The obesity paradox: is it really a paradox? Hypertension.

This article is a narrative overview of the role of hypertension on the relationships between obesity, morbidity, and mortality. We used as sources MEDLINE/PubMed, CINAHL, EMBASE, and Cochrane Library, from inception to March 2016. Key words include overweight, obesity, visceral obesity, obesity paradox, and hypertension. In addition, we hand-searched references from the retrieved articles. This work is one of the works of the topical collection "Obesity Paradox". The positive association between overweight, obesity, and cardiovascular diseases is well established, though this relation is typically U shaped with an increased risk in low-weight subjects or even a beneficial effect of overweight and obesity, the so-called "obesity paradox". In addition, the relationship between obesity and arterial hypertension has been demonstrated in both children and adults by many epidemiological studies. Moreover, weight reduction is followed by a decrease in blood pressure in many patients and ameliorates the cardiovascular risk profile. Recent studies using more appropriate obesity indices raise some doubt about the real significance of obesity paradox and there are several studies that central obesity shows either no protective or even a worse effect. These observations raise the question: what kind of obesity is protective and what kind of obesity is harmful? The studies of obesity paradox suffer from several methodological limitations: most of these are retrospective analyses or were not specifically designed to study obesity paradox as a primary goal; a few studies have data on preceding unintentional weight loss and on some particular confounding variables. In conclusion, more prospective and accurate studies are necessary to better elucidate the clinical importance of obesity paradox. When weight loss is functional to reduce hypertension and cardiovascular risk, it should be encouraged, while an unintentional weight in a patient with chronic diseases may indicate an unfavorable course.

Increased protein nitration in mitochondrial diseases: evidence for vessel wall involvement.

Mitochondrial diseases (MD) are heterogeneous disorders because of impairment of respiratory chain function leading to oxidative stress. We hypothesized that in MD the vascular endothelium may be affected by increased oxidative/nitrative stress causing a reduction of nitric oxide availability. We therefore, investigated the pathobiology of vasculature in MD patients by assaying the presence of 3-nitrotyrosine in muscle biopsies followed by the proteomic identification of proteins which undergo tyrosine nitration. We then measured the flow-mediated vasodilatation as a proof of altered nitric oxide generation/bioactivity. Here, we show that 3-nitrotyrosine staining is specifically located in the small vessels of muscle tissue and that the reaction is stronger and more evident in a significant percentage of vessels from MD patients as compared with controls. Eleven specific proteins which are nitrated under pathological conditions were identified; most of them are involved in energy metabolism and are located mainly in mitochondria. In MD patients the flow-mediated vasodilatation was reduced whereas baseline arterial diameters, blood flow velocity and endothelium-independent vasodilatation were similar to controls. The present results provide evidence that in MD the vessel wall is a target of increased oxidative/nitrative stress.

Endothelial dysfunction and increased oxidative stress in mitochondrial diseases.

MDs (mitochondrial diseases) are a clinically heterogeneous group of disorders characterized by impairment of the respiratory chain function with altered oxidative phosphorylation. We tested the hypothesis that the function of vascular endothelium is affected by increased oxidative stress in MDs. A total of 12 patients with MDs and pair-matched controls were studied. Endothelial function was assessed by measuring FMD (flow-mediated vasodilation) of brachial and common femoral arteries. The test was repeated after vitamin C (500 mg, twice a day) and E (400 mg, once a day) supplementation for 30 days and 90 days after vitamin withdrawal. FMD was reduced in patients compared with controls [AUC/τ (time-averaged area under the curve) for the brachial artery, 1.05±0.24 compared with 4.19±0.59% respectively, P<0.001; AUC/τ for the femoral artery, 0.98±0.19 compared with 2.36±0.29% respectively, P=0.001; values are means±S.E.M.] and correlated (brachial artery) with plasma lactate (r=-0.63, P<0.01). Urinary 8-iso-PGF2α (8-iso-prostaglandin F2α) was higher in patients than controls (505.6±85.9 compared with 302.5±38.7 pg/mg of creatinine; P<0.05) and correlated with plasma lactate (r=0.70, P<0.05). Immunohistochemical analysis showed 8-iso-PGF2α staining in MD-affected striated muscle cells and in blood vessels in muscle biopsies of patients. Antioxidant vitamins transiently restored FMD in patients [ΔAUC/τ (change in AUC/τ) for the brachial artery, +1.38±0.49%, P<0.05; ΔAUC/τ for the femoral artery, +0.98±0.24%, P<0.01] but had no effect on FMD in controls (brachial artery, -1.3±0.63%; and common femoral artery, -0.58±0.30%), thus abolishing the differences between patients and controls. The results of the present study indicate that oxidative stress is increased and is, at least partly, responsible for endothelial dysfunction in MDs.

