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Objective The aim of this research was to investigate relationships between cognitive function and non-invasive, repeatable cardiac parameters in elderly subjects suffering from mild cognitive impairment (MCI) or Alzheimer's disease (AD). Methods Two hundred and twenty-four community-living elderly subjects, 31 AD patients, 77 MCI patients, and 116 cognitively normal subjects (CNS), were evaluated for cognitive abilities (Mini Mental State Examination score (MMSE)) and for electrocardiographic [corrected heart rate QT interval dispersion (QTcD)] and echocardiographic [Left ventricular ejection fraction (LVEF)] parameters. Results Mean values of LVEF were not significantly different between the three groups; QTcD mean values were significantly lower in CNS group than in subjects with MCI and AD. The Pearson Product Moment Correlation test, carried out in the three study groups, showed a significant inverse correlation between QTcD and MMSE score (r = −0.357; p

Objectives: The long term effects of a low protein diet (LPD) on depressive symptoms and the quality of life in elderly Type 2 diabetic are unclear. Methods: 38 elderly Type 2 diabetic patients with CRD (Stage 3 - 4) were enrolled in the study. After 4 weeks on a normal protein diet regimen (NPD) providing 1.0 g/kg per day, all participants were assigned for 30 months, randomly, to a LPD (0.7 g/kg per day), either 7 days a week (LPD 7/7) or 6 days a week (LPD 6/7). Mini mental state examination (MMSE), activities daily living (ADL), cumulative illness severity (CIRS-IS), geriatric depression scale (GDS-15) and short-form healthy survey (SF-36) were evaluated every 3 months. Results: Before the LPD regimen creatinine clearance (CrCl), MMSE, ADL, CIRS-IS, GDS-15 and SF-36 were similar in both LPD 7/7 and LPD 6/7 groups. After 30 months, the mean GDS-15 increased significantly more in LPD 7/7 group than in LPD 6/7 group (p < 0.05). Both mean SF-36 MCS and SF-36 PCS were decreased significantly more in LPD 7/7 group than in LPD 6/7 group (p < 0.05). After 30 months, the decline in CrCl observed was similar in LPD 7/7 and LPD 6/7 groups (2.77 +/- 0.3 and 2.84 +/- 0.3 ml/min/year, respectively). Conclusion: In elderly Type 2 diabetic patients, long term effects of LPD 6/7 regimen in comparison to LPD 7/7 are associated with a similar decline in CrCl, but with decreased depressive symptoms and a better quality of life.

Coppola L, Pastore A, Adamo G, Coppola A, Manzella D, Gombos I, Luongo M, Mastrolorenzo L. Circulating free nitrotyrosine and cognitive decline. Acta Neurol Scand: 122: 175–181. © 2009 The Authors Journal compilation © 2009 Blackwell Munksgaard. Objective – To determine if the circulating nitrotyrosine level significantly correlates with parameters measuring cognitive abilities. Materials and methods – One-hundred and twelve community-living subjects (ranging in age from 27 to 98 years) were evaluated for cognitive abilities [Mini Mental State Examination (MMSE) score] and circulating free nitrotyrosine plasma level, as well as for several variables that might influence cognitive abilities (age, education) and nitrotyrosine level (body mass index, haematological parameters, cardiovascular and inflammatory indices). Results – In the sub-group of cognitively impaired subjects (score at MMSE

Postprandial hyperglycaemia is an independent predictor of cardiovascular risk. Increased blood viscosity has been considered a major cardiovascular risk factor and may play a role in the vascular complications of diabetes. The present study aimed to verify whether blood viscosity is altered by the increased postprandial hyperglycaemia in aged type 2 diabetic patients. The whole blood viscosity, haematocrit, fibrinogen, glucose, insulin, total cholesterol, and triglyceride plasma levels, heart rate, and systolic and diastolic blood pressures were measured in 15 aged patients affected by type 2 diabetes and 15 healthy age-matched individuals before and 60 and 120 min after a test meal (670 kcal energy intake). In the basal condition, in both healthy control individuals and diabetic patients, the whole blood viscosity at higher shear rate (450/s) was significantly correlated in a negative way with the index of insulin resistance (P < 0.05), and in a positive way with the haematocrit value (P < 0.05) and the platelet count (P < 0.01). After the test meal, the whole blood viscosity significantly decreased (P < 0.01 or less) in aged healthy individuals, whereas it remained unchanged in type 2 diabetic patients. In conclusion, the negative action of postprandial hyperglycaemia in diabetes does not occur via a measurable increase of blood viscosity during that period. The decrease of blood viscosity observed during the postprandial period in normal individuals, however, points to the occurrence of alterations in the regulation of the haemorheological equilibrium in the postprandial period in aged type 2 diabetic patients.

Whether morning blood pressure surge influences the molecular mechanisms of plaque progression toward instability is not known. Recently, we have demonstrated enhanced activity of the ubiquitin–proteasome system in human plaques and evidenced that it is associated with inflammatory-induced plaque rupture. We evaluated the inflammatory infiltration and ubiquitin–proteasome activity in asymptomatic carotid plaques of hypertensive patients with different patterns of morning blood pressure surge. Plaques were obtained from 32 hypertensive patients without morning blood pressure surge and 28 with morning blood pressure surge enlisted to undergo carotid endarterectomy for extracranial high-grade (>70%) internal carotid artery stenosis. Plaques were analyzed for macrophages, T-lymphocytes, human leukocyte antigen–DR+cells, ubiquitin–proteasome activity, nuclear factor-κB, inhibitor kB-β, tumor necrosis factor-α, nitrotyrosine, matrix metalloproteinase-9, and collagen content (immunohistochemistry and ELISA). Compared with plaques obtained from hypertensive patients without morning blood pressure surge, plaques from with morning blood pressure surge had more macrophages, T-lymphocytes, human leukocyte antigen–DR+cells ( P P P P

