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Andrea Mezzetti

Publications and source records attributed to Andrea Mezzetti.

At least 19 recordsLinked to original sources
PubMed2007

Enhanced plasma soluble CD40 ligand levels in essential hypertensive patients with blunted nocturnal blood pressure decrease.

BACKGROUND: Hypertensives with a blunted nocturnal blood pressure (BP) decrease have increased risk of developing atherosclerotic disease. Soluble CD40 ligand (sCD40L) is involved in the pathogenesis of risk factor-related vascular damage. Therefore, we evaluated the relationship between circulating sCD40L levels, circadian BP profile, and early carotid atherosclerosis in essential hypertensives. METHODS: Plasma sCD40L concentrations were assessed in two groups of 25 never-treated hypertensives, without additional cardiovascular risk factors, differentiated on the basis of a nocturnal decrease of BP either of >10% (dippers) or <10% (nondippers) of daytime values, and in 25 matched normotensives. Carotid intima-media thickness (IMT) was also measured in all participants. RESULTS: Plasma sCD40L concentrations were higher in nondippers (4.9 +/- 1.2 ng/mL) than in dippers (3.7 +/- 0.7, P = .0005) and controls (1.6 +/- 0.6, P < .0001). These latter had lower sCD40L concentrations than dippers (P < .0001). The IMT was higher in both hypertensive groups than in normotensives (P < .0001). In the entire hypertensive population IMT directly correlated with circulating levels of sCD40L (r = 0.365, P = .01) and inversely correlated with nocturnal systolic BP decreases (r = -0.286, P = .043). In a multivariate regression analysis sCD40L was the main determinant of IMT (r(2) = 0.157, P = .004). CONCLUSIONS: Nondippers have enhanced plasma sCD40L levels, which may contribute to their increased susceptibility to develop vascular damage.

Blood Pressure↗
PubMed2006

Mutational analysis of the HER2 gene in lung tumors from Caucasian patients: mutations are mainly present in adenocarcinomas with bronchioloalveolar features.

Activating mutations in the tyrosine kinase domain of the HER2 gene have recently been reported in lung adenocarcinomas, mainly in East Asian patients. Our study was devised to evaluate the prevalence and nature of HER2 mutations in lung adenocarcinomas from Caucasian patients. The mutational status of the HER2 gene was evaluated in 403 lung adenocarcinomas by PCR-single strand conformation polymorphism analysis and direct sequencing of Exons 19 and 20. We found HER2 mutations in 9 (2.2%) cases. Seven (78%) of the mutations were in frame duplications/insertions at codons 776-779 (YVMA), the other 2 were base substitutions resulting in aminoacid changes. The hotspot mutation at bases 776-779 was previously found to be the most frequent HER2 mutation in Asiatic patients. The distribution of mutations was significantly different between conventional lung adenocarcinomas (CLAs) and lung adenocarcinomas with bronchioloalveolar features (ABAFs). Seven (6.2%) of 113 ABAFs and 2 (0.7%) of 290 CLA were mutated (p = 0.0025). In addition, the frequency of HER2 mutations was slightly higher in females (4.1%) than in males (1.8%) and in never smokers (3.1%) than in smokers (1.9%), but differences were not statistically significant. This series of tumors was also investigated for EGFR and K-ras mutations. EGFR mutations were observed in 43 (10.7%) cases, and K-ras mutations in 110 (27.3%) cases. EGFR, HER2 and K-ras mutations were found to be mutually exclusive events. The presence of HER2 mutations in a subset of patients with lung adenocarcinoma raise hope to treat these patients with HER2 specific kinase inhibitors.

Adenocarcinoma↗
PubMed2006

Enhanced soluble CD40 ligand and Alzheimer's disease: evidence of a possible pathogenetic role.