Prevention of medication errors: detection and audit.

1. Medication errors have important implications for patient safety, and their identification is a main target in improving clinical practice errors, in order to prevent adverse events. 2. Error detection is the first crucial step. Approaches to this are likely to be different in research and routine care, and the most suitable must be chosen according to the setting. 3. The major methods for detecting medication errors and associated adverse drug-related events are chart review, computerized monitoring, administrative databases, and claims data, using direct observation, incident reporting, and patient monitoring. All of these methods have both advantages and limitations. 4. Reporting discloses medication errors, can trigger warnings, and encourages the diffusion of a culture of safe practice. Combining and comparing data from various and encourages the diffusion of a culture of safe practice sources increases the reliability of the system. 5. Error prevention can be planned by means of retroactive and proactive tools, such as audit and Failure Mode, Effect, and Criticality Analysis (FMECA). Audit is also an educational activity, which promotes high-quality care; it should be carried out regularly. In an audit cycle we can compare what is actually done against reference standards and put in place corrective actions to improve the performances of individuals and systems. 6. Patient safety must be the first aim in every setting, in order to build safer systems, learning from errors and reducing the human and fiscal costs.

Opportunistic Screening for Atrial Fibrillation in the Pharmacies: A Population-Based Cross-Sectional Study.

INTRODUCTION: Opportunistic screening of atrial fibrillation is a valuable approach to the identification of subjects with unknown or non-symptomatic atrial fibrillation (AF) with the potential of reducing the burden of ischemic stroke in the population. AIM: To evaluate the feasibility of a large-scale screening for atrial fibrillation using a blood pressure monitor (MicrolifeAFIB) endowed with a validated algorithm able to detect AF calculating the irregularity of interval times between heartbeats. METHODS: In this cross-sectional study conducted in 74 pharmacies in Verona participated 3071 people aged 50 years or more. In 6 months, information about drugs, previous diagnoses of cardiovascular diseases, anthropometric and demographic data was recorded, together with the measurement of blood pressure and cardiac rhythm by using the MicrolifeAFIB device. Pharmacists also collected anthropometric and demographic data of the participants, along with information concerning their personal history of cardiovascular disease and the use of antihypertensive and antithrombotic agents. All those who were positive at the screening for atrial fibrillation were referred to their family doctor. RESULTS: The screening revealed 98 subjects (3.2%) positive for AF; 44 of these reported a previous diagnosis of AF and were treated with anticoagulants (77%) or with antiplatelet agents (7%). By logistic regression analysis, age, male sex and heart failure were independently associated with positivity for AF. Association between positive test and previous stroke/TIA was found in the 54 subjects without a previous diagnosis of AF (9% had a previous stroke/TIA). CONCLUSIONS: Opportunistic screening for atrial fibrillation in the pharmacies is feasible and allows to identify a number of subjects with silent, non-previously diagnosed AF, therefore is potentially useful in large-scale projects aimed at the prevention of cardiovascular morbidity and mortality.

Forearm haemodynamics, arterial stiffness and microcirculatory reactivity in rheumatoid arthritis.

