Search

Background: Ritonavir-boosted nirmatrelvir (N/r) is an antiviral which targets the main viral protease, administered to prevent the progression of SARS-CoV-2 infection in patients at high risk for severe COVID-19. We present a real-life case-control study evaluating the efficacy of N/r therapy in SARS-CoV-2 omicron variants positive outpatients in Campania region, Italy, with the aim of assessing the occurrence of three outcomes (hospital admission, admission in ICU and death) in cases and controls., Methods: We enrolled SARS-CoV-2 positive subjects that came to our attention in Early antiviral treatment ambulatory of Infectious Diseases ward of University Federico II of Naples, Italy from January 1st, 2022, to December 31st, 2022, during the first five days from symptoms occurrence. Patients were enrolled as cases or controls if they were treated with N/r or not treated at all, respectively., Results: 1064 patients were included (cases: 423, controls: 1184). Cases showed a lower mortality compared with controls while no differences were observed for other outcomes. Vaccinated patients showed a lower mortality compared with non-vaccinated ones (0.5% vs. 7.8%, p < 0.001). After full-matching propensity score, N/r reduced hospitalization rate only in unvaccinated patients. In contrast N/r significantly reduced mortality regardless of vaccination status., Conclusions: Treatment with N/r has proven effective in reducing mortality among outpatients with SARS-CoV-2 infection during several omicron variant surges. The beneficial effect of N/r treatment in reducing progression is more pronounced in unvaccinated patients., Competing Interests: Declarations. Ethical approval and consent to participate: This study was approved by the ethics committee “Comitato Etico Università Federico II-A.O.R.N. A.Cardarelli” (protocol number 0015191, 22nd March 2023). The informed consent was collected for all patients included in the study. The informed consent from control patients was obtained via telephone interview. This method of consent collection was thoroughly reviewed by the ethics committee, ensuring that it met all ethical standards. The informed consent from case patients was written. The records of the telephonic interviews conducted with control participants, included their verbal informed consent, are stored by the study’s data manager at the Department of Clinical Medicine and Surgery, University of Naples Federico II, Via Sergio Pansini 5, 80131, Naples, Italy. These can be retrieved and reviewed upon request by any relevant authority. Consent for publication: Not applicable. Competing interests: Prof. IVAN GENTILE reports personal fees from MSD, AbbVie, Gilead, Pfizer, GSK, SOBI, Nordic/Infecto Pharm, Angelini and Abbott, as well as departmental grants from Gilead and support for attending a meeting from Janssen, outside the submitted work.All other authors have no competing interests to declare., (© 2024. The Author(s).)

