***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Rheumatoid arthritis ( RA ) is associated with high rates of cardiovascular events mainly due to coronary and cerebrovascular atherosclerotic disease . Asymmetric ( ADMA ) and symmetric ( SDMA ) dimethylarginines are endogenous inhibitors of nitric oxide synthase and have been repeatedly linked with adverse cardiovascular outcomes in the general population and various disease setting s. Alanine – glyoxylate aminotransferase 2 ( AGTX2 ) is considered an alternative metabolic pathway contributing to the clearance of dimethylarginines in humans . The aim of the current study was to investigate the effect of specific AGXT-2 gene polymorphisms on circulating levels of ADMA or SDMA in patients with RA .  Serum ADMA and SDMA levels were measured in 201 individuals with RA [ median age : 67 years ( IQR : 59–73 ) , 155 females ] . Two single nucleotide polymorphisms ( SNPs ) in the AGXT-2 gene — rs37369 and rs28305—were genotyped . Distributions of SDMA and ADMA were skewed , hence comparisons across the gene polymorphisms were performed using Kruskal – Wallis tests , and summarized using medians and interquartile ranges . Univariable analysis did not demonstrate a significant difference in the levels of SDMA or ADMA amongst the different genotypic groups of either rs37369AGXT2 ( p = 0.800 , 0.977 ) or rs28305AGXT2 ( p = 0.463 , 0.634 ) . In multivariable analyses , ADMA levels were found to be significantly associated with erythrocyte sedimentation rate and estimated glomerular filtration rate , whilst SDMA levels were significantly associated with estimated glomerular filtration rate and quantitative insulin sensitivity check index . After adjustments for these factors , the relationship between the AGXT2 gene variants and both ADMA and SDMA remained non-significant . Our study in a well-characterized RA population did not show an association between serum concentrations of dimethylarginines and genetic variants of the AGXT2 gene BACKGROUND  Asymmetric dimethylarginine ( ADMA ) is associated with endothelial injury . Increased ADMA levels are found in rheumatoid arthritis ( RA ) and ankylosing spondylitis ( AS ) . We set out to assess the  ADMA and symmetric dimethylarginine ( SDMA ) levels in AS , RA , and healthy controls , and in the anti-TNF treated patients with active AS . METHODS In 78AS patients and 29 RA patients who were anti-TNF treatment naive at baseline , along with 23 healthy control subjects , we assessed erythrocyte sedimentation rate ( ESR ) , high-sensitivity C-reactive protein ( hsCRP ) , ADMA , and SDMA . For AS patients , the Bath Ankylosing Spondylitis Disease Activity Index ( BASDAI ) , back pain VAS and patient 's global activity of disease were calculated . After 6 months , we repeated the assessment in 30 out of the 78 AS patients in whom the anti-TNF treatment was initiated . RESULTS The baseline mean ( SD ) plasma ADMA concentration of AS patients was 0.64 ( 0.19 ) μmol/l and did not differ from controls ( 0.65 [ 0.19 ] μmol/l , p > 0.05 ) . In the RA group , ADMA concentration was higher than in controls ( 0.77 vs. 0.65 μmol/l , p < 0.05 ) . Both at baseline and at follow-up , ADMA levels correlated positively with BASDAI ( R = 0.52 , p = 0.02 , and R = 0.47 , p = 0.04 , baseline and follow-up , respectively ) . Six months of anti-TNF treatment did not influence ADMA concentration ( 0.51 [ 0.12 ] vs. 0.51 [ 0.11 ] μmol/l , p = 0.70 ) . CONCLUSION An absence of changes in plasma ADMA levels in the anti-TNF treated AS group despite the improvement in disease activity ( BASDAI ) and inflammation ( ESR , CRP ) may suggest either a lack of effect , or , even if such an effect were to take place , it needs not imply measurable changes in blood ADMA We explored the role of asymmetrical dimethylarginine ( ADMA ) as a cause of endothelial dysfunction induced by systemic inflammation . In vitro data suggest that ADMA bioavailability is regulated by proinflammatory stimuli , but it is unclear whether ADMA is a link between inflammation and endothelial dysfunction in humans . In study 1 we recruited 351 patients with coronary artery disease ( CAD ) and 87 healthy controls . In study 2 we recruited 69 CAD , 69 healthy , and 10 patients with rheumatoid arthritis , whereas in study 3 , 22 healthy and 70 CAD subjects were r and omly assigned to Salmonella typhii vaccination ( n=11 healthy and n=60 CAD ) or placebo ( n=11 healthy and n=10 CAD ) . Circulating interleukin 6/ADMA and flow-mediated dilation ( FMD ) were measured at 0 and 8 hours . In study 1 , ADMA was inversely correlated with FMD in healthy individuals and CAD patients ( P<0.0001 for both ) . However , interleukin 6 was inversely correlated with FMD ( P<0.0001 ) in healthy subjects but not in CAD patients . The positive correlation between ADMA and interleukin 6 was stronger in healthy ( r=0.515 ; P<0.0001 ) compared with CAD ( r=0.289 ; P=0.0001 ) subjects . In study 2 , both patients with rheumatoid arthritis and CAD had higher interleukin 6 ( P<0.0001 ) and ADMA ( P=0.004 ) but lower FMD ( P=0.001 ) versus healthy subjects . In study 3 , vaccination increased interleukin 6 in healthy ( P<0.001 ) and CAD ( P<0.001 ) subjects . FMD was reduced in healthy subjects ( P<0.05 ) , but its reduction in CAD was borderline . Vaccination increased ADMA only in healthy subjects ( P<0.001 ) . Systemic , low- grade inflammation leads to increased ADMA that may induce endothelial dysfunction . This study demonstrated that ADMA may be a link between inflammation and endothelial dysfunction in humans OBJECTIVE The aim of the present study was to investigate the associations of cumulative inflammatory burden ( assessed by serial measurements of inflammatory markers ) and classical cardiovascular disease ( CVD ) risk factors with  asymmetric dimethylarginine ( ADMA )  in a large prospect i ve cohort of patients with established RA . METHODS Two hundred and one RA patients [ 155 females , median age 67 years ( range 59 - 73 ) ] were assessed at baseline ( 2006 ) for the presence of classical CVD risk factors and determination of systemic inflammation by CRP and ESR . Global CVD risk was identified by the Framingham Risk Score and the Reynolds Risk Score . At follow-up ( 2012 ) ,  ADMA levels were measured by ELISA . A quarterly measurement of CRP and ESR for each year the patient was in the study was used to produce an average area under the curve ( AAUC ) for ESR and CRP . RESULTS Regression analysis revealed that baseline ESR in 2006 and the AAUC of ESR and CRP all had significant positive relationships with current ADMA ( P = 0.004 , P < 0.001 and P = 0.002 , respectively ) . Baseline CRP in 2006 was not a significant predictor of ADMA ( P = 0.093 ) , although this relationship was in the same direction as the other factors . These results remained consistent after adjustment for classical CVD risk factors . CONCLUSION Cumulative inflammatory burden is positively associated with  ADMA levels , suggesting a potential pathogenic mechanism through which chronic systemic inflammation exerts deleterious effects on nitric oxide metabolism and endothelial homeostasis . This association is independent of classical CVD risk factors OBJECTIVES The present study was design ed to test the hypothesis that long-term dietary supplementation with the nitric oxide precursor L-arginine would enhance vascular or platelet-derived nitric oxide activity , or both , and thereby inhibit platelet reactivity in hypercholesterolemic humans . BACKGROUND We have shown that reduced vascular activity of nitric oxide in hypercholesterolemic rabbits can be restored by L-arginine supplementation . The improvement in nitric oxide activity is associated with an inhibition of platelet aggregation ex vivo . This effect is most likely due to increased elaboration of endothelium- or platelet-derived nitric oxide , or both , because the inhibition of platelet reactivity was associated with elevation of intraplatelet cyclic guanosine monophosphate and was reversed by the nitric oxide synthase antagonist N-methyl-arginine . METHODS In a double-blinded , r and omized , placebo-controlled trial , hypercholesterolemic patients were assigned to L-arginine hydrochloride , 8.4 g/day orally , or placebo for 2 weeks . Platelet-rich plasma was obtained