It has been suggested that cerebrovascular factors contribute to Alzheimer's disease. Soluble CD40 ligand (sCD40L) is directly involved in the development of vascular damage. We tested the hypothesis that sCD40L may be enhanced in Alzheimer's disease and predictive of its clinical course. Plasma sCD40L levels were evaluated in three groups of 40 consecutive patients each referring for mild or moderate or severe Alzheimer's disease, as assessed by the Clinical Dementia Rating (CDR), and in 40 healthy subjects. Seventy-seven patients with mild or moderate disease were re-evaluated after 2 years. Cross-sectional comparisons revealed higher plasma sCD40L levels in Alzheimer's disease patients than in controls (9.3+/-4.7 ng/mL versus 3.4+/-1.3 ng/mL, p<0.0001). Circulating sCD40L levels significantly increased through the three CDR stages (p=0.0011 or less) and were correlated with MMSE (r=-0.574, p<0.0001) and ADAS-cog subscale (r=0.538, p<0.0001) scores. Longitudinal evaluation identified sCD40L as an independent predictor of MMSE (beta=-0.157, t=-3.650, p=0.0005) and ADAS-cog subscale (beta=0.484, t=3.890, p=0.0002) score changes after 2 years. Patients with plasma sCD40L level>or=6.0 ng/mL, identified by ROC curve analysis as the best discriminating value for disease progression, had a three-fold increase in the risk of progression toward a worse CDR stage (odd ratio: 3.0, C.I. 95% 1.2-8.1). In conclusion, circulating sCD40L is enhanced in patients with Alzheimer's disease and independently associated with the severity and progression of the disease. These data might suggest a pathogenetic role for sCD40L in Alzheimer's disease.

Aged↗
PubMed2006

Suppression of RAGE as a basis of simvastatin-dependent plaque stabilization in type 2 diabetes.

OBJECTIVE: Receptor for advanced glycation end products (AGEs) (RAGE) plays a central role in the process of plaque rupture in diabetic patients. Recently, it has been reported that RAGE may be downregulated by improving glycemic control. In contrast, despite being well known that RAGE may be induced in human vessels in a glucose-independent fashion, also by myeloperoxidase (MPO)-dependent AGE generation, no data exist regarding the possibility of a pharmacological modulation of glucose-independent RAGE generation. Thus, the aim of this study was to characterize the effect of simvastatin on the expression of RAGE and RAGE-dependent plaque-destabilizing genes in human atherosclerotic plaques. METHODS AND RESULTS: Seventy type 2 diabetic patients with asymptomatic carotid artery stenosis (>70%) were randomized to American Heart Association (AHA) step 1 diet plus simvastatin (40 mg/d) or AHA step 1 diet alone for 4 months before endarterectomy. Plaque expression of MPO, AGEs, RAGE, NF-kappaB, COX-2, mPGES-1, matrix metalloproteinase (MMP)-2 and MMP-9, lipid and oxidized LDL (oxLDL) content, procollagen 1, and interstitial collagen was analyzed by immunohistochemistry and Western blot; zymography was used to detect MMP activity. Plaques from the simvastatin group had less (P<0.0001) immunoreactivity for MPO, AGEs, RAGE, p65, COX-2, mPGES-1, MMP-2, and MMP-9, lipids and oxLDL; reduced (P<0.0001) gelatinolytic activity; increased (P<0.0001) procollagen 1 and collagen content; and fewer (P<0.0001) macrophages, T-lymphocytes, and HLA-DR+ cells. Of interest, RAGE inhibition by simvastatin, observed not only in plaque sections but also in plaque-derived macrophages, was reverted by addition of AGEs in vitro. CONCLUSIONS: This study supports the hypothesis that simvastatin inhibits plaque RAGE expression by decreasing MPO-dependent AGE generation. This effect in turn might contribute to plaque stabilization by inhibiting the biosynthesis of PGE2-dependent MMPs, responsible for plaque rupture.

Aged↗
PubMed2006

PIK3CA mutation and histological type in breast carcinoma: high frequency of mutations in lobular carcinoma.

