Biomedical subjects

A Mezzetti

Publications and source records attributed to A Mezzetti.

At least 19 recordsLinked to original sources

PubMed2007

Multivariate curve resolution of rapid-scan FTIR difference spectra of quinone photoreduction in bacterial photosynthetic membranes.

Photosynthetic reaction centres and membranes are systems of particular interest and are often taken as models to investigate the molecular mechanisms of selected bioenergetic reactions. In this work, a multivariate curve resolution by alternating least squares procedure is detailed for resolution of time-resolved difference FTIR spectra probing the evolution of quinone reduction in photosynthetic membranes from Rhodobacter sphaeroides under photoexcitation. For this purpose, different data sets were acquired in the same time range and spectroscopic domain under slightly different experimental conditions. To enable resolution and provide meaningful results the different data sets were arranged in an augmented matrix. This strategy enabled recovery of three different species despite rank-deficiency conditions. It also results in better definition (identity and evolution) of the contributions. From the resolved spectra, the species have been attributed to: 1. the formation of ubiquinol, more precisely the disappearance of Q/appearance of QH(2); 2. conformational change of the protein in the surrounding biological medium; 3. oxidation of diaminodurene, a redox mediator. Because, moreover, results obtained from augmented data sets strategies enable quantitative and qualitative interpretation of concentration profiles, other effects, for example the consequence of repeated light excitation of the same sample, choice of illumination power, or the number of spectra accumulated could be compared and discussed.

Algorithms↗

PubMed2005

Enhanced soluble CD40 ligand contributes to endothelial cell dysfunction in vitro and monocyte activation in patients with diabetes mellitus: effect of improved metabolic control.

AIMS/HYPOTHESIS: Inflammation plays a pathogenic role in the development of accelerated atherosclerosis in diabetes. Soluble CD40 ligand (sCD40L) is enhanced in diabetes; however, the molecular mechanisms linking sCD40L to accelerated atherosclerosis in diabetes are still unclear. We tested the hypothesis that sCD40L may be involved in the vascular complications in diabetes and exerts its effect by triggering inflammatory reactions on mononuclear and endothelial cells (ECs). METHODS: We studied 70 patients, 40 with type 2 and 30 with type 1 diabetes, with a history or physical examination negative for cardiovascular disease, and 40 non-diabetic and 30 healthy subjects, matched with the type 2 and type 1 diabetic patients, respectively. Plasma and serum sCD40L, and plasma soluble intercellular adhesion molecule-1, soluble vascular cell adhesion molecule-1, E-selectin and monocyte chemo-attractant protein-1 (MCP-1) were measured. Adhesion molecules and MCP-1 release, the ability to repair an injury in ECs, and O2- generation in monocytes were analysed in vitro after stimulation with serum from patients or controls. RESULTS: Type 2 and type 1 diabetic patients had significantly higher sCD40L levels than controls. Furthermore, high sCD40L was associated with in vitro adhesion molecules and MCP-1 release, impaired migration in ECs and enhanced O2- generation in monocytes. Improved metabolic control was associated with a reduction of plasma sCD40L by 37.5% in 12 type 1 diabetic patients. Furthermore, elevated sCD40L in diabetic patients was significantly correlated with HbA1c levels. CONCLUSIONS/INTERPRETATION: Upregulation of sCD40L as a consequence of persistent hyperglycaemia in diabetic patients results in EC activation and monocyte recruitment to the arterial wall, possibly contributing to accelerated atherosclerosis development in diabetes.

Adult↗

PubMed2005

Novel determinants of plaque instability.