Background: The independent prognostic significance of the metabolic syndrome (MetS) in the elderly is not yet clear. We investigated the association between MetS and cardiovascular risk (composite endpoint of stroke and coronary events) in elderly treated hypertensive patients., Methods: Cardiovascular outcome was evaluated in 1,191 elderly treated hypertensive patients (≥60 years). Among them, 578 (48.5%) had MetS according to a modified joint interim statement definition (body mass index in place of waist circumference)., Results: During the follow-up (9.1±4.9 years, range 0.4-20 years), 139 strokes and 120 coronary events occurred. In univariate analysis, patients with MetS had higher risk of the composite endpoint (hazard ratio (HR) 1.322, 95% confidence interval (CI) 1.035-1.688, P < 0.05). Among the single components of MetS, only blood pressure (BP) level and impaired fasting glucose/diabetes were significantly associated with increased cardiovascular risk. After adjustment for age, previous events, estimated glomerular filtration rate (eGFR), left ventricular (LV) hypertrophy and left atrial (LA) enlargement, the prognostic relevance of MetS was attenuated (HR 1.245, 95% CI 0.974-1.591, P = 0.08). After further adjustment for the above-mentioned variables and ambulatory BP parameters and impaired fasting glucose/diabetes, Cox regression analysis showed that MetS was not independently associated with increased cardiovascular risk (HR 1.090, 95% CI 0.805-1.475, P = 0.58)., Conclusions: In elderly treated hypertensive patients, MetS is associated with increased cardiovascular risk, but not independently of BP and glucose levels and of organ damage., (© American Journal of Hypertension, Ltd 2015. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: The independent prognostic significance of morning surge (MS) of blood pressure (BP) is not yet clear. We investigated the association between MS of systolic BP and risk of coronary events in elderly treated hypertensive patients., Methods: The occurrence of coronary events was evaluated in 1,191 elderly treated hypertensive patients (age range 60-90 years). Subjects were divided according to tertiles of MS of systolic BP of the population as a whole, by dipping status and by group-specific tertiles of MS of systolic BP in dippers and nondippers., Results: During the follow-up (9.1 ± 4.9 years, range 0.4-20 years), 120 coronary events occurred. In the population as a whole, coronary event risk was not significantly associated with tertiles of MS of systolic BP, whereas nondippers were at higher risk than dippers. When nondippers and dippers were analyzed separately, by group-specific tertiles of MS of systolic BP, coronary event risk was associated with MS of systolic BP in dippers but not in nondippers. After adjustment for various covariates, Cox regression analysis showed that dippers in the third tertile (>23 mm Hg) of MS of systolic BP (hazard ratio 1.912, 95% confidence interval 1.048-3.488, P = 0.03) and nondippers (hazard ratio 1.739, 95% confidence interval 1.074-2.815, P = 0.02) were at higher coronary event risk than dippers with MS of systolic BP <23 mm Hg ., Conclusions: In elderly treated hypertensive patients, high MS of systolic BP predicts coronary events in dippers but not in nondippers. Nondippers, however, show higher risk of coronary events independently of MS in systolic BP., (© American Journal of Hypertension, Ltd 2015. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Immunocompromised patients are at high risk of developing persisting/prolonged COVID-19. Data on the early combined use of antivirals and monoclonal antibodies in this population are scarce., Research Design and Methods: We performed an observational, prospective study, enrolling immunocompromised outpatients with mild-to-moderate COVID-19, treated with a combination of sotrovimab plus one antiviral (remdesivir or nirmatrelvir/ritonavir) within 7 days from symptom onset. Primary outcome was hospitalization within 30 days. Secondary outcomes were: needing for oxygen therapy; development of persistent infection; death within 60 days and reinfection or relapse within 90 days., Results: We enrolled 52 patients. No patient was hospitalized within 30 days of disease onset, required oxygen administration, died within 60 days, or experienced a reinfection or clinical relapse within 90 days.The clearance rates were 67% and 97% on the 14th day after the end of therapy and at the end of the follow-up period, respectively.Factors associated with longer infection were initiation of therapy 3 days after symptom onset and enrollment for more than 180 days from the beginning of the study. However, only the latter factor was independently associated with a longer SARS-CoV-2 infection, suggesting a loss of efficacy of this strategy with the evolution of SARS-CoV-2 variants., Conclusions: Early administration of combination therapy with a direct antiviral and sotrovimab seems to be effective in preventing hospitalization, progression to severe COVID-19, and development of prolonged/persisting SARS-CoV-2 infection in immunocompromised patients.