OBJECTIVES: Cardiovascular disease is the major cause of mortality in patients with rheumatoid arthritis. This work studied the presence of impaired forearm haemodynamics, arterial stiffness and microcirculatory reactivity in young women with rheumatoid arthritis. METHODS: Sixty-five women aged 41-52 years, with rheumatoid arthritis, were screened for the absence of common cardiovascular risk factors. They underwent laser Doppler study on the hand at rest and after ischaemia, endothelium-dependent dilation with colour Doppler ultrasound and pulsewave velocity (PWV). Forty healthy subjects were also examined. RESULTS: Microcirculatory flux at rest with laser Doppler was reduced in rheumatoid arthritis patients (112 +/- 45 versus 220 +/- 65 perfusion units (PU, arbitrary units); P < 0.005), post-ischaemic peak flow was lower in rheumatoid arthritis patients (235 +/- 65 versus 329 +/- 76 PU; P < 0.05); percentage increase in peak flow was higher in rheumatoid arthritis patients compared with healthy subjects (153 +/- 12 versus 65 +/- 18%; P < 0.005). Time to peak flow was longer in rheumatoid arthritis patients (12.7 +/- 8 versus 6.2 +/- 2 s; P < 0.005). Higher microcirculatory resistance was detected in rheumatoid arthritis patients (0.656 +/- 0.011 versus 0.358 +/- 0.009 mmHg/PU; P < 0.05). Endothelium-dependent dilation was impaired in rheumatoid arthritis patients (increase in artery dilation 8.2 +/- 2 versus 11.5 +/- 3%; P < 0.05) and correlated directly with actual C-reactive protein. PWV was higher in rheumatoid arthritis patients (9.3 +/- 0.2 versus 8.4 +/- 0.4 m/s; P < 0.05) and correlated directly with the duration of disease. District resistance by the arm was higher in rheumatoid arthritis patients (1098 +/- 190 versus 661 +/- 55 mmHg/l per minute; P < 0.005). CONCLUSION: Female rheumatoid arthritis patients present with impaired microcirculatory reactivity, endothelial dysfunction and increased arterial stiffness. Alterations in the vascular bed are extended and may explain the increased incidence of cardiovascular events in these patients.

Endothelial progenitor cells in patients with essential hypertension.

OBJECTIVE(S): The eventual role of blood pressure on the endothelial progenitor cell (EPC) has rarely been evaluated and data collected so far relate to patients with co-existing coronary heart disease. METHODS: We have studied the number and functional activity of EPC as well as the number of EPC endothelial colony-forming units (CFU) in a carefully selected group of 36 patients with essential hypertension and 24 normotensive control subjects. RESULTS: In patients with essential hypertension, the EPC number was not statistically different from that found in control subjects (mean +/- SD, essential hypertension 58 +/- 29, controls 53 +/- 20; EPC/high power field). CFU per well were not statistically different in patients with essential hypertension compared with normotensive controls (mean +/- SD, patients with essential hypertension 2.4 +/- 2.6, normotensive controls 3 +/- 3.3 CFU/well). In essential hypertension patients, the EPC number was inversely correlated with both total (R=0.635, P < 0.0001) and low-density lipoprotein (LDL)-cholesterol (R=0.486, P < 0.05). Neither the EPC number nor the EPC CFU were correlated with age, systolic blood pressure, diastolic blood pressure, body mass index, lipoprotein(a), high-sensitivity C-reactive protein or homocysteine. CONCLUSIONS: The present study shows that essential hypertension is not characterized by the altered number or functional activity of EPC. Plasma total and LDL-cholesterol are independent predictors of reduced numbers of circulating EPC in essential hypertension patients. The absence of any correlation between the characteristics of EPC and several markers predictive of cardiovascular damage merits further investigation.

Patients in long-term maintenance therapy for drug use in Italy: analysis of some parameters of social integration and serological status for infectious diseases in a cohort of 1091 patients.

