***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: The mechanisms underlying the  skin blood flow ( SkBF ) response  to local heating are complex and poorly understood . Our goal was to examine the role of axon reflexes and nitric oxide ( NO ) in the SkBF response to a local heating protocol . We performed 40 experiments following a st and ardized heating protocol  with different interventions , including blockade of the axon reflex ( EMLA cream ) , antebrachial nerve blockade ( 0.5 % bupivacaine injection ) , and NO synthase ( NOS ) inhibition ( > or = 10 mM N(G)-nitro-L-arginine methyl ester ; microdialysis ) . Appropriate controls were performed to verify the efficacy of the various blocks . Values are expressed as a percentage of maximal SkBF ( SkBF(max ) ; 50 mM sodium nitroprusside ) . At the initiation of local heating , SkBF rose to an initial peak , followed by a brief nadir , and a secondary , progressive rise to a plateau . Axon reflex block decreased the initial peak from 75 + 3 to 32 + /- 2 % SkBF(max ) ( P < 0.01 vs. control ) but did not affect the plateau . NOS inhibition before and throughout local heating reduced the initial peak from 75 + /- 3 to 56 + /- 3 % SkBF(max ) ( P < 0.01 ) and the plateau from 87 + /- 4 to 40 + /- 5 % . NOS inhibition during axon reflex block did not further reduce the initial SkBF peak compared with axon reflex block alone . Antebrachial nerve block did not affect the local heating SkBF response . The primary finding of these studies is that there are at least two independent mechanisms contributing to the rise in SkBF during nonpainful local heating : a fast-responding vasodilator system mediated by the axon reflexes and a more slowly responding vasodilator system that relies on local production of NO OBJECTIVE : To test the feasibility of creating a valid and reliable checklist with the following features : appropriate for assessing both r and omised and non-r and omised studies ; provision of both an overall score for study quality and a profile of scores not only for the quality of reporting , internal validity ( bias and confounding ) and power , but also for external validity . DESIGN : A pilot version was first developed , based on epidemiological principles , review s , and existing checklists for r and omised studies . Face and content validity were assessed by three experienced review ers and reliability was determined using two raters assessing 10 r and omised and 10 non-r and omised studies . Using different raters , the checklist was revised and tested for internal consistency ( Kuder-Richardson 20 ) , test-retest and inter-rater reliability ( Spearman correlation coefficient and sign rank test ; kappa statistics ) , criterion validity , and respondent burden . MAIN RESULTS : The performance of the checklist improved considerably after revision of a pilot version . The Quality Index had high internal consistency ( KR-20 : 0.89 ) as did the subscales apart from external validity ( KR-20 : 0.54 ) . Test-retest ( r 0.88 ) and inter-rater ( r 0.75 ) reliability of the Quality Index were good . Reliability of the subscales varied from good ( bias ) to poor ( external validity ) . The Quality Index correlated highly with an existing , established instrument for assessing r and omised studies ( r 0.90 ) . There was little difference between its performance with non-r and omised and with r and omised studies . Raters took about 20 minutes to assess each paper ( range 10 to 45 minutes ) . CONCLUSIONS : This study has shown that it is feasible to develop a checklist that can be used to assess the method ological quality not only of r and omised controlled trials but also non-r and omised studies . It has also shown that it is possible to produce a checklist that provides a profile of the paper , alerting review ers to its particular method ological strengths and weaknesses . Further work is required to improve the checklist and the training of raters in the assessment of external validity OBJECTIVE To evaluate the vasodilation induced by topical application of methyl nicotinate ( MN ) and to compare it with the vasodilatory response to acetylcholine ( ACh ) and sodium