Objective: To investigate enzymatic reactive aldehyde-scavenging enzyme capacity together with lipid peroxidation as expression of oxidative stress in atherosclerotic plaques of cigarette smokers and nonsmokers., Methods: We have assessed specific enzymatic activities of class 1, 2, and 3 aldehyde dehydrogenase (ALDH1, ALDH2, and ALDH3, respectively), glutathione S-transferase (isozyme A4-4, GSTA4-4), and aldose reductase (AR), namely the major reactive aldehyde-scavenging enzymes, together with lipid peroxidation, i.e., fluorescent damage products of lipid peroxidation (FDPL), in carotid atherosclerotic plaques surgically removed from 17 cigarette smokers and 17 nonsmokers., Results: The enzymatic activities of ALDH1 plus ALDH2, ALDH3, GSTA4-4, and AR were significantly lower in the atherosclerotic plaques of smokers than in those of nonsmokers, while plaque FDPL levels were significantly higher in the smokers than in the nonsmokers. The amount of cigarette smoking was correlated inversely with the aforementioned plaque enzymatic activities and directly with plaque FDPL content. Plaque FDPL levels were inversely correlated with plaque enzymatic activities in smokers and nonsmokers. The degree of carotid atherosclerotic stenosis, as expression of atherosclerosis severity, was correlated inversely with plaque enzymatic activities and directly with plaque FDPL levels in smokers and nonsmokers; moreover, the degree of carotid stenosis was directly correlated with the amount of cigarette smoking., Conclusion: atherosclerotic lesions of cigarette smokers are endowed with a depressed enzymatic reactive aldehyde-scavenging capacity eventually favoring oxidative stress and the severity of atherosclerosis., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: The independent prognostic significance of left atrial enlargement is not yet completely clear. We investigated the association between left atrial enlargement and risk of ischemic stroke in elderly treated hypertensive patients., Methods: The occurrence of ischemic stroke was evaluated in 1,191 elderly treated hypertensive patients (age range = 60-90 years). Left atrium diameter (cm) was indexed by body surface area (m(2)) and subjects were divided into those with normal or enlarged (≥2.4cm/m(2)) left atrium., Results: During the follow-up (9.1±4.9 years; range = 0.4-20 years), 139 ischemic strokes occurred. The event rate per 100 patient-years was 1.28. There were 86 strokes in patients with normal (= 928) left atrium and 53 strokes in patients with enlarged (= 263) left atrium, respectively. Stroke-free survival curves were significantly different between the groups (P < 0.01). After adjustment for various covariables, including clinical variables, left ventricular hypertrophy, and ambulatory blood pressure parameters, Cox regression analysis showed that left atrial enlargement was significantly associated with increased risk of ischemic stroke (hazard ratio = 1.54; 95% confidence interval = 1.05-2.27; P = 0.03)., Conclusions: In elderly treated hypertensive patients, left atrial enlargement is an independent predictor of ischemic stroke., (© American Journal of Hypertension, Ltd 2014. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Introduction: Assessment of EGFR mutation in non-small cell lung cancer (NSCLC) patients is mandatory for optimization of pharmacologic treatment. In this respect, mutation analysis of circulating tumor cells (CTCs) may be desirable since they may provide real-time information on patient's disease status., Experimental Design: Blood samples were collected from 37 patients enrolled in the TRIGGER study, a prospective phase II multi-center trial of erlotinib treatment in advanced NSCLC patients with activating EGFR mutations in tumor tissue. 10 CTC preparations from breast cancer patients without EGFR mutations in their primary tumors and 12 blood samples from healthy subjects were analyzed as negative controls. CTC preparations, obtained by the Veridex CellSearch System, were subjected to ultra-deep next generation sequencing (NGS) on the Roche 454 GS junior platform., Results: CTCs fulfilling all Veridex criteria were present in 41% of the patients examined, ranging in number between 1 and 29. In addition to validated CTCs, potential neoplastic elements were seen in 33 cases. These included cells not fulfilling all Veridex criteria (also known as "suspicious objects") found in 5 (13%) of 37 cases, and isolated or clustered large naked nuclei with irregular shape observed in 33 (89%) cases. EGFR mutations were identified by NGS in CTC preparations of 31 (84%) patients, corresponding to those present in matching tumor tissue. Twenty-five (96%) of 26 deletions at exon 19 and 6 (55%) of 11 mutations at exon 21 were detectable (P = 0.005). In 4 (13%) cases, multiple EGFR mutations, suggesting CTC heterogeneity, were documented. No mutations were found in control samples., Conclusions: We report for the first time that the CellSearch System coupled with NGS is a very sensitive and specific diagnostic tool for EGFR mutation analysis in CTC preparations with potential clinical impact.

Short-term fat feeding could exert adverse cardiac effects by altering myocardial glutathione-related antioxidant defenses. We have here assessed total glutathione (TG), the activities of glutathione reductase (GSSG-Red), γ-glutamylcysteine synthetase (γ-GCS), γ-glutamyl transpeptidase (γ-GT) and glutathione peroxidase (GSH-Px), fluorescent damage products of lipid peroxidation (FDPL), thiobarbituric acid-reactive substances (TBARS), H2O2, and ATP in the aerobically perfused hearts of control rabbits and of rabbits fed a fat-enriched diet for 18 days. Such biochemical parameters, myocardial hemodynamics and infarct size were assessed in the perfused hearts of other control and fat-fed rabbits subjected to 60 min global ischemia plus 30 min reperfusion. Compared to controls, a reduced activity of GSSG-Red and γ-GT associated with decreased TG content was detected in the aerobically perfused hearts of fat-fed rabbits, which also showed insignificant γ-GCS activation, GSH-Px depressed activity, FDPL, TBARS and H2O2 burden, and unaltered ATP content. Ischemia-reperfusion decreased the myocardial levels of TG, ATP, and γ-GCS activity and augmented those of FDPL, TBARS, and H2O2 especially in the fat-fed rabbits, without significant changes in myocardial GSSG-Red, γ-GT, and GSH-Px activities. Ischemia-reperfusion induced greater hemodynamic dysfunction and infarct size in the hearts of fat-fed rabbits than in those of controls. Thus, short-term fat feeding and hyperlipidemia alter glutathione metabolic status of the rabbit myocardium, inducing a GSSG-Red- and γ-GT-related decrement of myocardial glutathione content, which, together with GSH-Px dysfunction, may favor tissue oxidative stress and render the myocardium more susceptible to ischemia-reperfusion injury.