Background: Increased plasma levels of fibrinogen are been associated with an increased risk of cardiovascular accident. We aimed at verifying whether the changes of fibrinogen levels are associated with red blood cell (and/or hemoglobin) concentration. Methods: A group of 381 carefully selected healthy volunteers (219 male and 162 female), aged from 18 to 101 years, were enrolled in this study. Fasting blood samples were taken and all measurements (fibrinogen plasma level, whole blood viscosity, hemoglobin concentration, hematocrit value, red blood cell and white blood cell count, platelet count, glucose, total cholesterol and triglycerides plasma concentration, and C-reactive protein level) were obtained with standardized methodology using appropriate equipment, procedures, and controls. Results and Conclusions: In the male but not in the female group, plasma fibrinogen concentration inversely correlated with hemoglobin (P * 0.0001) and hematocrit value (P * 0.01). In a post hoc analysis, plasma fibrinogen level inversely correlated with hemoglobin in the subgroup of the 93 premenopausal women and directly correlated with age and inversely correlated with platelet count in the subgroup of the 69 postmenopausal women. Results of multiple regression analysis revealed that in all the subjects, except in the postmenopausal women, hemoglobin level is an independent predictor of fibrinogen plasma level. Considering the physiopathologic role of increased plasma fibrinogen concentration and the scarcity of pharmacologic approaches to decrease its level, these findings could be important in designing a preventive therapy of cardiovascular disease

Ozonized autohemotransfusion has been used as a complementary therapy in patients with peripheral arterial disease (PAD). To determine whether ozone therapy could acutely modify artery vasodilatory capacity, a flow-mediated dilation test was performed at the brachial artery level before and after an ozonized autohemotransfusion in 16 patients with PAD, mean (± SD) age 55±1.8 years, and 14 healthy volunteers matched for age, sex and body mass index. Before ozonized autohemotransfusion, the mean baseline diameter of the brachial artery was higher in PAD patients than in healthy subjects (4.6±0.54 mm versus 3.6±0.54 mm, P

Increased Activity of the Ubiquitin-Proteasome System in Patients With Symptomatic Carotid Disease Is Associated With Enhanced Inflammation and May Destabilize the Atherosclerotic Plaque: Effects o...

The role of ubiquitin-proteasome system in the accelerated atherosclerotic progression of diabetic patients is unclear. We evaluated ubiquitin-proteasome activity in carotid plaques of asymptomatic diabetic and nondiabetic patients, as well as the effect of rosiglitazone, a peroxisome proliferator–activated receptor (PPAR)-γ activator, in diabetic plaques. Plaques were obtained from 46 type 2 diabetic and 30 nondiabetic patients undergoing carotid endarterectomy. Diabetic patients received 8 mg rosiglitazone (n = 23) or placebo (n = 23) for 4 months before scheduled endarterectomy. Plaques were analyzed for macrophages (CD68), T-cells (CD3), inflammatory cells (HLA-DR), ubiquitin, proteasome 20S activity, nuclear factor (NF)-κB, inhibitor of κB (IκB)-β, tumor necrosis factor (TNF)-α, nitrotyrosine, matrix metalloproteinase (MMP)-9, and collagen content (immunohistochemistry and enzyme-linked immunosorbent assay). Compared with nondiabetic plaques, diabetic plaques had more macrophages, T-cells, and HLA-DR+ cells (P < 0.001); more ubiquitin, proteasome 20S activity (TNF-α), and NF-κB (P < 0.001); and more markers of oxidative stress (nitrotyrosine and O2− production) and MMP-9 (P < 0.01), along with a lesser collagen content and IκB-β levels (P < 0.001). Compared with placebo-treated plaques, rosiglitazone-treated diabetic plaques presented less inflammatory cells (P < 0.01); less ubiquitin, proteasome 20S, TNF-α, and NF-κB (P < 0.01); less nitrotyrosine and superoxide anion production (P < 0.01); and greater collagen content (P < 0.01), indicating a more stable plaque phenotype. Similar findings were obtained in circulating monocytes obtained from the two groups of diabetic patients and cultured in the presence or absence of rosiglitazone (7.0 μmol/l). Ubiquitin-proteasome over-activity is associated with enhanced inflammatory reaction and NF-κB expression in diabetic plaques. The inhibition of ubiquitin-proteasome activity in atherosclerotic lesions of diabetic patients by rosiglitazone is associated with morphological and compositional characteristics of a potential stable plaque phenotype, possibly by downregulating NF-κB-mediated inflammatory pathways.

Regular physical activity is associated with reduced risk of cardiovascular disease although the mechanisms are unclear. Recent population-based studies suggest that the effect of physical activity may be at least partly a result of action on hemostasis. We tested the hypothesis that moderate-intensity aerobic training improves fibrinolytic activity and reduces platelet aggregation and blood viscosity. In 15 young (11 males and four females; age, 24-32 years) and 15 middle-aged (11 males and four females; age, 45-65 years) healthy, non-smoker, sedentary subjects, the maximum oxygen consumption, adenosine diphosphate-induced platelet aggregation, tissue plasminogen activator and plasminogen activator inhibitor type 1, antigen, hematocrit and blood viscosity were measured at baseline and after 12 weeks of aerobic exercise training (40 min three times a week at a training intensity adjusted to 60% of the individual heart rate reserve). After training, the maximum oxygen consumption was increased by 9% (P < 0.01) in the young group and by 7.3% (P < 0.05) in the middle-aged group. Adenosine diphosphate-platelet aggregation significantly decreased in the young (-30%; P < 0.05). The middle-aged group showed a 10.4% decrease in hematocrit (P < 0.05), and a 11.6 and 16.6% decrease in blood viscosity at 450/s and at 90/s rates of shear, respectively (P < 0.05), while the plasminogen activator inhibitor type 1 antigen plasma level increased 135% (P < 0.01). These data, some not consistent with others, only partially support the hypothesis that the beneficial effects of physical activity result from action on hemostatic balance. In particular, the changes in the fibrinolytic system in middle-aged subjects might suggest increased thrombotic risk. Thus a simple, straightforward conclusion is not possible at present, and further studies are required.