Arachidonic acid metabolism plays an important role in acute ischemic syndromes affecting the coronary or cerebrovascular territory, as reflected by biochemical measurements of eicosanoid biosynthesis and the results of inhibitor trials in these settings. Two cyclooxygenase (COX)-isozymes have been characterized, COX-1 and COX-2, that differ in terms of regulatory mechanisms of expression, tissue distribution, substrate specificity, preferential coupling to upstream and downstream enzymes and susceptibility to inhibition by the extremely heterogeneous class of COX-inhibitors. While the role of platelet COX-1 in acute coronary syndromes and ischemic stroke is firmly established through approximately 20 years of thromboxane metabolite measurements and aspirin trials, the role of COX-2 expression and inhibition in atherothrombosis is substantially uncertain, because the enzyme was first characterized in 1991 and selective COX-2 inhibitors became commercially available only in 1998. In this review, we discuss the pattern of expression of COX-2 in the cellular players of atherothrombosis, its role as a determinant of plaque 'vulnerability,' and the clinical consequences of COX-2 inhibition. Recent studies from our group suggest that variable expression of upstream and downstream enzymes in the prostanoid biosynthetic cascade may represent important determinants of the functional consequences of COX-2 expression and inhibition in different clinical settings.

Atherosclerosis↗

PubMed2005

Pharmacological modulation of plaque instability.

Atherosclerotic plaque rupture is promoted by metalloproteinase (MMP)-2 and MMP-9, enzymes that degrade the fibrous cap leading to plaque erosion. MMP biosynthesis is mediated by prostaglandin (PG)E2, the product of cyclooxygenase (COX)-2/inducible PGE synthase (mPGES) activity. We have recently reported the overexpression of COX-2/mPGES-1 in vulnerable plaques as a basis of MMP-mediated plaque instability. Hypercholesterolemia and hypertension are two important risk factors for atherosclerosis. Recent trial showed that statins and AT1 receptor blockers significantly reduce the incidence of cardiovascular events in humans. Since anti-inflammatory effects have been reported in association to therapy with statins or AT1 receptor blockers, in two different studies we hypothesized that these drugs can stabilize atherosclerotic plaques through modulation of COX-2/mPGES-1-dependent MMP biosynthesis. Our data demonstrated the stabilizing effect of atherosclerotic plaques by simvastatin or irbesartan, that is due, at least in part, to the reduction of inflammatory burden and suppression of PGE2-dependent metalloproteinases release.

Angiotensin II Type 1 Receptor Blockers↗

PubMed2004

The role of nitric oxide in the development of diabetic angiopathy.

Diabetic angiopathy is the main cause of morbidity and mortality in patients with diabetes mellitus. Clinical manifestations and pathophysiological mechanisms of diabetic angiopathy can be traced back to the development of endothelial cell dysfunction with alterations in the eNOS/NO system production or availability as the primum movens in its natural history. Hyperglycemia per se or through the accumulation of AGEs, increased oxidative stress, leading to NOS uncoupling and NO-quenching by excess superoxide and peroxynitrite, and individual genetic background are thought to be responsible for this NO metabolism imbalance. The complex interplay of these mechanisms results in a perturbation of the physiological properties of NO in the maintenance of endothelial homeostasis, such as vasodilation, anticoagulation, leukocyte adhesion, smooth muscle cell proliferation, and antioxidant capacity. Hence, abnormality in NO availability results in generalized accelerated atherosclerosis, hyperfiltration, glomerulosclerosis, tubulointerstitial fibrosis and progressive decline in glomerular filtration rate, and apoptosis and neovascularization in the retina. Indeed, the parallel development of nephropathy, retinopathy, and macroangiopathy may be considered as manifestations of endothelial dysfunction at distinct vascular sites. Given this scenario, intervention targeting any of the pathways involved in the NOS/NO system cascade may prove potential therapeutic targets in the prevention of long-term diabetic complications.

Animals↗

PubMed2003

Circulating homocysteine levels in sustained and white coat hypertension.

