***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: Microvascular pathophysiology associated with type 2 diabetes mellitus ( T2DM ) contributes to several aspects of the morbidity associated with the disease . We quantified the contribution of nitric oxide ( NO ) to the cutaneous vasodilator response to nonpainful local warming in subjects with T2DM ( average duration of diabetes mellitus 7 + /- 1 yr ) and in age-matched control subjects . We measured skin blood flow in conjunction with intradermal microdialysis of N(G)-nitro-l-arginine methyl ester ( l-NAME ; NO synthase inhibitor ) or vehicle during 35 min of local warming to 42 degrees C. Microdialysis of sodium nitroprusside ( SNP ) was used for assessment of maximum cutaneous vascular conductance ( CVC ) . Resting CVC was higher in T2DM subjects at vehicle sites ( T2DM : 19 + /- 2 vs. control : 11 + /- 3%maxCVC ; P < 0.05 ) ; this difference was abolished by l-NAME ( T2DM : 10 + /- 1 vs. control : 8 + /- 1%maxCVC ; P > 0.05 ) . The relative contribution of NO to the vasodilator response to local warming was not different between groups ( T2DM : 46 + /- 4 vs. control : 44 + /- 6%maxCVC ; P > 0.05 ) . However , absolute CVC during local warming was approximately 25 % lower in T2DM subjects ( T2DM : 1.79 + /- 0.15 AU/mmHg ; controls : 2.42 + /- 0.20 AU/mmHg ; P < 0.01 ) , and absolute CVC during SNP was approximately 20 % lower ( T2DM : 1.91 + /- 0.12 vs. control : 2.38 + /- 0.13 AU/mmHg ; P < 0.01 ) . We conclude that the relative contribution of NO to vasodilation during local warming is similar between subjects with T2DM and control subjects , although T2DM was associated with a lower absolute maximum vasodilation BACKGROUND Endothelial vasodilator dysfunction is a characteristic feature of patients at risk for coronary atherosclerosis . Therefore , we prospect ively investigated whether coronary endothelial dysfunction predicts disease progression and cardiovascular event rates . METHODS AND RESULTS Coronary vasoreactivity was assessed in 147 patients using the endothelium-dependent dilator acetylcholine , sympathetic activation by cold pressor testing , dilator responses to increased blood flow , and dilation in response to nitroglycerin .  Cardiovascular events ( cardiovascular death , unstable angina , myocardial infa rct ion , percutaneous transluminal coronary angioplasty , coronary bypass grafting , ischemic stroke , or peripheral artery revascularization ) served as outcome variables over a median follow-up period of 7.7 years . Patients suffering from cardiovascular events during follow-up ( n=16 ) had significantly increased vasoconstrictor responses to acetylcholine infusion ( P=0 . 009 ) and cold pressor testing ( P=0.002 ) , as well as significantly blunted vasodilator responses to increased blood flow ( P<0.001 ) and the intracoronary injection of nitroglycerin ( P=0.001 ) . Impaired endothelial and endothelium-independent coronary vasoreactivity were associated with a significantly higher incidence of cardiovascular events by Kaplan-Meier analysis . By multivariate analysis , all tests of coronary vasoreactivity were significant , independent predictors of a poor prognosis , even after adjustment for traditional cardiovascular risk factors or the presence of atherosclerosis itself . CONCLUSIONS Coronary endothelial vasodilator dysfunction predicts long-term atherosclerotic disease progression and cardiovascular event rates . Thus , the assessment of coronary endothelial vasoreactivity can provide pivotal information as both a diagnostic and prognostic tool in patients at risk for coronary heart disease In perinatal psychiatry , r and omized controlled trials are often not feasible on ethical grounds . Many studies are observational in nature , while others employ large data bases not design ed primarily for research purpose s. Quality assessment of the result ing research is complicated by a lack of st and ardized tools specifically for this purpose . The aim of this paper is to describe the  Systematic Assessment of Quality in Observational Research ( SAQOR )  , a quality assessment tool our team devised for a series of