This study aimed at evaluating whether increased availability of the natural precursor of nitric oxide, L-arginine, could influence systemic hemodynamic and rheologic parameters in humans and whether the effects of L-arginine are mediated by endogenous insulin. 10 healthy young subjects participated in the following studies: study I, infusion of L-arginine (1 g/min for 30 min); study II, infusion of L-arginine plus octreotide (25 microg as i.v. bolus + 0.5 microg/min) to block endogenous insulin and glucagon secretion, plus replacement of basal insulin and glucagon; study III, infusion of L-arginine plus octreotide plus basal glucagon plus an insulin infusion designed to mimic the insulin response of study I. L-Arginine infusion significantly reduced systolic (11+/-3, mean+/-SE) and diastolic (8+/-2 mmHg, P < 0.001) blood pressure, platelet aggregation (20+/-4%), and blood viscosity (1.6+/-0.2 centipois, P < 0.01), and increased leg blood flow (97+/-16 ml/min), heart rate, and plasma catecholamine levels (P < 0.01). In study II, plasma insulin levels remained suppressed at baseline; in this condition, the vascular responses to L-arginine were significantly reduced, except for plasma catecholamines which did not change significantly. In study III, the plasma insulin response to L-arginine was reestablished; this was associated with hemodynamic and rheologic changes following L-arginine not significantly different from those recorded in study I. These findings show that systemic infusion of L-arginine in healthy subjects induces vasodilation and inhibits platelet aggregation and blood viscosity. These effects are mediated, in part, by endogenous released insulin.

The purpose of the present study was to determine if opioid agonism (beta-endorphin) and antagonism (Naloxone) exert rheological and cardiovascular effects in normal humans and in patients with essential hypertension. Eight hypertensive patients were matched for age, sex, and body habitus (body mass index, waist to hip ratio) with eight normotensive healthy subjects. In all subjects, heart rate and blood pressure (continuous automatic recording), blood and plasma viscosity, fibrinogen, hematocrit, and platelet aggregation to ADP were evaluated during an infusion of human synthetic beta-endorphin (0.5 mg/h). On a different day and in randomized order, the subjects were submitted to another beta-endorphin infusion preceded by an i.v. naloxone bolus (5 mg in 5 min). beta-Endorphin and naloxone failed to significantly alter heart rate or blood pressure in both normotensive and hypertensive subjects. In hypertensive patients, beta-endorphin significantly increased blood viscosity and ADP-induced platelet aggregation, but only the former effect was naloxone-sensitive. In normotensive subjects, beta-endorphin caused a transient but significant decrease of platelet aggregation that was reversed by naloxone. These data suggest that beta-endorphin may play some role in the inhibitory control of platelet aggregation in normal subjects. An altered responsiveness of some rheological determinants to beta-endorphin seems to be present in human hypertension.

The aim of this research was to investigate relationships between cognitive function and non-invasive, repeatable cardiac parameters in elderly subjects suffering from mild cognitive impairment (MCI) or Alzheimer's disease (AD).Two hundred and twenty-four community-living elderly subjects, 31 AD patients, 77 MCI patients, and 116 cognitively normal subjects (CNS), were evaluated for cognitive abilities (Mini Mental State Examination score (MMSE)) and for electrocardiographic [corrected heart rate QT interval dispersion (QTcD)] and echocardiographic [Left ventricular ejection fraction (LVEF)] parameters.Mean values of LVEF were not significantly different between the three groups; QTcD mean values were significantly lower in CNS group than in subjects with MCI and AD. The Pearson Product Moment Correlation test, carried out in the three study groups, showed a significant inverse correlation between QTcD and MMSE score (r = -0.357; p 0.01) in the group of MCI patients, only. In multivariable-adjusted linear regression tests, QTcD (p = 0.030) and education (p = 0.021) are associated with MMSE score in MCI group. Only the parameter of education appears to predict MMSE in CNS group; none of these parameters appear to predict MMSE in the group of patients with AD.The association between QTcD and MMSE requires cautious interpretation and further extensive investigation. However, if confirmed by longitudinal studies, the finding could play a role in the management of the subjects with MCI.

Late-life depression is one of the main health problems among elderly diabetic subjects. In addition, depression is a common psychopathological condition among renal failure patients and most of these patients follow a low protein diet regimen (LPD). However, the effects of LPD on depressive symptoms are unclear.In the present study, the effects of LPD regimen on depressive symptoms in elderly type 2 diabetic subjects with renal failure were investigated.Fifty-two young-old type 2 diabetic patients with renal failure were enrolled in the study. All participants after normal protein diet regimen providing 1.2g/kg per d were instructed to consume either a LPD providing 0.8 g/kg per d, 7 d a wk (LPD 7/7), or a LPD providing 0.8 g/kg per d 6 d a wk (LPD 6/7) randomly.Mean 15-item Geriatric Depression Scale (GDS-15) (2.0±0.6) and Beck Depression Inventory (BDI) (4.1±1.0), during normal protein diet regimen, significantly increased to (6.7±1.6) and (12.2±1.4), respectively, after LPD 7/7 (P0.05 versus normal protein diet). However, after LPD 6/7, mean GDS-15 and BDI significantly decreased to (4.4±1.5) and (6.7±1.6), respectively (P0.05 versus LPD 7/7).LPD 6/7 regimen significantly decreased depressive symptoms in young-old type 2 diabetic patients.

Objective and design: We tested here the effects of acute administration of an oxygen/ozone (O3) mixture on the myocardial tissutal damage following an ischemic event. Material or subjects: The study was done in Sprague-Daw- ley rats subjected to acute myocardial ischemia/reperfusion (I/R). Treatment: 100; 150; and 300 µg/kg oxygen/O3 mixture were insufflated intraperitoneally 1 h prior to I/R. Methods: Myocardial infarct size measurement and im- munhistochemistry or ELISA for nitrotyrosine, CD68, CD8, CD4 and caspase-3 were done. Results: I/R produced a marked damage in the rat left ventri- cle with an infarct size as percentage of the area at risk (IS/ AR) of ∼45 ± 4 %. Rats insufflated with a oxygen/O 3 mixture showed a significant 2-h cardio-protection (e. g. infarct size over area at risk for the dose of 300 µg/kg was ∼30 ± 3 %,) as compared with control rats (P

Background Obesity is independently associated with coronary endothelial dysfunction. Adiponectin, a protein whose circulating levels are decreased in obesity, has direct effects on vascular function. The aim of this study was to investigate in obese women the effect of sustained weight loss on coronary circulation and circulating adiponectin levels. Methods Coronary flow velocity reserve (CFVR), assessed by transthoracic Doppler echocardiography (TTDE), blood pressure, lipid, glucose and insulin, HOMA scores, CRP-protein (CRP), and adiponectin parameters were investigated in forty obese pre-menopausal women and 40 healthy matched normal weight women at baseline and after sustained weight loss. Results At baseline, the obese group had significantly higher fasting glucose ( P P P P P P P P P P P P r =0.47, P r =0.38, P Conclusions In obese women the weight loss improves coronary circulation and increases adiponectin levels. The improvement in coronary circulation is associated with adiponectin levels.