Mutations in the PIK3CA gene have recently been reported in different human neoplasms, including breast cancer. This paper reports the results of a systematic analysis of PIK3CA mutations in different histological types of breast carcinoma. One hundred and eighty invasive breast carcinomas, comprising 74 ductal, 56 lobular, 22 mucinous, 20 medullary, and eight papillary, were selected on the basis of their histological type in a consecutive series of 780 breast cancers. Exons 1-20 of the PIK3CA gene were subjected to SSCP analysis followed by direct sequencing. PIK3CA mutations were observed in 46 (26%) of the 180 tumours examined: 23 (50%) mutations were located in exon 9, and 23 (50%) in exon 20. Mutations were frequent in lobular (46%), less frequent in ductal (22%), and uncommon in medullary (10%), mucinous (5%), and papillary tumours (12%) (p = 0.0002). Mutations in exon 9 were more frequent in lobular carcinomas (30% of cases) than in the other histological types (less than 5% of cases) (p = 0.00014). No significant differences were observed in the distribution of mutations in exon 20. There was no significant correlation between PIK3CA mutations and other clinicopathological and biological variables, including age, tumour size, lymph node metastases, oestrogen receptor (ER) status, progesterone receptor (PgR) status, p53 gene mutations, and p53 protein expression. The findings indicate that in invasive breast carcinomas, PIK3CA alterations are mainly present in lobular and ductal tumours, whereas the other histological types, known to be associated with a favourable prognosis, show a very low incidence of PIK3CA mutations.

Aged↗
PubMed2006

Blood pressure variability and cardiovascular risk in treated hypertensive patients.

BACKGROUND: The independent prognostic value of blood pressure (BP) variability in treated hypertension is not yet clear. We investigated the relationship between BP variability, evaluated by noninvasive monitoring, and cardiovascular outcome in treated hypertensive patients. METHODS: The occurrence of fatal and nonfatal cardiovascular events was evaluated in 1472 treated patients. Subjects with the standard deviation of daytime or night-time systolic BP below or above the median of the population were classified as having low or high BP variability. Specifically, 738 and 734 patients had low and high daytime BP variability, respectively, and 739 and 733 subjects had low and high night-time BP variability, respectively. RESULTS: During follow-up (4.88 +/- 2.9 years, range 0.2-11.6 years) there were 119 events. The event rates per 100 patient-years in subjects with low and high BP variability according to daytime BP were 1.18 and 2.01, respectively, and in those with low and high BP variability according to night-time BP were 1.2 and 2.05, respectively. Event-free survival was significantly different between the low and high BP variability groups (P = .006 for both daytime and night-time BP). However, after adjustment for other covariates in a Cox multivariate analysis, the adverse prognostic relevance of high BP variability was no longer detectable, whereas age, smoking habit, LDL cholesterol, diabetes, previous events, LV hypertrophy, and daytime or night-time systolic BP resulted independent predictors of risk. CONCLUSIONS: Increased BP variability is associated with higher incidence of cardiovascular events, but also with other relevant prognostic factors. Indeed, in multivariate analysis the possible adverse prognostic impact of BP variability is no longer evident. Thus, in treated hypertension, BP variability evaluated by noninvasive monitoring is not an independent predictor of outcome.

Aged↗
PubMed2006

Cardiovascular risk in patients receiving double therapy with false and true nonresponder hypertension.

OBJECTIVE: The aim of this study was to evaluate cardiovascular risk in hypertensive patients receiving double therapy with false and true nonresponder hypertension. METHODS: The occurrence of fatal and nonfatal cardiovascular events was evaluated in 730 patients receiving double therapy with uncontrolled clinic blood pressure. Two hundred and seventy had false nonresponder hypertension (clinic blood pressure > or =140 or 90 mmHg and daytime blood pressure <135/85 mmHg) and 460 had true nonresponder hypertension (clinic blood pressure > or =140 or 90 mmHg and daytime blood pressure > or =135 or 85 mmHg). RESULTS: During the follow-up (4.77+/-2.9 years, range 0.2-11.7 years), 55 cardiovascular events occurred. The event rates per 100 patient-years in patients with false and true nonresponder hypertension were 1.03 and 1.9, respectively. Event-free survival was significantly different between the groups (P<0.05). After adjustment for several covariates, including clinic blood pressure (forced into the model), Cox regression analysis showed that cardiovascular risk was significantly higher in true than in false nonresponder hypertension (relative risk 2.33, 95% confidence interval 1.14-4.77, P=0.02). CONCLUSIONS: This study shows that, among treated hypertensive patients receiving double therapy with uncontrolled clinic blood pressure those with true nonresponder hypertension are at higher cardiovascular risk. Ambulatory blood pressure monitoring should be performed in this population to achieve a better prognostic stratification.