systematic review s and meta‐analyses of evidence ‐based literature regarding risks and benefits of antidepressant medication during pregnancy . Copyright © 2011 John Wiley & Sons , AIMS In conditions such as type 2 diabetes , hypertension , and smoking , in which haematocrit ( Hct ) tends to be higher , endothelial function is impaired . In vitro , haemoglobin neutralizes nitric oxide very effectively . Whether red blood cells participate in the regulation of endothelial function in vivo has not been established . METHODS AND RESULTS Clinical and haematological parameters and forearm blood flow responses to acetylcholine ( ACh ) and sodium nitroprusside ( SNP ) were measured in 84 type 2 diabetic patients and 19 control subjects . Diabetics showed blunted dose-response curves to both SNP and ACh . In diabetics , across quartiles of Hct , ACh blood flow responses were progressively lower ( 881+/-96 , 652+/-81 , 513+/-54 , 307+/-46 % , P</0.0001 ) , and maximal SNP responses tended to be lower ( 706+/-72 , 578+/-61 , 607+/-69 , 499+/-53 % , P=0.06 ) despite similar age , body mass index , glycated haemoglobin ( HbA(1c ) ) , blood pressure , serum total and HDL-cholesterol levels , indices of insulin sensitivity , and markers of inflammation . After normalizing the ACh response for the SNP response ( ACh/SNP ratio ) , a progressive reduction across Hct quartiles ( 1.54+/-0.23 , 1.22+/-0.15 , 0.93+/-0.09 , 0.66+/-0.09 , P<0.0001 ) was still observed , with patients in the III and IV quartile showing a blunted response compared with controls ( 1.44+/-0.08 ) . Both in diabetics and controls , the  ACh/SNP ratio was reciprocally related to Hct ( r=-0.46 and r=-0.66 , respectively , P<0.002 for both ) . This association was independent of comorbidities , gender , metabolic control , plasma lipids , or concomitant treatments , was stronger in the subjects with preserved endothelium-dependent dilatation , and was unchanged when haemoglobin replaced Hct . CONCLUSION Both in diabetics and non-diabetics , haematocrit is inversely related to small vessel endothelium-dependent dilatation . Thus , in addition to blood rheology , a direct negative effect on nitric oxide availability might explain the link between high Hct and cardiovascular disease AIM Nitroglycerin-mediated vasodilatation ( NMD ) provides insight into the NTG-induced bioactivity of smooth muscle . It is plausible that in dysfunctional smooth muscle cells , the response to nitroglycerin may become blunted . The relationship between impaired brachial artery NMD and subsequent cardiovascular events is not well established . METHODS We examined brachial artery flow-mediated dilatation ( FMD ) and NMD using ultrasound in 93 subjects ( 71±7 years , including 26 with peripheral artery disease ( PAD ) , 37 with aortic aneurysms , 10 with PAD complicated with aneurysms , and 20 without evident arterial disease ) . Brachial artery responses to hyperemia and nitroglycerin were measured every minute after cuff deflation and nitroglycerin administration . Time courses of vasodilatation were assessed and maximal FMD and NMD were measured . RESULTS The time courses in response to NTG were sigmoidal and maximal diameter reached 7.2±1.6 minutes after NTG was administered sublingually . The mean FMD was 2.3±2.0 % and the mean NMD was 17.6±7.1 % . Subjects were prospect ively followed for an average of 47±13 months . Eighteen subjects had an event during follow-up ; events included myocardial infa rct ion ( five ) , unstable angina pectoris ( four ) , stroke ( two ) , aortic dissection ( one ) , ruptured aortic aneurysm ( three ) , symptomatic abdominal aortic aneurysm ( two ) , and lower limb ischemia requiring revascularization ( one ) . NMD and FMD were significantly lower in subjects with events than in those without an event . In a Cox proportional-hazards model , lower FMD as well as lower NMD independently predicted future cardiovascular events . CONCLUSION Brachial artery nitroglycerin-mediated vasodilatation may add information to conventional risk stratification We compared endothelial function noninvasively in 15 elderly patients with noninsulin‐dependent diabetes