BACKGROUND: Heroin addiction often severely disrupts normal social functioning. The aims of this multi-centre study of heroin users in long-term replacement treatment were: i) to provide information on aspects of social condition such as employment, educational background, living status, partner status and any history of drug addiction for partners, comparing these data with that of the general population; ii) to assess the prevalence of hepatitis, syphilis and HIV, because serological status could be a reflection of the social conditions of patients undergoing replacement treatment for drug addiction; iii) to analyse possible relationships between social conditions and serological status. METHODS: A cross-sectional study was carried out in sixteen National Health Service Drug Addiction Units in northern Italy. The data were collected from February 1, 2002 to August 31, 2002. Recruitment eligibility was: maintenance treatment with methadone or buprenorphine, treatment for the previous six months, and at least 18 years of age. In the centres involved in the study no specific criteria or regulations were established concerning the duration of replacement therapy. Participants underwent a face-to-face interview. RESULTS: The conditions of 1091 drug treatment patients were evaluated. The mean duration of drug use was 14.5 years. Duration was shorter in females, in subjects with a higher educational background, and in stable relationships. Most (68%) had completed middle school (11-14 years of age). Seventy-nine percent were employed and 16% were unemployed. Fifty percent lived with their parents, 34% with a partner and 14% alone. Males lived more frequently with their parents (55%), and females more frequently with a partner (60%). Sixty-seven percent of male patients with a stable relationship had a partner who had never used heroin. HCV prevalence was 72%, HBV antibodies were detected in 42% of patients, while 30% had been vaccinated; 12.5% of subjects were HIV positive and 1.5% were positive for TPHA. CONCLUSION: A significant percentage of heroin users in treatment for opiate addiction in the cohort study have characteristics which indicate reasonable integration within broader society. We posit that the combination of effective treatment and a setting of economic prosperity may enhance the social integration of patients with a history of heroin use.

Lipid peroxidation, isoprostanes and vascular damage.

Increased lipid peroxidation has been identified as a key mechanism for the development of atherosclerosis and inflammatory vascular damage. Determination of plasma concentration and urinary excretion of some F(2)-isoprostanes (by immunometric assays or by mass-spectrometry), has been demonstrated to be a reliable approach to the assessment of lipid peroxidation, and therefore of oxidative stress in vivo . Several lines of evidence suggest that isoprostane generation may reflect oxidative stress in experimental and human atherosclerosis. Increased lipid peroxidation may precede the development of atherosclerosis. In fact, urinary excretion or plasma levels of an abundantly generated F(2)-isoprostane, 8-iso-PGF(2alpha) have been found to be more elevated in subject with cardiovascular risk factors than in healthy subjects. Some isoprostanes, in particular 8-iso-PGF(2alpha) have been demonstrated to have biological activities that may contribute to the progression of vascular damage inducing endothelial and platelet activation and being powerful vasocostrictors. Increased lipid proxidation may be implicated in the bioactivity of angiotensin II. Experimental data indicate that increased oxidative stress due to activation of NAD(P)H oxidase is an obligatory step in its pro-hypertensive and pro-atherosclerotic effects. Increased generation of F(2)-isoprostanes is observed in clinical and experimental conditions in which angiotensin II activity is increased. In conclusion, measurement of some F(2)-isoprostanes in biological liquids represents a reliable marker of oxidative stress in vivo. The potential contribution of these compounds to the pathophysiology of the vascular damage and atherosclerosis has not yet been defined.

Insulin causes endothelial dysfunction in humans: sites and mechanisms.

BACKGROUND: Insulin resistance is often accompanied by hyperinsulinemia and may predispose to atherosclerosis. Endothelium plays a central role in atherogenesis. The in vivo effects of hyperinsulinemia on endothelial function of large conduit arteries are unknown. METHODS AND RESULTS: Twenty-five healthy subjects were enrolled for study. In study A (n=9), subjects underwent both a time-control saline study and a euglycemic low-dose insulin (insulin approximately 110 pmol/L) clamp for 6 hours. Study B (n=5) was identical to study A except that the euglycemic clamp was performed at high physiological insulin concentrations (approximately 440 pmol/L). In study C (n=7), subjects underwent two 4-hour euglycemic insulin (approximately 110 pmol/L) clamps with and without the concomitant infusion of an antioxidant (vitamin C). In study D (n=4), two saline time-control studies were performed with and without the concomitant infusion of vitamin C. In all studies, both at baseline and throughout the experimental period, endothelium-dependent (flow-mediated) and endothelium-independent (nitroglycerin-induced) vasodilation was assessed in femoral and brachial arteries by echo Doppler. Both low (study A) and high physiological (study B) hyperinsulinemia abolished endothelium-dependent vasodilation, whereas endothelium-independent vasodilation was unaffected. Vitamin C fully restored insulin-impaired endothelial function without affecting endothelium-independent vasodilation (study C). Vitamin C had no effects on endothelium-dependent or endothelium-independent vasodilation during saline control studies (study D). CONCLUSIONS: Modest hyperinsulinemia, mimicking fasting hyperinsulinemia of insulin-resistant states, abrogates endothelium-dependent vasodilation in large conduit arteries, probably by increasing oxidant stress. These data may provide a novel pathophysiological basis to the epidemiological link between hyperinsulinemia/insulin-resistance and atherosclerosis in humans.