Aged↗
PubMed2006

Role of angiotensin II receptor blockers in atherosclerotic plaque stability.

Several clinical trials have shown that agents blocking the renin-angiotensin system reduce the incidence of acute ischaemic events. This effect was independent from blood pressure reduction and was presumably related to plaque stabilisation. With the aim of investigating potential mechanisms underlying this effect, carotid plaques were analysed in a recent study from patients randomised to treatment with the angiotensin receptor blocker irbesartan, or the diuretic chlorthalidone for 4 months before carotid endarterectomy. It was found that irbesartan decreased inflammatory infiltration, increased collagen content and downregulated prostaglandin E2-dependent metalloproteases as a consequence of suppression of inducible COX-2/prostaglandin E synthase. This article reviews the results of this study and the most recent evidence that supports the possibility that angiotensin II receptor blockers represent a novel therapy for plaque stabilisation.

Angiotensin II↗
PubMed2005

Thromboxane-dependent CD40 ligand release in type 2 diabetes mellitus.

OBJECTIVES: The goals of this study were to characterize the platelet contribution to soluble CD40 ligand (sCD40L), to correlate its formation with the extent of oxidative stress and platelet activation, and to investigate the effects of improved metabolic control and low-dose aspirin on these processes. BACKGROUND: Inflammation, oxidative stress, and platelet activation are involved in the pathogenesis of type 2 diabetes (T2DM) and its complications. The CD40-CD40L interactions result in inflammatory and pro-thrombotic responses. METHODS: Urinary 8-iso-prostaglandin (PG)F2alpha and 11-dehydro-thromboxane (TX)B2, in vivo markers of oxidative stress and platelet activation, respectively, plasma CD40L, and C-reactive protein (CRP) were measured in 114 T2DM patients and 114 control patients. A randomized, parallel group, 17-day study of aspirin (30, 100, or 325 mg/day) was performed in 18 T2DM patients. A similar study was performed in six healthy volunteers (aspirin, 100 mg/day). Twenty poorly controlled T2DM patients were studied before and after improved metabolic control. RESULTS: Compared with control patients, diabetic patients showed significantly higher levels of 8-iso-PGF2alpha, 11-dehydro-TXB2, sCD40L, and CRP. On multiple regression analysis, 11-dehydro-TXB2 and 8-iso-PGF2alpha excretion rates predicted sCD40L levels. Soluble CD40L linearly correlated with 11-dehydro-TXB2 (rho = 0.67, p < 0.0001), and both were reduced after one week of aspirin (p < 0.0026), with slow recovery over 10 days after aspirin withdrawal. Improved metabolic control was associated with a reduction in sCD40L, 8-iso-PGF2alpha, and 11-dehydro-TXB2. CONCLUSIONS: This study provides several lines of evidence for the dependence of sCD40L release on TXA(2)-dependent platelet activation in T2DM and provides novel mechanistic insight into the amplification loops of persistent platelet activation in this setting.

Aged↗
PubMed2005

Association between prostaglandin E receptor subtype EP4 overexpression and unstable phenotype in atherosclerotic plaques in human.