Although white coat hypertension has been widely studied in the last years, its risk profile is not yet completely clear. The aim of this study was to evaluate circulating homocysteine levels, an emerging cardiovascular risk factor, in subjects with white coat and sustained hypertension. We selected 31 sustained hypertensive subjects, 31 white coat hypertensive subjects and 31 normotensive subjects matched for age, gender, body mass index and occupation. Women were also matched for menopausal status. Subjects with smoking habit, dyslipidaemia and diabetes mellitus were excluded from the study. White coat hypertension was defined as clinical hypertension and daytime ambulatory blood pressure <135/85 mmHg. Blood samples were drawn after a fasting period of 12 h for routine laboratory tests and homocysteine determination. Homocysteine levels were evaluated by fluorescence polarization immunoassay. Creatinine, glucose, cholesterol and triglycerides were not different among the groups. White coat hypertensive subjects had significantly lower homocysteine levels than sustained hypertensive patients (8.2+/-2.0 vs 12.6+/-3.9 micromol/l, P=0.0003). No significant difference was observed between white coat hypertensive and normotensive subjects regarding this parameter (8.2+/-2.0 vs 7.6+/-1.9 micromol/l, P=0.9). In conclusion, our data show that middle-aged white coat hypertensive subjects without other cardiovascular risk factors have lower circulating homocysteine levels than sustained hypertensive patients suggesting that they are at lower cardiovascular risk.

Adult↗

PubMed2003

Resveratrol and quercetin down-regulate tissue factor expression by human stimulated vascular cells.

BACKGROUND: Epidemiological studies have shown that consumption of wine reduces the risk of coronary heart disease. Resveratrol and quercetin, two polyphenolic compounds found in grapes and red wine, have been shown to contribute to this protection by exerting several biological properties which could be associated with cardioprotection. Tissue factor (TF), the cellular receptor that initiates blood coagulation, plays a primary role both in hemostasis following tissue injury and in the pathogenesis of atherosclerosis which predisposes to thrombosis. OBJECTIVES: We investigated the role of resveratrol and quercetin on TF expression by endothelial and mononuclear cells (MN). METHODS: Confluent human umbilical vein endothelial cells and MN collected from healthy donors were stimulated with bacterial lipopolysaccharide, interleukin-1beta or tumor necrosis factor-alpha after incubation with increasing concentrations of resveratrol or quercetin. RESULTS: In both cell types, TF activity induced by any agonist was significantly reduced by resveratrol or quercetin in a dose-dependent fashion. Northern blot analysis indicated that resveratrol and quercetin strongly reduce TF mRNA in both cell types. The inhibition of TF mRNA originated from a reduction in nuclear binding activity of the transacting factor c-Rel/p65, which was induced by the agonists and measured by electromobility shift assay. Western blot analysis revealed that the diminished c-Rel/p65 activity was dependent upon inhibition of degradation of the c-Rel/p65 inhibitory protein IkappaBalpha. CONCLUSIONS: These results provide a molecular basis which could help explain the protective activity of red wine against cardiovascular disease.

Active Transport, Cell Nucleus↗

PubMed2003

High preprocedural non-HDL cholesterol is associated with enhanced oxidative stress and monocyte activation after coronary angioplasty: possible implications in restenosis.

OBJECTIVE: To investigate whether enhanced oxidant stress in patients undergoing percutaneous transluminal coronary angioplasty (PTCA) is associated with a higher concentration of non-high density lipoprotein (HDL) cholesterol at baseline, and whether this contributes to the inflammatory reaction and luminal renarrowing after PTCA. DESIGN: An ex vivo and in vitro study of 46 patients who underwent PTCA and who had repeat angiograms after six months. Blood samples were collected immediately before PTCA, and at 24 hours, 48 hours, and 15 days after. SETTING: Tertiary referral centre. SUBJECTS: 46 patients (30 male, 16 female; mean (SD) age, 62 (5) years) with stable or unstable angina who underwent elective PTCA. MAIN OUTCOME MEASURES: Continuous variable luminal loss as defined by change in minimum lumen diameter during follow up, normalised for vessel size; lag phase of low density lipoprotein to in vitro oxidation; plasma fluorescent products of lipid peroxidation (FPLP); plasma vitamin C and E; interleukin (IL) 1beta secretion from unstimulated monocytes; plasma C reactive protein (CRP). RESULTS: Restenosis occurred in 12 patients (26%). Oxidant stress after PTCA was greater (p < 0.0001 at 15 days) in the patients with restenosis and showed a significant correlation with the preprocedural concentration of non-HDL cholesterol (p < 0.001). Inflammatory reaction (as reflected by IL-1beta production and CRP) and late lumen loss were linearly correlated (p < 0.001) with lag phase and FPLP throughout the study, and inversely (p < 0.05) with vitamin C and E measured at two and 15 days after PTCA. CONCLUSIONS: This study provides evidence for the critical role of cholesterol dependent oxidant stress in the pathophysiology of restenosis after PTCA. The findings raise the possibility that drugs capable of modulating oxidant status might provide a novel form of adjuvant treatment in patients with hypercholesterolaemia undergoing PTCA.