NCX-4016 (NO-aspirin) inhibits lipopolysaccharide-induced tissue factor expression in vivo: role of nitric oxide.

BACKGROUND: NCX-4016 is an acetylsalicylic acid (ASA) derivative containing a nitric oxide-releasing moiety. Compared with ASA, NCX-4016 has a broader spectrum of antithrombotic and antiinflammatory activities. We hypothesized that NCX-4016 might inhibit in vivo lipopolysaccharide (LPS)-induced expression of tissue factor (TF). METHODS AND RESULTS: Rats were administered 90 mg/kg NCX-4016 orally for 5 days. Placebo, 50 mg/kg ASA, and 80 mg/kg isosorbide-5-mononitrate (ISMN) were used in control groups. On day 5, rats were injected intraperitoneally with 100 microg/kg LPS and killed 6 hours later. The expression of TF in monocytes was measured by flow cytometry and Western blot analysis. Reverse transcriptase-polymerase chain reaction was performed to assess expression of TF and cyclooxygenase-2 (COX-2) genes. Plasma concentrations of interleukin-1beta and tumor necrosis factor-alpha were measured. Urine samples were collected to evaluate the excretion of the thromboxane metabolite 11-dehydro-thromboxane (TX)B2. Gastric mucosa was inspected. LPS injection was followed by synthesis TF and COX-2 mRNAs in circulating monocytes, which were blunted by NCX-4016 but not by ASA or ISMN. Both NCX-4016 and ISMN reduced TF expression on surface of circulating monocyte. LPS increased the excretion 11-dehydro-TXB2, and this was prevented by NCX-4016 and ASA. Unlike ASA, NCX-4016 reduced plasma interleukin-1beta and tumor necrosis factor-alpha. In addition, NCX-4016 almost completely prevented mucosal damage, whereas ASA increased the extension of gastric lesions in LPS-injected rats. CONCLUSIONS: NCX-4016 prevents monocyte TF expression; this is accompanied by inhibition of TX and cytokine biosynthesis. These additive effects of nitric oxide release and COX inhibition may help explain efficacy and tolerability of NCX-4016.

Beta2 integrin-dependent neutrophil adhesion induced by minimally modified low-density lipoproteins is mainly mediated by F2-isoprostanes.

BACKGROUND: Oxidation of LDL produces a series of biologically active, oxidized lipids. Among them, isoprostanes, and in particular iPF(2alpha)-III, seem to be crucial in mediating some of the key cellular events seen in myocardial ischemia-reperfusion injury. METHODS AND RESULTS: Minimally modified LDL (MM-LDL) triggers a dose-dependent, very rapid neutrophil adhesion to human fibrinogen. Rapid adhesion triggering correlates with degree of LDL oxidation and accumulation of isoprostanes. Isoprostanes accumulated in MM-LDL are major determinants of the proadhesive effect of oxidized LDL, as shown by experiments of receptor functional deletion. Moreover, evidence is provided of expression on human neutrophils of a biological active isoprostane receptor distinct from the classical thromboxane A2 receptor. CONCLUSIONS: These data suggest that isoprostanes are major contributors to the proadhesive effect induced by MM-LDL on neutrophils and provide additional evidence for the involvement of isoprostanes in the pathogenesis of myocardial ischemia/reperfusion injury.