In diabetic patients the incidence of cardiovascular diseases (CVD) is higher compared with those without diabetes. This elevated incidence may be due to an increased prevalence of established risk factors, such as obesity, dyslipidemia and hypertension. However, several other determinants must be considered. Attention must be paid to the role that specific factors strictly related to diabetes, insulin-resistance and post-prandial hyperglycemia, play in the etiopathogenesis of CVD, as for example atherosclerosis. This review acknowledges the incidence of diabetes on cardiovascular diseases and atherosclerosis from endothelial dysfunction to plaque destabilization, suggesting that insulin resistance and postprandial hyperglycemia should be considered keys in the generation of these worst diabetic cardiovascular outcomes. It finds in hyperglycemia the primum movens that mediates the cascade of vascular damaging events from the beginning of ROS formation to plaque rupture, through increased inflammation. It also adds insights of why diverse therapeutic interventions, which have in common the ability to reduce oxidative stress and inflammation, can impede or delay the onset of complication of atherosclerosis in diabetic patients.

The role of ubiquitin-proteasome system in the accelerated atherosclerotic progression of diabetic patients is unclear. We evaluated ubiquitin-proteasome activity in carotid plaques of asymptomatic diabetic and nondiabetic patients, as well as the effect of rosiglitazone, a peroxisome proliferator-activated receptor (PPAR)-gamma activator, in diabetic plaques. Plaques were obtained from 46 type 2 diabetic and 30 nondiabetic patients undergoing carotid endarterectomy. Diabetic patients received 8 mg rosiglitazone (n = 23) or placebo (n = 23) for 4 months before scheduled endarterectomy. Plaques were analyzed for macrophages (CD68), T-cells (CD3), inflammatory cells (HLA-DR), ubiquitin, proteasome 20S activity, nuclear factor (NF)-kappaB, inhibitor of kappaB (IkappaB)-beta, tumor necrosis factor (TNF)-alpha, nitrotyrosine, matrix metalloproteinase (MMP)-9, and collagen content (immunohistochemistry and enzyme-linked immunosorbent assay). Compared with nondiabetic plaques, diabetic plaques had more macrophages, T-cells, and HLA-DR+ cells (P0.001); more ubiquitin, proteasome 20S activity (TNF-alpha), and NF-kappaB (P0.001); and more markers of oxidative stress (nitrotyrosine and O2(-) production) and MMP-9 (P0.01), along with a lesser collagen content and IkappaB-beta levels (P0.001). Compared with placebo-treated plaques, rosiglitazone-treated diabetic plaques presented less inflammatory cells (P0.01); less ubiquitin, proteasome 20S, TNF-alpha, and NF-kappaB (P0.01); less nitrotyrosine and superoxide anion production (P0.01); and greater collagen content (P0.01), indicating a more stable plaque phenotype. Similar findings were obtained in circulating monocytes obtained from the two groups of diabetic patients and cultured in the presence or absence of rosiglitazone (7.0 micromol/l). Ubiquitin-proteasome over-activity is associated with enhanced inflammatory reaction and NF-kappaB expression in diabetic plaques. The inhibition of ubiquitin-proteasome activity in atherosclerotic lesions of diabetic patients by rosiglitazone is associated with morphological and compositional characteristics of a potential stable plaque phenotype, possibly by downregulating NF-kappaB-mediated inflammatory pathways.

We evaluated ubiquitin-proteasome activity in carotid plaques of asymptomatic and symptomatic patients and the effect of rosiglitazone, a peroxisome proliferator-activated receptor-gamma activator, in symptomatic plaques.The role of the ubiquitin-proteasome system, the major pathway for non-lysosomal intracellular protein degradation in eucaryotic cells, in the progression of atherosclerotic plaque to instability is unclear.Plaques were obtained from 40 symptomatic and 38 asymptomatic patients undergoing carotid endarterectomy. Symptomatic patients received 8 mg rosiglitazone (n = 20) or placebo (n = 20) for 4 months before scheduled endarterectomy. Plaques were analyzed for macrophages (CD68), T-lymphocytes (CD3), inflammatory cells (HLA-DR), ubiquitin-proteasome activity, nuclear factor kappa B (NFkB), inhibitory kappa B (IkB)-beta, nitrotyrosine, matrix metalloproteinase (MMP)-9, and collagen content (immunohistochemistry and enzyme-linked immunosorbent assay).Compared with asymptomatic plaques, symptomatic plaques had more macrophages, T-lymphocytes, and HLA-DR+ cells (p0.001); more ubiquitin-proteasome activity and NFkB (p0.001); and more markers of oxidative stress (nitrotyrosine and O2- production) and MMP-9 (p0.01) along with a lesser collagen content and IkB-beta levels (p0.001). Compared with placebo-treated plaques, rosiglitazone-treated symptomatic plaques presented fewer inflammatory cells (p0.01); less ubiquitin, proteasome 20S, and NFkB (p0.01); less nitrotyrosine and O2- production (p0.01); and greater collagen content (p0.01), indicating a more stable plaque phenotype.Ubiquitin-proteasome overactivity is associated with enhanced inflammatory reaction in symptomatic plaques. The inhibition of ubiquitin-proteasome activity in lesions of symptomatic patients by rosiglitazone is associated with plaque stabilization, possibly by down-regulating NFkB-mediated inflammatory pathways.