mellitus ( NIDDM ) with 12 nondiabetic elderly patients . Using high resolution ultrasound , we measured flow‐mediated dilatation ( FMD ) of the brachial artery and sublingual nitroglycerin (NTG)‐mediated dilatation . FMD was significantly impaired in subjects with NIDDM compared with control subjects . In NIDDM subjects , FMD with complications was lower than in subjects with noncomplications . However , there was no significant difference in NTG between NIDDM subjects and the control group . Hyperemic blood flow change was lower in NIDDM subjects , but not significant . These results suggest that elderly patients with NIDDM have impaired L‐arginine/nitric oxide ( NO ) pathways and the possibility of capillary rarefaction Heading Abstract Aims /hypothesis . Patients with diabetes are characterised by endothelial dysfunction and cardiovascular mortality . In particular endothelium-derived nitric oxide has emerged as a first line mechanism against atherosclerosis . Hyperglycaemia causes oxygen radical stress but has also been associated with endothelial nitric oxide synthase uncoupling , both lead to decreased nitric oxide-availability . We recently showed that folate reverses eNOS uncoupling in vitro . Therefore we hypothesise that folate improves endothelial function in Type II ( non-insulin-dependent ) diabetes mellitus in vivo . Methods . Using forearm plethysmography , we evaluated the effect of local , intra-arterial administration of 5-methyltetrahydrofolate ( 5-MTHF , the active form of folic acid , 1 µg/100 ml FAV/min ) on forearm blood flow in 23 patients with Type II diabetes and 21 control subjects , matched for age , sex , blood pressure , body mass index , weight and smoking habits . Serotonin as a stimulator of nitric oxide-dependent vasodilation and sodium nitroprusside as a stimulator of endothelium-independent vasodilation were infused . Results . Serotonin-induced vasodilation was blunted ( 53±30 vs 102±66 M/C% , p<0.005 ) and nitroprusside-induced vasodilation was mildly reduced ( 275±146 vs 391±203 M/C% , p<0.05 ) in patients with Type II diabetes compared to control subjects . 5-MTHF  improved nitric oxide-mediated vasodilation ( from 53±30 to 88±59 M/C% , p<0.05 ) in patients with Type II diabetes mellitus . As expected , 5-MTHF had no effect on forearm blood flow in control subjects . Conclusion /interpretation . These data imply that folate can be used to improve nitric oxide status and to restore endothelial dysfunction in patients with Type II diabetes . Our results provide a strong rationale for the initiation of studies that investigate whether supplementation with folic acid prevents future cardiovascular events in this patient group OBJECTIVE Although type 2 diabetes is recognized as an independent risk factor for cardiovascular disease and cardiovascular disease is associated with endothelial dysfunction , the influence of type 2 diabetes per se on the endothelial function is controversial . HMG-CoA-reductase inhibitors have been shown to have short-term beneficial effects on endothelial dysfunction among patients with dyslipidemia or cardiovascular disease . The effect of HMG-CoA reductase inhibitors on the endothelial function in diabetes is largely unknown . METHODS Seventeen patients with type 2 diabetes , free of cardiovascular disease and no other cardiovascular risk factors , except for dyslipidemia , were studied together with ten healthy volunteers . The effect of 5-hydroxytryptamine , as an endothelium-dependent vasodilator , and sodium nitroprusside , as an endothelium-independent vasodilator , on the forearm blood flow was measured using venous occlusion plethysmography . RESULTS 5-Hydroxytryptamine and sodium nitroprusside , infused in the brachial ar 
    Output:
    
In meta-regression , VSM function in the microcirculation was inversely associated with BMI and triacylglycerols and was positively associated with HDL-cholesterol .
Conclusions /interpretationIn addition to the endothelium , the VSM is a source of vascular dysfunction in type 2 diabetes .
An exacerbation of VSM function in the microcirculation may be a distinctive feature in type 2 diabetes