for aggregometry induced by collagen ( 1 to 10 micrograms/ml ) at four points : baseline , after 2 weeks of treatment , after a 2-week washout and after a long-term washout of 16 weeks on average . Aggregation was quantified by light transmittance and expressed as a percent transmittance observed with platelet-poor plasma . RESULTS Compared with normocholesterolemic control subjects , platelets from hypercholesterolemic subjects stimulated with 5 micrograms/ml of collagen showed increased aggregability ( 68.6 % in hypercholesterolemic patients vs. 54.5 % in normocholesterolemic control subjects , p < or = 0.02 ) . After 2 weeks of treatment with L-arginine ( but not placebo ) , platelet reactivity was modestly reduced ; this effect persisted for 2 weeks after discontinuation of arginine ( 52.6 % in arginine-treated patients vs. 65.1 % in normocholesterolemic control subjects , p = 0.07 ) . After 18 weeks ( i.e. , 16 weeks after discontinuing arginine treatment ) , the platelets of hypercholesterolemic patients once again became hyperaggregable , and the extent of platelet aggregation was significantly increased compared with the 4-week point ( 73.6 % after vs. 52.6 % during arginine treatment , p < 0.01 ) . No significant change in platelet reactivity was seen in placebo-treated hypercholesterolemic patients throughout the study . L-Arginine treatment was well tolerated without side effects . CONCLUSIONS This double-blinded , placebo-controlled study demonstrates that dietary supplementation with L-arginine can modestly attenuate the increased platelet reactivity seen in hypercholesterolemic patients . The data are consistent with our previous studies in hypercholesterolemic animals , demonstrating that L-arginine restores endogenous nitric oxide activity and inhibits platelet aggregation . Enhancement of endogenous nitric oxide activity is a potential novel therapeutic strategy worthy of further study Objectives . Impaired endothelial function represents the early stage of atherosclerosis , which is typically associated with systemic inflammatory diseases like rheumatoid arthritis ( RA ) . As modulators of endothelial nitric oxide synthase expression , asymmetric-dimethylarginine ( ADMA ) and apelin might be measured in the blood of RA patients to detect early atherosclerotic changes . We conducted a prospect i ve , case-control study to investigate serum ADMA and apelin profiles of patients with early-stage RA ( ERA ) before and after disease-modifying antirheumatic drug ( DMARD ) therapy . Methods . We enrolled 20 consecutively diagnosed , treatment-naïve patients with ERA and 20 matched healthy controls .  Serum ADMA and apelin levels and the 28-joint disease activity scores ( DAS28 ) were assessed before and after 12 months of DMARDs treatment . All patients underwent ultrasonographic assessment for intima-media tickness ( IMT ) evaluation . Results . In the ERA group , ADMA serum levels were significantly higher than controls at baseline ( P = 0.007 ) and significantly decreased after treatment ( P = 0.012 versus controls ) . Baseline serum apelin levels were significantly decreased in this group ( P = 0.0001 versus controls ) , but they were not significantly altered by treatment . IMT did not show significant changes . Conclusions . ERA is associated with alterations of serum ADMA and apelin levels , which might be used as biomarkers to detect early endothelial dysfunction in these patients Chronic inflammatory diseases such as rheumatoid arthritis ( RA ) are associated with accelerated atherosclerosis and increased morbidity and mortality for cardiovascular events . Asymmetric dimethyl arginine ( ADMA ) , an endogenous inhibitor of nitric oxide synthase , contributes to the impairment of endothelial function , the earlier and reversible stage of atherosclerotic plaque formation . Since tumor necrosis factor ( TNF ) inhibits enzymatic degradation of ADMA , anti-TNF agents could restore its physiological level . 
    Output:
    
Circulating ADMA levels are higher in RA patients compared with healthy controls .
In addition , ADMA levels are influenced by age , disease duration and disease activity