nitroprusside ( SNP ) in healthy subjects and diabetic neuropathic patients . RESEARCH DESIGN AND METHODS Ten diabetic patients with peripheral neuropathy ( DN ) and 10 age- and sex-matched healthy control subjects ( C ) were enrolled . The vasodilatory response to topical application of 1 % MN and a placebo emulsion at the forearm and dorsum of the foot skin at 5 , 15 , 30 , 60 and 120 min was measured using Laser Doppler Perfusion Imaging . The vasodilatory response to iontophoresis of 1 % ACh and 1 % SNP solutions was also evaluated . RESULTS The maximal vasodilatory response to ACh , SNP and MN was similar at the forearm and foot level in the diabetic patients . In the control group , the responses to MN , ACh and SNP were similar on the forearm but in the foot , the MN vasodilatory response was higher when compared to the ACh and SNP responses . MN-related vasodilation was present 5 min after the application , reached its peak at 15 - 30 min and declined to pre-application levels 120 min afterward . CONCLUSIONS Topical application of MN at the forearm and foot levels of diabetic neuropathic patients results in skin vasodilation that is comparable to the maximal vasodilation that can be induced by iontophoresis of ACh or SNP and lasts for less than 2 h. Further studies will be required to explore the potential of MN to increase blood flow and to prevent diabetic foot problems in clinical practice The aim of the present study was to examine the relationship among water diuresis-induced changes in renal oxygenation , endothelial function , and various metabolic parameters in type 2 diabetic patients and healthy subjects at risk of type 2 diabetes . Thirty-eight subjects with type 2 diabetes ( D : age , 54 + /- 10 years , mean + /- SD , 24 men ) and 7 healthy subjects with parental history of type 2 diabetes or with impaired glucose tolerance ( IGT ) ( relatives [ R ] : age 46 + /- 11 years , 4 men ) were included .  Laser Doppler imaging scanning was used to measure vasodilatation in the forearm skin in response to iontophoresis of 1 % acetylcholine ( Ach ) and 1 % sodium nitroprusside ( SNP ) , and ultrasound was used to measure the flow-mediated dilation ( FMD ) and nitroglycerin-induced dilation ( NID ) in the brachial artery . Renal oxygenation was assessed by magnetic resonance imaging ( MRI ) before and during water diuresis . A decrease in the magnetic parameter R2 * implies an increase in oxygenation . Renal medullary oxygenation did not improve with diuresis in either group ( D : -0.5 + /- 1.9 , R : -0.4 + /- 2.1 , P = not significant [ NS ] ) . The renal cortical oxygenation showed a small , but statistically significant , improvement after diuresis in the 2 groups ( D : -0.6 + /- 1.1 , R : -0.5 + /- 0.5 , P < .05 ) . There were no correlations between the change in cortical R2 * ( R2 * post-minus R2 * prewater diuresis ) and the micro- and macrovascular reactivity . The postdiuresis renal cortical R2 * was negatively correlated with both the Ach- and SNP-induced skin vasodilation ( % change over baseline)(r = -.40 , P < .01 and r = -.39 , P < .05 , respectively ) , while no correlation existed with the FMD and NID . The baseline renal cortical oxygenation was also negatively correlated with the SNP-induced skin vasodilation ( r = -.36 , P < .05 ) and positively correlated with the fasting plasma glucose , total cholesterol , and vascular cell adhesion molecule ( VCAM ) concentrations ( r = .34 , P < .05 , r = .31 , P < .05 and r = .37 , P < .05 , respectively ) . These preliminary findings suggest an association between the kidney cortical oxygenation and the skin microvascular reactivity , glycemia , and lipidemia . Water diuresis failed to produce an improvement in renal medullary oxygenation in both patients with diabetes and subjects at risk for diabetes OBJECTIVES Capillary rarefaction is a hallmark of untreated hypertension . Recent data indicate that rarefaction may be reversed by antihypertensive treatment in nondiabetic hypertensive patients . Despite the frequent association of diabetes with hypertension , nothing is known on the capillary density of treated diabetic patients with hypertension . METHODS