OBJECTIVE: We recently demonstrated that inducible cyclooxygenase/PGE synthase-1 (COX-2/mPGES-1) are overexpressed in symptomatic plaques in association with PGE2-dependent metalloproteinase (matrix metalloproteinase [MMP]) biosynthesis and plaque rupture. However, it is not known which of the 4 PGE2 receptors (EP1-4) mediates macrophage metalloproteinase generation. The aim of this study was to characterize EP1-4 expression in plaques from symptomatic and asymptomatic patients undergoing carotid endarterectomy and correlate it with the extent of inflammatory infiltration, COX-2/mPGES-1 and MMP expression and clinical features of patients' presentation. METHODS AND RESULTS: Plaques were analyzed for COX-2, mPGES-1, EP1-4, MMP-2, and MMP-9 by immunohistochemistry, reverse-transcription polymerase chain reaction and Western blot; zymography was used to detect MMP activity. We observed strong EP4 immunoreactivity, only very weak staining for EP2, and no expression of EP1 and EP3 in atherosclerotic plaques. EP4 was more abundant in MMP-rich symptomatic lesions, whereas EP2 was no different between symptomatic and asymptomatic plaques. Finally, MMP induction by PGE2 in vitro was inhibited by the EP4 antagonist L-161 982, but not by its inactive analog L-161 983 or by the EP2 antagonist AH6809. CONCLUSIONS: This study shows that EP4 overexpression is associated with enhanced inflammatory reaction in atherosclerotic plaques. This effect might contribute to plaque destabilization by inducing culprit metalloproteinase expression.

Aged↗
PubMed2005

Association between 5-lipoxygenase expression and plaque instability in humans.

OBJECTIVE: The participation of 5-lipoxygenase (5-LO) in the development of atherosclerosis has been suggested by recent studies. However, a role for 5-LO as a modulator of atherosclerotic plaque instability has not been previously reported in humans. Thus, the aims of this study was to analyze the expression of 5-LO in human carotid plaques and to investigate the mechanism by which this enzyme could lead to plaque instability and rupture. METHODS AND RESULTS: We obtained atherosclerotic plaques from 60 patients undergoing carotid endarterectomy. We divided the plaques into symptomatic and symptomatic according to clinical evidence of plaque instability. Clinical evidence of plaque instability was provided by the assessment of recent ischemic symptoms attributable to the stenosis and by the presence of ipsilateral cerebral lesion(s) determined by computed tomography. Plaques were analyzed for CD68+ macrophages, CD3+ T cells, alpha-actin+ smooth muscle cells, 5-LO, cyclooxygenase 2, matrix metalloproteinase (MMP)-2, and MMP-9 by immunohistochemical, immunoblotting, and densitometric analyses. MMP activity was assessed by zymography. Leukotriene (LT) B4 and collagen were quantified by ELISA and Sirius red polarization, respectively. The percentage of macrophage-rich and T-cell-rich areas was larger in symptomatic compared with asymptomatic patients (25+/-6% versus 8+/-4%, P<0.0001, and 74+/-17 versus 18+/-4 cell/mm2, P<0.003). 5-LO expression was higher in symptomatic compared with asymptomatic plaques (24+/-4% versus 6+/-3%, P<0.0001) and was associated with increased MMP-2 and MMP-9 expression (27+/-4% versus 7+/-3%, P<0.0001, and 29+/-5% versus 8+/-2%, P<0.0001) and activity and with decreased collagen content (6.9+/-2.4% versus 17.8+/-3.1%, P<0.01). Immunofluorescence showed that 5-LO and MMPs colocalize in activated macrophages. Notably, higher 5-LO in symptomatic plaques correlated with increased LTB4 production (18.15+/-3.56 versus 11.27+/-3.04 ng/g tissue, P<0.0001). CONCLUSIONS: The expression of 5-LO is elevated in symptomatic compared with asymptomatic plaques and is associated with acute ischemic syndromes, possibly through the generation of LTB4, subsequent MMP biosynthesis, and plaque rupture.

Acute Disease↗
PubMed2005

Int6 expression can predict survival in early-stage non-small cell lung cancer patients.