Angioplasty, Balloon, Coronary↗

PubMed2002

Serum angiogenin concentrations in young patients with diabetes mellitus.

BACKGROUND: Angiogenin serum levels were measured in a large group of type 1 diabetic young patients, looking at whether increased Angiogenin concentrations are associated with long-term glycemic control and microvascular complications. MATERIALS AND METHODS: Four groups of patients were compared to 223 age- and sex- matched healthy controls: 196 type 1 diabetic patients (age range 3-24 years, onset of diabetes before the age of 12 years; duration of disease longer than 2 years), without microvascular complications were divided into three groups on the basis of age (group 1, n = 37, age < 6 years; group 2, n = 71, age 6-12 years; group 3, n = 88, age > 12 years); 53 adolescents and young adults (age 16.1-29.7 years) with diabetic microvascular complications (background, preproliferative or proliferative retinopathy, albumin excretion rate 20-200 microg min-1) (group 4). RESULTS: Angiogenin serum levels were significantly increased in diabetic pre-school and pre-pubertal children, and particularly elevated in pubertal subjects compared with age- and sex-matched controls. Adolescents and young adults with microvascular complications had very high angiogenin concentrations. One-year mean HbA1c values were correlated with angiogenin levels (r = 0.389; p < 0.01). In poorly controlled diabetics (HbA1c > 10%), long-term (2 years) improvement of glycemic control determined a significant reduction of angiogenin concentrations in both pre-school and pre-pubertal children as well as in pubertal youngsters. CONCLUSIONS: Angiogenin serum concentrations are increased in diabetic children even before puberty. Severity of microvascular complications is associated with markedly increased angiogenin serum levels. Long-term tight glycemic control determines a consistent reduction of angiogenin concentrations.

Adolescent↗

PubMed2001

Overexpression of functionally coupled cyclooxygenase-2 and prostaglandin E synthase in symptomatic atherosclerotic plaques as a basis of prostaglandin E(2)-dependent plaque instability.

BACKGROUND: Studies have implicated a role for prostaglandin (PG) E(2)-dependent matrix metalloproteinase (MMP) biosynthesis in the rupture of atherosclerotic plaque. Cyclooxygenase-2 (COX-2) and PGE synthase (PGES) are coregulated in nucleated cells by inflammatory stimuli. The aim of this study was to characterize the expression of COX-2 and PGES in carotid plaques and to correlate it with the extent of inflammatory infiltration and MMP activity and with clinical features of patients' presentation. METHODS AND RESULTS: Plaques were obtained from 50 patients undergoing carotid endarterectomy and divided into 2 groups (symptomatic and asymptomatic) according to clinical evidence of recent transient ischemic attack or stroke. Plaques were analyzed for COX-2, PGES, MMP-2, and MMP-9 by immunocytochemistry and Western blot, whereas zymography was used to detect MMP activity. Immunocytochemistry was used to identify CD68+ macrophages, CD3+ T lymphocytes, and HLA-DR+ cells. The percentage of macrophage-rich areas was larger (P<0.0001) in symptomatic plaques. COX-2, PGES, and MMPs were detected in all specimens; enzyme concentration, however, was significantly higher in symptomatic plaques. COX-2, PGES, and MMPs were especially noted in shoulders of symptomatic plaques, colocalizing with HLA-DR+ macrophages. All symptomatic plaques contained activated forms of MMPs. Finally, inhibition of COX-2 by NS-398 was accompanied by decreased production of MMPs that was reversed by PGE(2). CONCLUSIONS: This study demonstrates the colocalization of COX-2 and PGES in symptomatic lesions and provides evidence that synthesis of COX-2 and PGES by activated macrophages is associated with acute ischemic syndromes, possibly through metalloproteinase-induced plaque rupture.