CD39/ATP diphosphohydrolase is expressed on B lymphocytes, cytotoxic T lymphocytes, monocytes, platelets, and endothelial cells, and it has a critical role in the inhibition of platelet responsiveness. To determine whether strenuous exercise could acutely change expression of CD39 in platelets and lymphocytes, eight healthy sedentary men, 34 yr old (SD 7), and eight physically active men, 34 yr old (SD 6), performed graded upright cycle ergometry to volitional exhaustion. Blood samples collected both at baseline and after exercise test were employed to measure CD39 expression in platelets and lymphocytes. The percentage of circulating platelet-platelet aggregates, the “in vitro” ADP and collagen-induced platelet aggregation, and the expression of both platelet glycoprotein IIb-IIIa (PAC-1) and P-selectin (CD62) were also considered markers of platelet activation. After strenuous exercise, all subjects demonstrated significant platelet activation as judged by the increased percentage of platelet-platelet aggregates. The in vitro ADP-induced platelet aggregation and the expression of CD62P on ADP-stimulated platelets significantly increased in sedentary but not in active subjects. After exercise, all of the subjects showed a significant reduction of CD39 expression in platelet [sedentary: from 2.2 (SD 0.8) to 1.1% (SD 0.8), P = 0.008; active: from 0.6 (SD 0.2) to 0.35% (SD 0.1), P = 0.009] and an increase of CD39 expression in B lymphocytes [sedentary: from 47 (SD 13) to 60% (SD 11), P = 0.0039; active: from 46 (SD 11) to 59% (SD 11), P = 0.0038]. Taken together, these findings confirm the critical role of this ADPase in inhibition of platelet responsiveness, also suggesting a possible role of B lymphocytes in thromboregulation mechanism.

We read with interest the report of Cao and coworkers1 J.J. Cao, M. Hudson, M. Jankowski, F. Whitehouse and W.D. Weaver, Relation of chronic and acute glycemic control on mortality in acute myocardial infarction with diabetes mellitus, Am J Cardiol 96 (2005), pp. 183–186. Article | PDF (62 K) | View Record in Scopus | Cited By in Scopus (45)1 describing the existence of a relation between elevated admission glucose levels and adverse outcome and mortality in diabetic patients during myocardial infarction (MI). Although it has been described in other patient populations, the question of whether hyperglycemia is a mediator or marker of adverse outcomes remains unclear. Recommendations are being developed for strict glucose management in all hospitalized patients; however, glucose measurement has not been included in MI risk indexes, and current MI guidelines do not suggest specific therapeutic targets for glucose control. This relative lack of guidance concerning the risk management of patients with MI and hyperglycemia may be because many aspects of the relation between glucose levels and mortality in patients with MI have not been adequately defined, nor have the pathogenetic mechanisms responsible for adverse outcomes. This gap in knowledge may limit treatment of elevated glucose levels in hospitalized patients with acute MI and hyperglycemia. However, an active inflammatory infiltrate in the peri-infarct area and in unaffected viable myocardium has been described in patients with recent MI.2 The inflammatory burden in the peri-infarct region is associated with worse short- and mid-term outcomes. This is not surprising because the inflammatory response in this region probably amplified myocardial necrosis. In this context, we have shown that hyperglycemic stress during MI is associated with increased levels of some inflammatory markers, including C-reactive protein and interleukin-18, and enhanced expression of natural killer cells (CD16/CD56) associated with reduced expression of some T cells (CD152) known to limit the immune process in patients presenting with acute MI.3 These results fit with animal studies showing increased levels of proinflammatory cytokines (tumor necrosis factor-α, interleukin-6, interleukin-18) and peroxynitrite (an index of oxidative stress) in the heart tissue of hyperglycemic mice. These correlated strictly with the glucose levels,4 leading to myocardial apoptosis and greater infarct size. Finally, analysis of ventricular biopsy specimens obtained from type 2 diabetic patients presenting with acute coronary syndromes and undergoing coronary bypass surgery have shown reduced expression of some important angiogenic factors, such hypoxia-inducible factor-1α and vascular endothelial growth factor, compared with nondiabetic patients with ischemia.5 The results of these studies suggest that hyperglycemia amplifying oxidative stress and the inflammatory responses to myocardial ischemia, as well as impairing angiogenesis factors, may affect the prognosis of patients presenting with MI.

To assess whether acute hyperglycemia affects fibrinolytic balance in elderly subjects with normal glucose tolerance (NGT) or impaired glucose tolerance (IGT), 40 non-obese elderly subjects (20 NGT, age 68 +/- 8 years; and 20 IGT, age 69 +/- 11 years) were studied. On two experimental days, randomly allocated and spaced 1 week apart, plasma concentrations of glucose, insulin, fibrinogen, tissue plasminogen activator, plasminogen activator inhibitor type 1 and von Willebrand factor (vWF) were measured in each subject at baseline (0) and 30, 60, 90, 120 min after the ingestion of 75 g glucose or a similarly sweet dose of aspartame (250 mg) (control test). In both NGT and IGT elderly subjects, tissue plasminogen activator, plasminogen activator inhibitor type 1 and fibrinogen plasma levels did not significantly change after both oral aspartame and glucose load. In IGT subjects, vWF plasmatic levels decreased after glucose (not aspartame) oral load, reaching the minimum level at 90 min after load (82.7 +/- 7.8 versus 93.7 +/- 10.2, P

Objective. To evaluate the effect of acute hyperhomocysteinaemia with and without antioxidant vitamins pretreatment on coronary circulation and circulating chemokine levels. Design. Observer-blinded, randomized crossover study. Setting. This study was conducted at a university hospital and at a general hospital in Italy. Subjects. Sixteen healthy hospital staff volunteers (nine men, seven women), aged 26–40 years. Interventions. Subjects were given each three loads in random order at 1-week intervals: oral methionine, 100 mg kg−1 in fruit juice; the same methionine load immediately following ingestion of antioxidant vitamin E, 800 IU, and ascorbic acid, 1000 mg; and methionine-free fruit juice (placebo). Main outcome measures. Coronary flow velocity reserve (CFVR), assessed by noninvasive transthoracic Doppler echocardiography, blood pressure, heart rate, lipid and glucose, monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) parameters evaluated at baseline and 4 h following ingestion of the loads. Results. The oral methionine load increased plasma homocysteine from 12.8 ± 1.8 to 33.3 ± 3.4 μmol L−1 at 4 h (P