PURPOSE: The Int6 gene was originally identified as a common insertion site for the mouse mammary tumor virus in virally induced mouse mammary tumors. Recent studies indicate that Int6 is a multifaceted protein involved in the regulation of protein translation and degradation through binding with three complexes: the eukaryotic translation initiation factor 3, the proteasome regulatory lid, and the constitutive photomorphogenesis 9 signalosome. This study aimed to investigate the prognostic role of Int6 in a large series of stage I non-small cell lung cancers (NSCLC) patients with long-term follow-up. EXPERIMENTAL DESIGN: We determined the methylation status of Int6 DNA by methylation-specific PCR and the steady-state levels of Int6 RNA by quantitative real-time reverse transcription-PCR in 101 NSCLCs and matched normal lung tissues. RESULTS: In 27% of the tumors, Int6 RNA levels were reduced relative to normal tissue. In 85% of the tumors with reduced Int6 expression, the transcription promoter and first exon were hypermethylated, whereas only 4% of the tumors with elevated Int6 RNA levels were hypermethylated (P <0.000001). Low levels of Int6 RNA were found a significant predictor of overall and disease-free survival (P=0.0004 and P=0.0020, respectively). A multivariate analysis confirmed that low Int6 expression was the only independent factor to predict poor prognosis, for both overall (P=0.0006) and disease-free (P=0.024) survival. CONCLUSIONS: Our results suggest that Int6 expression, evaluated by quantitative real-time PCR, may represent a new prognostic factor in patients with stage I NSCLC.

Adult↗
PubMed2005

EGFR mutations in non-small-cell lung cancer: analysis of a large series of cases and development of a rapid and sensitive method for diagnostic screening with potential implications on pharmacologic treatment.

PURPOSE: It has been reported that EGFR mutations in lung carcinomas make the disease more responsive to treatment with tyrosine kinase inhibitors. We decided to evaluate the prevalence of EGFR mutations in a large series of non-small-cell lung carcinomas (NSCLCs) and to develop a rapid and sensitive screening method. PATIENTS AND METHODS We examined 860 consecutive NSCLC patients for EGFR mutations in exons 18, 19, and 21 using a dual technical approach--direct sequencing of polymerase chain reaction (PCR) products and PCR single-strand conformation polymorphism (SSCP) analysis. Moreover, all lung adenocarcinomas were analyzed for K-ras mutations at codon 12 by allele-specific oligoprobe hybriditations. RESULTS: There were no EGFR mutations in 454 squamous carcinomas and 31 large cell carcinomas investigated. Thirty-nine mutations were found in the series of 375 adenocarcinomas (10%). Mutations were present in 26% of 86 bronchioloalveolar carcinomas (BACs) and in 6% of 289 conventional lung adenocarcinomas; P = .000002. EGFR mutations and K-ras mutations were mutually exclusive. A multivariable analysis revealed that BAC histotype, being a never smoker, and female sex were independently associated with EGFR mutations (odds ratios: 4.542, 3.632, and 2.895, respectively). The SSCP analysis was accurate and sensitive, allowing identification of mutations that were undetectable (21% of cases) by direct sequencing. CONCLUSION: Mutations in the EGFR tyrosine kinase domain define a new molecular type of lung carcinoma, more frequent in particular subsets of patients. The SSCP assay is a rapid and reliable method for the detection of EGFR kinase domain mutations in lung cancer.

Adenocarcinoma↗
PubMed2005

Blood pressure variability and prognosis in uncomplicated mild hypertension.