Aged↗

PubMed2001

Endogenous ouabain and hemodynamic and left ventricular geometric patterns in essential hypertension.

We sought to evaluate the relationships among circulating levels of an endogenous ouabain-like factor (EO) and systemic hemodynamics and left ventricular (LV) geometry in patients with recently diagnosed essential hypertension. We selected 92 never-treated patients with essential hypertension. Blood samples were drawn for estimation of plasma EO (radioimmunoassay) and subjects underwent echocardiographic examination to evaluate LV end-systolic and end-diastolic wall thickness and internal dimensions. LV volumes, stroke volume, cardiac output, total peripheral resistance, LV mass, and relative wall thickness were calculated, and all except the last parameter were indexed by body surface area. LV mass also was indexed by height. On the basis of the values of LV mass index (body surface area or height) and relative wall thickness, subjects were divided into groups with either normal geometry, concentric remodeling, concentric hypertrophy, or eccentric nondilated hypertrophy. In the study population as a whole, circulating EO levels were significantly and directly correlated with mean blood pressure (r = 0.21, P = .048), relative wall thickness (r = 0.34, P = .001), and total peripheral resistance index (r = 0.37, P = .0003). Plasma EO also was significantly and inversely correlated with LV end-diastolic volume index (r = -0.32, P = .002), stroke index (r = -0.34, P = .0009), and cardiac index (r = -0.35, P = .0007). In multiple regression analysis, plasma EO was an independent correlate of total peripheral resistance index, cardiac index, and relative wall thickness. Regardless of the indexation method used for LV mass, plasma EO was higher in patients with concentric remodeling than in those with either normal geometry or concentric hypertrophy. Plasma EO tended to be higher (indexation by body surface area) or was significantly higher (indexation by height) in subjects with concentric remodeling than in those with eccentric nondilated hypertrophy. Patients with concentric remodeling showed the highest total peripheral resistance index and the lowest cardiac index. Our data suggest that EO plays a role in regulating systemic hemodynamics and LV geometry in patients with essential hypertension.

Adult↗

PubMed2001

Vitamin E and lipid peroxide plasma levels predict the risk of cardiovascular events in a group of healthy very old people.

OBJECTIVES: To assess whether systemic oxidative stress can predict the risk of first myocardial infarction, ischemic stroke, and congestive heart failure. DESIGN: A longitudinal study started in 1992 and completed in 1997. SETTING: Community-based, outpatient. PARTICIPANTS: 102 apparently healthy, community-dwelling subjects age 80 and older from the Vibrata valley, Teramo, Italy. MEASUREMENTS: Plasma vitamin E, beta-carotene, vitamin C, fluorescent products of lipid peroxidation (FPLPs), and serum lipids were determined at enrollment. RESULTS: Thirty-two cardiovascular events were recorded in 47.4 months of follow-up. The subjects with vitamin E levels in the highest quartile had a risk of cardiovascular events one-sixth those with vitamin E levels in the lowest quartile (relative risk (RR) = 0.16; 95% confidence interval (CI) = 0.04-0.55). The subjects with FPLPs in the highest quartile had a risk seven times greater than those with FPLPs in the lowest quartile (RR = 7.61; 95% CI = 2.23-25.96). No association was observed for vitamin C, beta-carotene, or total cholesterol. Multivariate adjustment for known risk factors did not significantly change the results. CONCLUSIONS: Our results suggest that in apparently healthy, community-dwelling very old subjects, base-line plasma concentration of vitamin E and FPLPs predicts the risk of future cardiovascular events. We confirm previous data showing that total cholesterol is not a predictor of cardiovascular disease in people age 80 and older.