Hyperhomocysteinemia increases the risk of death in type 2 diabetic patients (1,2), although the causal relationship with regard to cardiovascular mortality still remains elusive. Acute elevations in circulating homocysteine levels have been shown to impair endothelial function in coronary microcirculation in normal subjects (3). The objective of the present study was to investigate the effect of acute hyperhomocysteinemia on coronary circulation in patients with type 2 diabetes. Coronary flow velocity reserve (CFVR) assessment by transthoracic Doppler echocardiography (TTDE) is a noninvasive method to evaluate coronary flow reserve and provides important information about coronary endothelial function (4). Twenty newly diagnosed (within 6 months of diagnosis) type 2 diabetic patients (14 men and 6 women, age 49 ± 8 years, BMI 26.1 ± 1.8 kg/m2) and 20 healthy control subjects, who were matched for age, sex, and BMI, volunteered for this study after informed written consent was obtained. All subjects (both patients and control subjects) were taking no medication or vitamin supplements, and the protocol was approved by the local ethics committee. The diabetic patients were normotensive, had cholesterol levels within normal ranges, and were free from both micro- and macro- …

In women, iron deficiency anemia-a result of chronic iron loss-is most common during the reproductive years because of physiologic demands such as menstrual blood losses and pregnancy. In other cases, iron deficiency anemia is generally attributed to occult gastrointestinal bleeding. Common causes of chronic gastrointestinal blood loss include erosive esophagitis, gastric and duodenal ulcers, vascular ectasias, colon adenomas, and cancers. Bleeding from the small intestine at sites beyond the duodenal bulb is uncommon. The lesions of the small intestine are responsible for approximately 4% of gastrointestinal bleeding [7]. In this report we describe a case of persistent iron deficiency anemia due to carcinoid tumor of the small intestine.

In the present study, β-endorphin and met-enkephalin were tested for their antiplatelet activity in human platelet-rich plasma (PRP). Blood samples were obtained from 15 healthy subjects. The results of the study show that these two endogenous opioids (200 pg/ml final concentration) reduce platelet aggregation when it is induced by ADP at low dose (0.5 μM). It is likely due to conformational changes on the platelet membrane that cause a non-specific decreased susceptibility to platelet-aggregating agonists. Am. J. Hematol. 68:1–3, 2001. © 2001 Wiley-Liss, Inc.

To the Editor: Blanco-Colio et l1 showed that a fat-enriched breakfast increased the activation of the transcription factor nuclear factor-κB in peripheral blood mononuclear cells of normal subjects, an effect prevented by antioxidants present in red wine. We compared the effects of a high-fat meal and a high-carbohydrate meal (pizza), with or without dietary antioxidants, on the levels of soluble intercellular adhesion molecule-1 (sICAM-1) and vascular adhesion molecule-1 (sVCAM-1) in normal subjects. The genes of adhesion molecules are regulated by nuclear factor-κB,2 and circulating adhesion molecules are considered a molecular marker of early atherosclerosis.3 We studied 25 healthy non-obese volunteers (13 men and 12 women) aged 27±5.3 years (mean±SD). Subjects ate the following meals in random order and separated by a 1-week interval: (1) a high-fat meal (760 kcal; 50 g of fat, 20.4 g of saturated fat, 58 g of carbohydrates); (2) an isoenergetic high-carbohydrate (pizza) meal (758 kcal; 17 g of fat, 2.2 g …

Twenty-seven subjects suffering from peripheral occlusive arterial disease (POAD, clinical stage II-III according to Fontaine) were enrolled in this study to evaluate the effect of oxygen-ozone therapy upon hemorheological parameters and hemoglobin-oxygen affinity in patients with POAD. All patients underwent a major ozonized autohemotransfusion consisting of the slow reinfusion of 100 ml of autologous blood, previously exposed to a O(2)-O(3) mixture in a glass box for 10 min. Whole blood viscosity, erythrocyte filterability, hematocrit, and fibrinogen levels were assessed at the basal time and 30 min after the reinfusion of ozonized blood. At the same time p50 standard (p50std) values (an indicator of hemoglobin-oxygen affinity) and plasma values of malonyl dialdehyde (MDA, an indicator of lipid peroxidation) were evaluated. At the baseline, patients had significantly higher ( p0.05- p0.001) whole blood viscosity, MDA, and p50std values and significantly lower blood filterability ( p0.01) as compared with 20 matched healthy volunteers (controls). Thirty minutes after the end of a major autohemotransfusion, whole blood viscosity significantly decreased ( p0.01). This was accompanied by a significant fall in plasma fibrinogen level ( p0.01) with no change in hematocrit. Blood filterability, MDA plasma level, and p50std values increased significantly at the same time ( p0.01- p0.005). The 2,3-DPG value did not change significantly. No significant changes occurred when the same patients received a non-ozonized autohemotransfusion (control test). In conclusion, ozonized autohemotransfusion may be useful to improve both the poor rheological properties of the blood and the oxygen delivery to tissues in patients suffering from POAD.