Increased oxidative stress and platelet activation in patients with hypertension and renovascular disease.

BACKGROUND: Hypertensive patients with renovascular disease (RVD) may be exposed to increased oxidative stress, possibly related to activation of the renin-angiotensin system. METHODS AND RESULTS: We measured the urinary excretion of 8-iso-prostaglandin (PG) F2alpha and 11-dehydro-thromboxane (TX) B2 as indexes of in vivo lipid peroxidation and platelet activation, respectively, in 25 patients with RVD, 25 patients with essential hypertension, and 25 healthy subjects. Plasma renin activity in peripheral and renal veins, angiotensin II in renal veins, cholesterol, glucose, triglycerides, homocysteine, and antioxidant vitamins A, C, and E were also determined. Patients were also studied 6 months after a technically successful angioplasty of the stenotic renal arteries. Urinary 8-iso-PGF2alpha was significantly higher in patients with RVD (median, 305 pg/mg creatinine; range, 124 to 1224 pg/mg creatinine) than in patients with essential hypertension (median, 176 pg/mg creatinine; range, 48 to 384 pg/mg creatinine) or in healthy subjects (median, 123 pg/mg creatinine; range, 58 to 385 pg/mg creatinine). Urinary 11-dehydro-TXB2 was also significantly higher in RVD patients compared with healthy subjects. In RVD patients, urinary 8-iso-PGF2alpha correlated with 11-dehydro-TXB2 (r(s)=0.48; P<0.05) and renal vein renin (r(s)=0.67; P<0.005) and angiotensin II (r(s)=0.65; P=0.005) ratios. A reduction in 8-iso-PGF2alpha after angioplasty was observed in RVD patients with high baseline levels of lipid peroxidation. Changes in 8-iso-PGF2alpha were related to baseline lipid peroxidation (r(s)=-0.73; P<0.001), renal vein angiotensin II (r(s)=-0.70; P<0.01) and renin (r(s)=-0.63; P<0.05) ratios. CONCLUSIONS: Lipid peroxidation is markedly enhanced in hypertensive patients with RVD and is related to activation of the renin-angiotensin system. Moreover, persistent platelet activation triggered or amplified by bioactive isoprostanes may contribute to the progression of cardiovascular and renal damage in this setting.

Co-administration of nitric oxide-aspirin (NCX-4016) and aspirin prevents platelet and monocyte activation and protects against gastric damage induced by aspirin in humans.

OBJECTIVES: The goal of this study was to test the hypothesis that NCX-4016 may have broader anti-inflammatory and antithrombotic effects as well as better gastric tolerability than aspirin in humans. BACKGROUND: NCX-4016 is an aspirin derivative containing a nitric oxide-releasing moiety that prevents platelet activation and modulates tissue factor (TF) expression and cytokine release from lipopolysaccharide (LPS)-stimulated monocytes. METHODS: This was a blind-observer, placebo-controlled, parallel-group study in which 48 healthy subjects were randomized to receive NCX-4016 800 mg twice a day, NCX-4016 800 mg twice a day plus aspirin 325 mg, aspirin 325 mg, or placebo for 21 days. RESULTS: Similar to aspirin alone, NCX-4016 effectively inhibited platelet aggregation induced by 0.6 mmol/ arachidonic acid, clot-stimulated thromboxane (TX) B2 generation in whole blood, and urinary excretion of 11-dehydro-TXB2. Unlike aspirin alone, the administration of NCX-4016 significantly inhibited TF expression in monocytes stimulated ex vivo with 10 micromol/l LPS (determined by flow-cytometry analysis of TF on CD14 positive cells). NCX-4016 also inhibited the rapid TF expression induced in monocytes by a proteinase activated receptor agonist (thrombin receptor activator protein, 2 micromol/l) as well as LPS-induced expression of CD11b . Ex vivo, release of MCP-1 and interleukin-6 were significantly inhibited by NCX-4016, but not by aspirin. NCX-4016 was not associated with gastric damage, and significantly reduced gastric injury when co-administered with aspirin, although both drugs reduced gastric PGE2 production to the same extent. CONCLUSIONS: NCX-4016 is equally effective as aspirin in inhibiting cyclooxygenase activity. However, NCX-4016 causes less gastric damage and prevents monocyte activation. Larger multicenter trials are warranted to establish clinical efficacy and safety of NCX-4016.