Age Distribution↗

PubMed2001

High vitamin E plasma levels and low low-density lipoprotein oxidation are associated with the absence of atherosclerosis in octogenarians.

OBJECTIVES: To identify the biological characteristics of older subjects with vascular successful aging (VASA), defined as the absence of instrumental signs and clinical symptoms of atherosclerosis in the extracoronary and coronary vessels. DESIGN: A cross-sectional study. SETTING: A university-affiliated outpatient clinic. PARTICIPANTS: Sixty older subjects (30 with VASA and 30 controls with moderate carotid atherosclerosis (AG group)) from a sample of 705 subjects age 75 and older consecutively screened. MEASUREMENTS: Clinical examination; ultrasonographic examination of carotid, vertebral, abdominal aortic, iliac, and femoral arteries; electrocardiogram; and laboratory evaluation (lipid profile, lipophilic antioxidants, and markers of low-density lipoprotein (LDL) oxidation). RESULTS: Compared with controls, there were more females in the VASA group (82% vs 50%, P <.01), and fewer previous smokers (20.5% vs 52.5%, P <.01). Vitamin E/total cholesterol levels both in plasma (4.81 vs 3.51 micromol/mmol, P <.001) and in isolated LDLs (2.71 vs 1.86 microg/mg LDL cholesterol (LDL-C), P <.01), were higher in the VASA group, as was the resistance of LDLs to in vitro oxidation (as indicated by a longer duration of the lag phase: 80.2 vs 65.6 minutes, P <.001). The level of fluorescent products of lipid peroxidation (FPLPs) in native LDLs was lower in the VASA group (13.5 vs 18.8 URF/mg LDL-C, P <.001). Multivariate logistic regression analysis showed that only plasma vitamin E level (odds ratio (OR) = 6.04, 95% confidence interval (CI) = 1.48-24.63) and FPLPs in LDLs (OR = 0.53, 95% CI = 0.31-0.91) were independently associated with VASA. CONCLUSIONS: These results suggest that an appropriate level of vitamin E and a low level of LDL oxidation might be important for reaching advanced age without developing atherosclerosis.

Aged↗

PubMed2001

Clinic and ambulatory heart rate in sustained and white-coat hypertension.

BACKGROUND: Sustained and white-coat hypertensives show hypertension in the office setting but different blood pressure values outside the clinical environment. So far, only a few incomplete data on heart rate are available inside and outside the clinical setting in these groups of patient. The aim of this study was to evaluate clinic and ambulatory heart in sustained hypertensives, white-coat hypertensives and normotensives. METHODS: We selected 236 sustained hypertensives, 236 white-coat hypertensives and 236 normotensives matched for age, gender and body mass index, and with a similar occupation. The subjects had been submitted to clinic evaluation and the non-invasive monitoring of blood pressure and heart rate. White-coat hypertension was defined as clinic hypertension and a daytime blood pressure of less than 135/85 mmHg. RESULTS: The clinic heart rate was significantly higher in sustained hypertensives and white-coat hypertensives than in normotensives (76 +/- 11 versus 75.5 +/- 10 versus 70 +/- 9 beats/min [bpm], respectively, P < 0.05). The daytime heart rate was significantly higher in sustained hypertensives than in white-coat hypertensives and normotensives (79.4 +/- 10 versus 74.6 +/- 8.5 versus 74.5 +/- 8.5 bpm, respectively, P < 0.05), as were the night-time heart rate (67 +/- 8.5 versus 63 +/- 8 versus 63 +/- 8 bpm, respectively, P < 0.05) and 24 h heart rate (76.3 +/- 9 versus 72 +/- 7.8 versus 72 +/- 8 bpm, respectively, P < 0.05). When men and women were analyzed separately, the same trend was observed. CONCLUSIONS: The clinic heart rate is similar in sustained and white-coat hypertensives, but the ambulatory heart rate is lower in white-coat hypertensives. As ambulatory heart rate is more representative of 24 h heart rate load and may be a better indicator of the detrimental effect of heart rate, our findings suggest that white-coat hypertensives are at lower cardiovascular risk than sustained hypertensives.

