multiple roles in disease)]TJ
2.175 -1.275 Td
(stress: development and remission of the inflammatory response.)Tj
0 -1.275 TD
[(Microsc Res )17.7 (T)69.9 (ech 2002;57:120-9.)]TJ
-2.175 -1.25 Td
[(18.)-875.1 (Asada )36.8 (Y)128.9 (, Hara S, Marutsuka K, et al. Novel distribution of)]TJ
2.175 -1.25 Td
(adrenomedullin-immunoreactive cells in human tissues. Histochem)Tj
0 -1.25 TD
[(Cell Biol 1999;1)36.8 (12:185-91.)]TJ
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