Haemodynamic effects of eprosartan and valsartan in hypertensive patients during isometric and mental stress.

OBJECTIVE: To assess the effects of eprosartan and valsartan on the haemodynamics of forearm circulation in hypertensives undergoing isometric and mental stress. DESIGN AND METHODS: Thirty-six patients with essential stable hypertension underwent haemodynamic evaluations on the left arm: humeral flux and calibre by means of colour Doppler ultrasound, microcirculatory flux on the third finger of left hand by means of laser Doppler flowmetry, blood pressure and heart rate monitor. District resistance was calculated as the ratio between mean arterial pressure and blood flow, and microcirculatory conductance was calculated as the ratio between flux and the mean pressure. The evaluations were performed at rest, during handgrip and during mental stress. Patients were randomized to receive eprosartan (600 mg) or valsartan (160 mg); tests were repeated after 15 days of therapy. RESULTS: Both treatments reduced blood pressure (P<0.05) and peripheral resistance during tests. Eprosartan obtained a greater reduction in resistance during handgrip than valsartan. Laser Doppler flowmetry showed a significant decrease of flux only with mental stress. Laser Doppler flowmetry showed a reduction in conductance during both tests--this reduction was smaller with eprosartan during handgrip. None of the molecules affected the conductance during mental stress. While both were able to reduce microcirculatory decrease in conductance; in particular, eprosartan controlled this drop during handgrip better than valsartan. CONCLUSIONS: Angiotensin II receptor type 1 inhibition exerts protective effects during adrenergic and noradrenergic stress in hypertensives. Eprosartan is more efficacious than valsartan in controlling noradrenergic effects.

Dependence on zolpidem: two case reports of detoxification with flumazenil infusion.

Zolpidem is a hypnotic drug that is chemically distinct from benzodiazepines (BDZ). It has been suggested that it acts selectively on gamma-aminobutyric acid receptors. However, recent evidence has shown that the behavioural effects of zolpidem are generally similar to those of BDZs. Flumazenil is usually considered to be a BDZ antagonist. Nonetheless, in chronic BDZ users, it acts as a partial, bland agonist. We describe two cases of zolpidem dependence that were detoxified by the use of flumazenil infusion. BDZ dependence is usually treated with tapering of the medication. As an alternative, abrupt discontinuation of the medication and rapid detoxification using flumazenil has been used. Flumazenil may represent an alternative to detoxification treatment by employing a tapering approach, or by replacement therapy with BDZs with a long half-life, particularly where patients are hard to treat or have low compliance to treatment.

[Depression in patients with cardiovascular disease]. / La depressione nel paziente con patologia cardiovascolare.

Cardiovascular disease and depression, which is frequently encountered in developed countries, are unexpectedly linked and someway interdependent. Although it has been proven that major depression is a risk factor for cardiovascular disease, it is also true that cardiovascular disease may often cause depression. This article provides epidemiological data regarding this phenomenon and focuses on the mechanisms and causes that link these apparently unrelated pathologies. The diagnosis of depression and the difficulty in recognizing it as such are reviewed and several tests useful for this purpose are presented. Finally, the most common antidepressants particularly suitable for cardiac patients are examined along with any possible interactions between these drugs and those currently used for treatment of cardiovascular disease.

Factors associated with hepatitis C virus infection in injection and noninjection drug users in Italy.