BACKGROUND: The independent prognostic value of blood pressure (BP) variability in essential hypertension and particularly in uncomplicated mild hypertension is not yet completely clear. We investigated the relationship between BP variability, evaluated by noninvasive monitoring, and cardiovascular outcome in uncomplicated mild hypertension patients. METHODS: The occurrence of fatal and nonfatal cardiovascular events was evaluated in 1088 uncomplicated mild hypertension patients, 626 with low BP variability (SD of daytime systolic BP below the mean of the study population) and 462 with high BP variability (SD of daytime systolic BP above the mean of the study population). RESULTS: During the follow-up (4.74 +/- 2.4 years, range 0.5-9.7 years), the event rates per 100 patient-years in subjects with low and high BP variability were 0.72 and 1.5, respectively. Event-free survival was significantly different between the groups (P = .01). However, after adjustment for other covariates in a Cox multivariate analysis, the adverse prognostic relevance of high BP variability was no longer detectable, whereas age, daytime systolic BP, low-density lipoprotein cholesterol, and smoking habit resulted as independent predictors of cardiovascular events. CONCLUSIONS: In uncomplicated mild hypertension population, BP variability evaluated by noninvasive monitoring is not an independent predictor of outcome.

Blood Pressure↗
PubMed2005

Cardiovascular outcome in treated hypertensive patients with responder, masked, false resistant, and true resistant hypertension.

BACKGROUND: The aim of this study was to evaluate the cardiovascular outcome in apparently responder hypertensive patients with responder and masked hypertension, and in apparently resistant hypertensive patients with false and true resistant hypertension. METHODS: The occurrence of fatal and nonfatal cardiovascular events was evaluated in 340 patients with responder hypertension (clinic blood pressure [BP] <140/90 mm Hg and daytime BP <135/85 mm Hg), 126 with masked hypertension (clinic BP <140/90 mm Hg and daytime BP >135 or 85 mm Hg), 146 with false resistant hypertension (clinic BP >or=140 or 90 mm Hg and daytime BP <135/85 mm Hg), and 130 with true resistant hypertension (clinic BP >or=140 or 90 mm Hg and daytime BP >135 or 85 mm Hg). RESULTS: During follow-up period (4.98 +/- 2.9 years), the event-rate per 100 patient-years was 0.87, 2.42, 1.2, and 4.1 in patients with responder, masked, false resistant, and true resistant hypertension, respectively. After adjustment for several covariates, including clinic BP (forced into the model), Cox regression analysis showed that cardiovascular risk was significantly higher in masked hypertension (masked versus responder hypertension, relative risk [RR] 2.28, 95% confidence interval [CI] 1.1-4.7, P < .05) and in true resistant hypertension (true resistant versus responder hypertension, RR 2.94, 95% CI 1.02-8.41, P < .05), whereas there was no significant difference between false resistant and responder hypertension. CONCLUSIONS: This study shows that patients with masked hypertension are at higher risk than those with responder hypertension, and that those with false resistant hypertension are at lower risk than those with true resistant hypertension. Ambulatory BP monitoring should be performed in treated hypertensive patients to obtain a better prognostic stratification.

Aged↗
PubMed2005

Effects of irbesartan on intracellular antioxidant enzyme expression and activity in adolescents and young adults with early diabetic angiopathy.