We enrolled 21 normotensive healthy , 25 hypertensive only , and 21 diabetic ( type 2 ) hypertensive subjects . All hypertensive patients were treated with a blocker of the renin-angiotensin system , and a majority had a home blood pressure ≤135/85 mmHg  . Capillary density was assessed with videomicroscopy on dorsal finger skin and with laser Doppler imaging on forearm skin ( maximal vasodilation elicited by local heating ) . RESULTS There was no difference between any of the study groups in either dorsal finger skin capillary density ( controls 101 ± 11 capillaries/mm(2 ) , nondiabetic hypertensive 99 ± 16 , diabetic hypertensive 96 ± 18 , p > 0.5 ) or maximal blood flow in forearm skin ( controls 666 ± 114 perfusion units , nondiabetic hypertensive 612 ± 126 , diabetic hypertensive 620 ± 103 , p > 0.5 ) . CONCLUSIONS Irrespective of the presence or not of type 2 diabetes , capillary density is normal in hypertensive patients with reasonable control of blood pressure achieved with a blocker of the renin-angiotensin system OBJECTIVE To examine the effect of a 12-week daily treatment with 160 mg of valsartan , an angiotensin II receptor blocker , on the microcirculation and macrocirculation of type 2 diabetic patients ( T2DM ) and healthy subjects . METHODS This was a prospect i ve , r and omized , double-blind , placebo-controlled crossover study . Thirteen T2DM with no severe complications and 13 healthy subjects completed the trial . RESULTS Treatment with valsartan in T2DM improved the resting forearm skin blood flow and increased the resting brachial artery diameter but had no effects on arterial blood pressure , large vessel vascular reactivity , or carotid intima-media thickness . Resting skin blood flow increased by 60 % ( 2%-90 % ; median and 25th-75th percentiles ) during valsartan treatment and by only 2 % ( -22 % to 27 % ) during placebo treatment ( P < .05 ) . No changes were observed in the nondiabetic subjects . Immunostaining studies of forearm skin biopsy sample s from T2DM and healthy subjects showed that valsartan reduced poly(adenosine diphosphate-ribose ) polymerase ( PARP ) activity in 50 % ( 6/12 ) of the subjects . PARP activity remained unchanged in placebo-treated subjects ( P < .02 ) . In addition , valsartan treatment increased CD31 staining in 33 % ( 4/12 ) of the subjects , whereas no change was noted in sequential skin biopsy sample s of placebo-treated subjects ( P = .057 ) . Valsartan had no effect on the biochemical markers of endothelial cell activation and other cytokines , including CAMs , interleukin 6 , tumor necrosis factor alpha , C-reactive protein , adiponectin , and plasma activator inhibitor 1 . CONCLUSIONS Valsartan increases the resting skin blood flow in T2DM , likely through reduction of PARP activity We have investigated the effect of atorvastatin on the endothelial function of patients with diabetes and subjects at risk for type 2 diabetes in a 12-wk , prospect i ve , r and omized , placebo-controlled , double-blind clinical trial . The flow- mediated dilation ( FMD ; endothelium dependent ) and nitroglycerin-induced dilation ( endothelium independent ) in the brachial artery and the vascular reactivity at the forearm skin were measured . FMD improved in the atorvastatin-treated , at-risk subjects [ median ( 25 - 75 percentile ) , 7.2 % ( 2.9 - 9.6 % ) at exit visit vs. 6.6 % ( 2.9 - 9.5 % ) at baseline ; P < 0.05 ] . A similar improvement of FMD was found in atorvastatin-treated  diabetic patients [ median ( 25 - 75 percentile ) , 5.6 ( 3.9 - 7.9 ) at exit visit vs. 4.2 ( 3.2 - 7.2 ) at baseline ; P = 0.07 ] . No changes were observed in nitroglycerin-induced dilation and the microcirculation reactivity measurements in either group . In the at-risk group , there was a decrease in the C-reactive protein [ median (  
    Output:
    
However , subgroup analysis revealed no difference between the type and duration of diabetes and other health related factors , indicating that diabetes per se causes the microvascular dysfunction .
Conclusion Our meta- analysis shows that diabetes is associated with a large reduction of dermal microvascular function  in diabetic patients .