We describe the prevalence of hepatitis C virus (HCV) infection among noninjection users of heroin in Italy and compare the prevalence of HCV infection among noninjection drug users (NIDUs) and injection drug users (IDUs). Multiple logistic regression analysis of data from NIDUs showed that hepatitis B virus (HBV) infection status was the only independent predictor of HCV seroprevalence. Among IDUs, the number of years of drug use and HBV and human immunodeficiency virus infection status were independent predictors of HCV seropositivity. We found an HCV infection prevalence of 20% among NIDUs. This rate was much lower than that for IDUs, who are 11 times more likely to have antibodies against HCV. The prevalence of HCV infection was much higher than that of HBV infection among the IDUs. In contrast, the prevalence of HBV infection was slightly higher than that of HCV infection among unvaccinated NIDUs. The prevalence of HCV infection among long-term IDUs approached true population saturation; among long-term NIDUs, however, it appeared to plateau at approximately 40%. Additional research on HCV infection among NIDUs is needed to develop a strategic prevention program for this patient subgroup.

Effects of nebivolol and atenolol on small arteries and microcirculatory endothelium-dependent dilation in hypertensive patients undergoing isometric stress.

OBJECTIVE: To examine the effects on small arteries and on the cutaneous microcirculatory system of nebivolol and atenolol in hypertensive patients. DESIGN: Twenty hypertensive patients were randomly assigned to receive nebivolol or atenolol in a single-blind, placebo-controlled cross-over study. Piezoelectric plethysmography on the third finger, laser Doppler on the third finger at rest and after iontophoretic administration of acetylcholine, and pressure-heart rate monitoring, were carried out both at rest and during handgrip. The tests were performed 45 min after 5 mg nebivolol or 100 mg atenolol administration, then repeated 2 days later with a placebo and, after a further 2 days, with atenolol or nebivolol again. RESULTS: Both atenolol and nebivolol reduced diastolic blood pressure values and heart rate, as well the increase of blood pressure and heart rate during handgrip. No change was recorded after placebo. Piezoelectric plethysmography showed a significant increase in the ratio between time to peak and total time (PT/TT), calculated on the sphygmic wave, during handgrip (0.295 0.005 versus 0.231 0.015, P<0.005). After nebivolol, a decrease was recorded in rest conditions (0.185 0.008 versus 0.231 0.015, P<0.005) with no statistically significant increase during handgrip, whereas atenolol showed an increase in the PT/TT ratio at rest, with a sustained response during handgrip. Laser Doppler showed an increased response to acetylcholine only after nebivolol. CONCLUSIONS: Nebivolol and atenolol significantly reduced diastolic blood pressure and heart rate, favourably modulating response to handgrip. Nebivolol improved small artery distensibility index. Endothelium-dependent cutaneous vasodilation after acetylcholine demonstrated a lack of response with atenolol whereas nebivolol favourably acts on endothelial function.

Acute hyperhomocysteinemia induces a reduction in arterial distensibility and compliance.

OBJECTIVE: The aim of the study was to evaluate the effects of acute hyperhomocysteinemia on distensibility and compliance of large peripheral arteries. Isoprostanes generation and antioxidant vitamins were used to assess the role of oxidative stress. DESIGN: A cross-over, double-blind study on distensibility (DC: distensibility coefficient) and compliance (CC: cross-sectional compliance) of common femoral and brachial arteries was performed in 12 healthy young male volunteers by means of a wall track system before and 4 h after a single oral methionine (100 mg/kg) or placebo administration. The effects of methionine load were investigated also after oral administration of vitamin C (1g/day) and vitamin E (800 mg/day) for 8 consecutive days. RESULTS: Oral methionine induced a significant increase in plasmatic levels of homocysteine. Distensibility and compliance of brachial and femoral arteries were significantly reduced after methionine load in comparison to placebo. This acute impairment of arterial wall mechanical properties was associated to endothelial dysfunction, since altered flow-dependent vasodilatation (P < 0.05 versus placebo) was observed in the same arterial districts. A significant increase in urinary 8-iso-prostaglandin F2alpha was observed after methionine. Pretreatment with vitamins C and E prevented the effects of methionine on femoral and brachial arteries as well as on urinary 8-iso-prostaglandin F2alpha excretion. CONCLUSIONS: Hyperhomocysteinemia seems responsible for altered arterial wall elasticity and for endothelial dysfunction. A pivotal role can be attributed to oxidative stress.