OBJECTIVE To compare the effects of the ACE inhibitor perindopril and the β-blocker carvedilol on blood pressure and endothelial functions in N1DDM patients with hypertension. RESEARCH DESIGN AND METHODS We conducted a double-blind randomized trial in 26 patients with NIDDM and mild hypertension. A 4-week run-in placebo period preceded the active 12-week treatment with perindopril (4–8 mg daily) or carvedilol (25–50 mg daily). Endothelial functions were assessed by evaluating the hemodynamic (mean blood pressure, leg blood flow) and rheological (platelet aggregation, blood viscosity, and blood filterability) responses to an intravenous bolus of 3 g L-arginine, the natural precursor of nitric oxide. RESULTS Both perindopril and carvedilol significantly reduced mean blood pressure (P < 0.001) and increased leg blood flow (P < 0.05) to the same extent; blood filterability remained unchanged in both perindopril- and carvedilol-treated groups. Carvedilol reduced platelet aggregation and blood viscosity significantly (P < 0.05) but perindopril did not. Before treatment, the hemodynamic and rheologic responses to L-arginine were significantly lower in patients (P < 0.05–0.01) than in 20 nondiabetic nonhypertensive control subjects. After 12 weeks of treatment, both drugs normalized the hemodynamic responses to L-arginine. Platelet aggregation response to L-arginine was ameliorated by carvedilol and remained unchanged in the perindopril group. CONCLUSIONS At the doses used, both drugs effectively reduce blood pressure and normalize the hemodynamic responses to L-arginine. The implications of the ameliorated endothelial function for the poor cardiovascular outlook of the NIDDM hypertensive patient need further assessment.

We evaluated the effect of insulin on platelet function, blood viscosity, and filterability in healthy subjects and in patients with Type 2 (non-insulin-dependent) diabetes mellitus. Fifteen diabetic patients were free from cardiovascular complications (group A), while the other 15 patients had both clinical and measured evidence of coronary or peripheral vascular disease (group B); 15 non-diabetic subjects served as controls. On blood samples taken without stasis, maximal platelet aggregation to 1.25 micromol l(-1) ADP, blood and plasma viscosity, and blood filterability were measured in basal conditions, and after incubation of blood, plasma or platelet-rich plasma with insulin at two physiological concentrations (120 and 480 pmol l(-1)). Compared with healthy subjects, the diabetic patients of group B had higher values of blood (p < 0.01) and plasma (p < 0.05) viscosity, and platelet aggregation response to ADP (p < 0.01), as well as lower values of blood filterability (p < 0.01). The diabetic patients of group A had values intermediate between normal subjects and the patients of group B. In non-diabetic subjects, insulin significantly decreased platelet aggregation and blood viscosity at low shear rates (22.5 s(-1)) (p < 0.01 for both), and had no significant effects on other parameters. In the diabetic patients of group A, insulin decreased blood viscosity at high (225 s(-1)) rates of shear (p < 0.01) and increased blood filterability (p < 0.01). The effects of insulin were not dose-related. In the diabetic patients of group B, none of the parameters evaluated was significantly influenced by insulin. Type 2 diabetic patients present many abnormalities of the rheologic properties of blood. The beneficial effects of insulin on platelet aggregation and blood viscosity are not evident in Type 2 diabetic patients, especially those with vascular complications and this may be relevant to the development of those complications.

Background Acute hyperglycemia may increase vascular tone in normal humans via a glutathione-sensitive, presumably free radical–mediated pathway. The objective of this study was to investigate whether or not the vascular effects of hyperglycemia are related to reduced availability of nitric oxide. Methods and Results Acute hyperglycemia (15 mmol/L, 270 mg/dL) was induced in 12 healthy subjects with an artificial pancreas. Systolic and diastolic blood pressures, heart rate, and plasma catecholamines showed significant increases ( P P P l -arginine (n=7, 1 g/min) but not d -arginine (n=5, 1 g/min) or l -lysine (n=5, 1 g/min) in the last 30 minutes of the hyperglycemic clamp completely reversed all hemodynamic and rheological changes brought about by hyperglycemia. Infusion of N G -monomethyl- l -arginine (L-NMMA; 2 mg/min) to inhibit endogenous nitric oxide synthesis in 8 normal subjects produced vascular effects qualitatively similar to those of hyperglycemia but quantitatively higher ( P Conclusions The results show that acute hyperglycemia in normal subjects causes significant hemodynamic and rheological changes that are reversed by l -arginine. Moreover, the effects of hyperglycemia are mimicked to a large extent, but not entirely, by infusion of L-NMMA. This suggests that hyperglycemia may reduce nitric oxide availability in humans.

To evaluate 1) the hemorrheologic and hemodynamic effects of glyceryl trinitrate in patients with non-insulin-dependent diabetes mellitus and 2) the influence of antioxidants on these effects.Case-control study.University hospital clinic.40 patients with diabetes and no evidence of cardiovascular complications and 40 controls matched for demographic variables and body habitus.Sublingual glyceryl trinitrate (0.3 mg) and transdermal glyceryl trinitrate patches (10 mg/d). Vitamin E, 300 mg/d orally for 7 days, and glutathione, 600 mg intravenously or intramuscularly, were given to test the effects of antioxidant supplementation.Systolic, diastolic, and mean arterial pressure and heart rate; left ventricular ejection fraction; platelet aggregation, blood viscosity, and blood filterability in vitro and ex vivo.Compared with controls, patients with diabetes had increased platelet aggregation to adenosine diphosphate (P0.005), increased blood viscosity (P0.001), and decreased blood filterability (P = 0.041) at baseline; blood pressure, heart rate, and ejection fraction were similar in the two groups. In controls, both sublingual glyceryl trinitrate and transdermal glyceryl trinitrate patches significantly reduced platelet aggregation (-38%; 95% CI, -49% to -27%) and blood viscosity (-8%; CI, -11% to -5%) and increased blood filterability (10%; CI, 7.0% to 13.1%). Slight but significant decreases in blood pressure and ejection fraction and an increase in heart rate were also seen in controls after administration of glyceryl trinitrate (both preparations). In patients with diabetes, glyceryl trinitrate paradoxically increased platelet aggregation (24%; CI, 15% to 33%) and blood viscosity (6%; CI, 2.9% to 8.8%) and decreased blood filterability (-7%; CI, -9.5% to -4.4%); hemodynamic values did not change significantly. In both groups, rheologic responses to glyceryl trinitrate (end concentration, 100 and 200 ng/mL) in vitro were similar to those seen in ex vivo studies. Vitamin E and glutathione normalized rheologic responses to glyceryl trinitrate in patients with diabetes.Organic nitrates have beneficial effects on blood rheology in controls but not in patients with diabetes, in whom a paradoxical deterioration is seen. Antioxidant supplementation can normalize primary tolerance to the rheologic effects of nitrates in diabetes.