Adult↗

PubMed2001

Elevated circulating levels of monocyte chemoattractant protein-1 in patients with restenosis after coronary angioplasty.

Inflammation plays a pathogenic role in the development of restenosis after percutaneous transluminal coronary angioplasty (PTCA). Monocyte chemoattractant protein-1 (MCP-1) is a potent chemoattractant of monocytes; however, its role in the pathophysiology of restenosis is still unclear. We set out to investigate the role of MCP-1 in restenosis after PTCA. In addition, we tested the hypothesis that MCP-1 exerts its effect, at least in part, by inducing O(2)(-) generation in circulating monocytes. Plasma levels of MCP-1 were measured before and 1, 5, 15, and 180 days after PTCA in 50 patients (30 males and 20 females, aged 62+/-5 years) who underwent PTCA and who had repeated angiograms at 6-month follow-up. Restenosis occurred in 14 (28%) patients. The MCP-1 level was no different at baseline between patients with or without restenosis. However, after the procedure, restenotic patients, compared with nonrestenotic patients, had statistically significant (P<0.0001) elevated levels of MCP-1. In contrast, plasma levels of other chemokines, such as RANTES and interleukin-8, did not differ between the 2 groups after PTCA. Higher MCP-1 throughout the study was correlated with restenosis. Moreover, increased MCP-1 was significantly correlated with increased monocyte activity, as reflected by enhanced O(2)(-) generation. Finally, multivariate regression analysis showed that the MCP-1 plasma level measured 15 days after PTCA was the only statistically significant independent predictor of restenosis (beta=0.688, P<0.0001). This study suggests that MCP-1 production and macrophage accumulation in the balloon-injured vessel may play a pivotal role in restenosis after PTCA. MCP-1 may induce luminal renarrowing, at least in part, by inducing O(2)(-) release in monocytes. Further understanding of the mechanism(s) by which MCP-1 is produced and acts after arterial injury may provide insight into therapies to limit the progression of atherosclerosis and restenosis after balloon angioplasty.

Aged↗

PubMed2001

Increased vascular endothelial growth factor serum concentrations may help to identify patients with onset of type 1 diabetes during childhood at risk for developing persistent microalbuminuria.

This study was designed to evaluate whether vascular endothelial growth factor serum concentrations may identify adolescents with onset of type 1 diabetes during childhood at greater risk to develop persistent microalbuminuria and incipient diabetic nephropathy. In January 1989, vascular endothelial growth factor serum levels were measured in 101 normoalbuminuric diabetic children and adolescents (aged 7-14.9 yr; onset of diabetes before age 18 yr; duration of diabetes >7 yr). Participants were clinically examined at baseline and annually thereafter. Vascular endothelial growth factor serum concentrations were measured every year during the 8-yr follow-up period. Over 8 yr, 11 of 101 patients (10.9%) developed persistent microalbuminuria; no patient developed overt nephropathy. The risk of developing microalbuminuria was higher in children with increased vascular endothelial growth factor serum levels (using 160 pg/ml as the arbitrary cut-off point; group 1) compared with those with normal vascular endothelial growth factor serum levels at the beginning of the study (group 2; 19.2 vs. 2.0%; P < 0.01; sensitivity, 90.9%; specificity, 53.3%). The odds ratio for the occurrence of microalbuminuria after adjustment for confounding variables (albumin excretion rate, sex, hemoglobin A(1c), mean blood pressure, cholesterol, and triglycerides) in type 1 diabetic adolescents with elevated vascular endothelial growth factor serum levels was 4.1 (95% confidence interval, 2.0-10.9). These results suggest that vascular endothelial growth factor serum concentrations may be one of the predictors and risk factors for microalbuminuria and incipient diabetic nephropathy in adolescents and young adults with onset of diabetes during childhood. Persistently increased vascular endothelial growth factor serum levels may help to identify normotensive, normoalbuminuric patients with type 1 diabetes who are predisposed to develop persistent microalbuminuria later in life.