OBJECTIVE: Defective intracellular antioxidant enzyme production (IAP) has been demonstrated in adults with diabetic nephropathy. The objective of this study was to evaluate the effects of irbesartan, an angiotensin II receptor antagonist, on IAP in adolescents and young adults with type 1 diabetes and early signs of retinopathy and nephropathy. RESEARCH DESIGN AND METHODS: This prospective, matched case-control study was conducted between November 2001 and December 2002 among 14 type 1 diabetic patients with early signs of angiopathy (ages 14-21 years), 11 type 1 diabetic patients without angiopathy (ages 12-22 years), and 10 healthy volunteers (ages 16-22 years). Skin fibroblasts were obtained by skin biopsies from the anterior part of the forearm and cultured in Dulbecco's modified Eagle's medium. The activity and mRNA expression of CuZn superoxide dismutase (CuZnSOD), Mn superoxide dismutase (MnSOD), catalase (CAT), and glutathione peroxidase (GPX) were measured before and after 6 months of treatment with irbesartan (150 mg/day); on both occasions, antioxidant enzyme activity was evaluated at different glucose concentrations (5 and 22 mmol/l). RESULTS: At a normal glucose concentration (5 mmol/l), the activity and mRNA expression of CuZnSOD (0.50 +/- 0.21 units/mg protein, 4.4 +/- 1.5 mRNA/glyceraldehyde-3-phosphate dehydrogenase), MnSOD (0.26 +/- 0.04 units/mg protein, 0.08 +/- 0.07 mRNA), CAT (0.32 +/- 0.08 units/mg protein, 4.8 +/- 1.3 mRNA), and GPX (0.53 +/- 0.09 units/mg protein, 2.2 +/- 0.9 mRNA) were not different among the three groups (only values of diabetic subjects with angiopathy are shown). At high glucose concentrations, the activity and mRNA expression of CuZnSOD increased similarly in all groups (diabetic subjects with angiopathy: 0.93 +/- 0.26 units/mg protein, 9.4 +/- 2.1 mRNA); that of CAT and GPX increased in only control subjects and diabetic subjects without angiopathy (diabetic subjects with angiopathy: 0.33 +/- 0.09 units/mg protein and 5.0 +/- 1.4 mRNA; 0.54 +/- 0.10 units/mg protein and 2.3 +/- 1.0 mRNA, respectively). MnSOD did not change in any group. Treatment with irbesartan in adolescents with diabetic angiopathy was able to restore CAT and GPX activity and mRNA expression after exposure to high glucose concentrations. Markers of oxidative stress (serum malondialdehyde, fluorescent products of lipid peroxidation, monocyte chemoattractant protein-1, and 8-isoprostanes prostaglandin F(2alpha)) were significantly reduced after treatment with irbesartan. CONCLUSIONS: Adolescents and young adults with early signs of diabetic angiopathy have defective intracellular antioxidant enzyme production and activity. Treatment with irbesartan can substantially improve the activity and production of these enzymes in skin fibroblasts.

Adolescent↗
PubMed2004

Effects of vitamin E supplementation on intracellular antioxidant enzyme production in adolescents with type 1 diabetes and early microangiopathy.

Defective intracellular antioxidant enzyme production (IAP) has been demonstrated in adults with diabetic nephropathy. To evaluate the effects on IAP of vitamin E administration in adolescents with type 1 diabetes and early signs of microangiopathy, 12 adolescents (aged 11-21 y; diabetes duration 10-18) were studied. Eight had retinopathy [background (four), preproliferative (three), or proliferative (one)], four had persistent microalbuminuria, and seven had both. Skin fibroblasts were obtained by biopsies and cultured in Dulbecco's modified Eagle's medium. CuZn superoxide dismutase (SOD), MnSOD, catalase (CAT), and glutathione-peroxidase (GPX) activity and mRNA expression were measured before and after 3 mo of synthetic vitamin E supplementation (600 mg twice daily); on both occasions, IAP was evaluated at different ex vivo glucose concentrations (5 and 22 mM). Ten adolescents with type 1 diabetes (aged 12-20 y) without angiopathy and eight healthy volunteers (aged 15-22 y) participated as control subjects. Vitamin E serum levels were measured throughout the study. In normal glucose concentrations, CuZnSOD, MnSOD, CAT, and GPX activity and mRNA expression were not different among the groups. In high glucose, CuZnSOD activity and mRNA increased similarly in all groups [angiopathics: 0.96 +/- 0.30 U/mg protein; 9.9 +/- 3.2 mRNA/glyceraldehyde-3-phosphate dehydrogenase). CAT and GPX activity and mRNA did not increase in high glucose only in adolescents with angiopathy (0.35 +/- 0.09; 4.2 +/- 0.1 and 0.52 +/- 0.14; 2.4 +/- 0.9, respectively). MnSOD did not change in any group. Vitamin E supplementation had no effect on any enzymatic activity and mRNA in both normal and hyperglycemic conditions. Adolescents with early signs of diabetic angiopathy have defective IAP and activity, which are not modified by vitamin E.

Adolescent↗