Although it has been demonstrated that diabetes mellitus may enhance apoptosis in myocardial (4) and endothelial cells (5), still, no evidence exists in humans about the potential role of diabetes in the evolution of diabetic atherosclerotic plaques toward instability by enhancing VSMC apoptosis. We hypothesize that by enhancing the proinflammatory cytokines, diabetes may exert proapoptotic effects on VSMCs of atherosclerotic plaque. To address these issues, cell death by apoptosis and expression and localization of TNF-9 and IL-1b was evaluated in carotid plaques of asymptomatic diabetic and nondiabetic patients. The study group consisted of 26 type 2 diabetic and 30 nondiabetic patients enlisted to undergo carotid endarterectomy for asymptomatic extracranial high-grade (.70%) internal carotid artery stenosis

This study examines the effect of baclofen, a specific gamma-aminobutyric acid analog which crosses the blood-brain barrier freely, upon insulin, glucagon, and GH responses to iv glucose in normal man. Normal subjects received two consecutive iv glucose tolerance tests (0.33 g/kg) before and after the acute oral administration of 5, or 10 or 20 mg baclofen, respectively, (10 subjects for each group). The dose of baclofen was divided and given 8 and 1 h before the performance of the posttreatment test. A fourth group of normal subjects served as placebo group (8 subjects). The highest dose of baclofen significantly increased insulin responses to glucose and raised basal glucagon levels (P less than 0.01). No significant change occurred with the other doses. Baclofen produced a dose-related increase in basal GH levels; a 10-fold increase was observed with the 20-mg dose. However, glucose-induced glucagon and GH suppression were not affected by baclofen. Despite the increased hormonal secretions, glucose tolerance did not change after baclofen. These results seem to indicate that gamma-aminobutyric acid may play a role in the neuroendocrine control of the pancreatic islets.

Context.—C1 inhibitor (C1-INH) is an α2-globulin that blocks esterolytic activity of the first component of the classic complement cascade. The α-granules of normal human platelets also contain C1-INH, which is expressed on the platelet surface during platelet secretion in healthy patients, but it is clearly reduced in patients with hereditary angioedema (HAE).Objective.—To evaluate the effects of in vivo C1-INH concentrate infusion on platelet responsiveness and coagulation system activity in patients with HAE.Design.—Assessment of the platelet activity and plasma levels of C1-INH, activated factor XII (XIIa), and prothrombin fragment F1.2 (F1.2) before and after infusion of 15 U/kg of C1-INH concentrate.Patients.—In 6 patients (4 men and 2 women), HAE was diagnosed according to the accepted clinical and laboratory criteria.Measurements.—Platelet aggregation (final concentrations: adenosine diphosphate, 0.5, 1.25, and 2.5μM; collagen, 5 μg/mL), C1-INH antigen (radial immunodiffusion), C1-INH activity (chromogenic substrates), and XIIa and F1.2 (enzyme-linked immunosorbent assay).Results.—After C1-INH infusion, we observed a prompt increase of C1-INH level and a slow return toward its plasma preinfusion values within 4 to 7 days, a significant decrease of both adenosine diphosphate– and collagen-induced platelet aggregation versus preinfusion values (maximum after 1–2 days; P < .001), and a rapid decrease of high basal values of XIIa and F1.2 in 30 and 120 minutes, respectively.Conclusions.—These data show a role of C1-INH in the control of platelet activity and that its deficiency increases platelet aggregability and plasma levels of XIIa and F1.2 in patients with HAE.

Objective: In Type 2 diabetes, it is not clear if renal size is constantly related to the glomerular filtration rate. In addition, it is not known ifkidney volume (KV) is associated with an increased urinary albumin and IgG excretion. Methods: The relationship between kidney volume, creatinine clearance (CrCI), urinary albumin and IgG excretion in 95 Type 2 diabetic patients with different stages of nephropathy (1 ― 4 Stage sec NKDF-QD) was elevated and compared to 85 non-diabetic subjects with similar degree of kidney function. Results: In Type 2 diabetic patients the KV/CrCl ratio was increased, in comparison with the control subjects, from about 15% in Stage 1 to 53% in Stage 4. In T2D subjects, significant correlations were found between KV and urinary albumin excretion (r = 0.665, p < 0.05), and between KV and urinary IgG excretion (r = 0.800, p < 0.001). Conclusion: The present study finds that Type 2 diabetic subjects, are characterized by an increased ratio between KV/CrCl, throughout the different progressive stages of nephropathy. In Type 2 diabetes relationships between KV and urinary albumin and between KV and IgG excretion also were found to be significant, suggesting a role for the impaired size selectivity of proteinuria as a possible determinant of KV.

The objective of this study was to assess the role of L-arginine, the natural precursor of nitric oxide, for testing endothelial function in physiological and pathophysiological conditions. In an initial study of 20 healthy subjects, mean blood pressure decreases in response to increasing doses of L-arginine (1, 2, 3, and 5 g) were 1.1 +/- 1.3, 2.6 +/- 1.5, 7.6 +/- 1.3, and 7.7 +/- 2 mmHg, respectively, P < 0.01. The enantiomer D-arginine (3 g) did not produce any change in mean blood pressure and platelet aggregation (n = 10), whereas the infusion of the L-arginine analog NG-monomethyl-L-arginine (6 mg/min) reduced by 70% the vascular effects of L-arginine. In the whole population of 52 healthy subjects, there was an inverse correlation between age and blood pressure or platelet aggregation changes after L-arginine. Compared with matched controls (n = 20), the changes in mean blood pressure and platelet aggregation after L-arginine were significantly lower in non-insulin-dependent diabetic (n = 20) and hypercholesterolemic (n = 16), but not in hypertensive (n = 20), subjects. Changes in blood viscosity were significantly lower only in hypercholesterolemic subjects. Our findings suggest that an intravenous bolus of 3 g L-arginine may be a simple and useful tool to assess the endothelial control of blood pressure and platelet activity in health and disease.