Adolescent↗

PubMed2000

Oxo complexes of osmium(IV) formed via dioxygen activation. X-ray structures of [OsX(dcpe)2]PF6 (X = Cl, Br), [OsCl(eta 2-O2)(dcpe)2]BPh4, and [OsCl(O)(dcpe)2]BPh4 (dcpe = 1,2-bis(dicyclohexylphosphino)ethane).

Dioxygen addition to the 16-electron complexes [OsX(P-P)2]+ (3) gives the dioxygen adducts [OsCl(eta 2-O2)(P-P)2]+ (3), which in turn react with HCl gas to give the novel osmium(IV) oxo complexes trans-[OsX(O)(P-P)2]+ (5) (X = Cl, Br; P-P = 1,2-bis(dicyclohexylphosphino)ethane (dcpe), 1,2-bis(diethylphosphino)ethane (depe), 1,2-bis((2R,5R)-2,5-dimethylphospholano)benzene (Me-duphos)). The complexes [OsX(dcpe)2]+ (X = Cl, Br) (3) are studied by X-ray crystallography and are shown to have a "Y-shaped" coordination geometry in the equatorial plane. The X-ray structural analysis of [OsCl(eta 2-O2)(dcpe)2]+ (4a) reveals an exceptionally short O-O bond (1.315(5) A). trans-[OsCl(O)(dcpe)2]+ (5a), the first oxo complex of osmium(IV) investigated crystallographically, exhibits a long Os-O distance of 1.834(3) A. The reactivity of 4 and 5 as oxidants is described. The dioxygen complex 4a transfers one oxygen atom to PPh3 (to give Ph3PO) or oxidizes iodide ions to triiodide ions in the presence of anhydrous HCl. In both reactions, the corresponding oxo species 5a is quantitatively formed as the only metal-containing product. Oxo complexes 5 are surprisingly stable and unreactive toward standard reducing agents such as phosphines.

Journal Article↗

PubMed2000

Oxidative stress and cardiovascular complications in diabetes: isoprostanes as new markers on an old paradigm.

Long-term vascular complications still represent the main cause of morbidity and mortality in diabetic patients. Although randomized long-term clinical studies comparing the effects of conventional and intensive therapy have demonstrated a clear link between hyperglycemia and the development of complications of diabetes, they have not defined the mechanism through which excess glucose results in tissue damage. Evidence has accumulated indicating that oxidative stress may play a key role in the etiology of diabetic complications. Isoprostanes are emerging as a new class of biologically active products of arachidonic acid metabolism of potential relevance to human vascular disease. Their formation in vivo seems to reflect primarily, if not exclusively, a nonenzymatic process of lipid peroxidation. Enhanced urinary excretion of 8-iso-PGF(2alpha) has been described in association with both type 1 and type 2 diabetes mellitus, and correlates with impaired glycemic control. Besides providing a likely noninvasive index of lipid peroxidation in this setting, measurements of specific F(2) isoprostanes in urine may provide a sensitive biochemical end point for dose-finding studies of natural and synthetic inhibitors of lipid peroxidation. Although the biological effects of 8-iso-PGF(2alpha) in vitro suggest that it and other isoeicosanoids may modulate the functional consequences of lipid peroxidation in diabetes, evidence that this is likely in vivo remains inadequate at this time.

Animals↗