Background: The independent prognostic significance of morning surge (MS) in blood pressure (BP) is not yet clear. We investigated the association between MS in systolic BP (SBP) and risk of ischemic stroke in elderly patients treated for hypertension., Methods: Occurrence of ischemic stroke was evaluated in 1,191 elderly patients treated for hypertension (aged 60-90 years). Patients were divided according to tertiles of MS in SBP in the population as a whole, dipping status, and group-specific tertiles of MS in SBP in dippers and nondippers., Results: During follow-up (9.1±4.9 years, range 0.4-20 years), 139 ischemic strokes occurred. The event rate per 100 patient-years was 1.28. After adjustment for various covariates, Cox regression analysis showed that stroke risk was not significantly associated with tertiles of MS in SBP in the population as a whole. When nondippers and dippers were analyzed separately by group-specific tertiles of MS in SBP, stroke risk was not associated with MS in nondippers. Conversely, in dippers, stroke risk was significantly higher in the third tertile (>23mm Hg) of MS in SBP (hazard ratio, 2.08; 95% confidence interval, 1.03-4.23; P = 0.04). Additional analysis showed that stroke risk was significantly and similarly higher in dippers with MS >23mm Hg and in nondippers than in dippers with MS <23mm Hg., Conclusions: In elderly patients treated for hypertension, high MS in SBP predicts stroke in dippers but not in nondippers. Nondippers are at high stroke risk with or without MS >23mm Hg.

Multidrug resistance (MDR) in cancer cells is often caused by the high expression of the plasma membrane drug transporter P-glycoprotein (Pgp) associated with an elevated intracellular glutathione (GSH) content in various human tumors. Several chemosensitizers reverse MDR but have significant toxicities. Antiemetic medications are often used for controlling chemotherapy-induced nausea and vomiting in cancer patient. In this in vitro study we investigated if the effects of two common antiemetic drugs such as dimenhydrinate (dime) and ondansentron (onda) and a natural compound (6)-gingerol (ginger), the active principle of ginger root, interfere on Pgp activity and intracellular GSH content in order to evaluate their potential use as chemosensitizing agents in anticancer chemotherapy. The human doxorubicin (doxo) resistant uterine sarcoma cells (MES-SA/Dx5) that overexpress Pgp, were treated with each antiemetic alone (1, 10 and 20 microM) or in combination with different doxo concentrations (2, 4, and 8 microM). We measured the intracellular accumulation and cytotoxicity of doxo (MTT assay), the cellular GSH content (GSH assay) and ROS production (DFC-DA assay), in comparison with verapamil (Ver), a specific inhibitor for Pgp, used as reference molecule. We found that exposure at 2, 4 and 8 microM doxo concentrations in the presence of dime, onda and ginger enhanced significantly doxo accumulation and cytotoxicity on resistant MES-SA/Dx5 cells when compared with doxo alone. Moreover, treatment with ginger (20 microM) increased cellular GSH content (greater than 10 percent) in resistant cells, while ROS production remained below the control values for all antiemetic compounds at all concentrations. These findings provide the rationale for innovative clinical trials of antiemetics or their derivatives as a new potential generation of chemosensitizers to improve effectiveness of the anticancer drugs in MDR human tumours.

Hypertension and other risk factors (RFs) predispose to carotid plaques (CPs). An association between left ventricular hypertrophy (LVH) or epicardial adipose tissue (EAT) and CPs has also been reported. The aim of the study was to evaluate whether the assessment of LVH and EAT thickness, beyond RFs, would be of additive value in predicting CPs in hypertensive subjects. We studied 548 hypertensive patients aged ≥ 50 years without carotid bruit. LVH and CPs were evaluated and defined according to standard criteria. EAT was measured by echocardiography above the free wall of the right ventricle at end diastole. The presence of LVH and EAT thickness above the median value (3.9 mm) together significantly increased prevalence of CPs in subjects with 0-1 risk factor, but not in those with ≥ 2 RFs who showed high prevalence of CPs independently of LVH and/or EAT. Receiver operating characteristic curve analysis showed that the addition of LVH and higher EAT thickness together significantly improved prediction of CPs in patients with 0-1 risk factor. Indeed, the area under the curve improved from 0.63 (0.56-0.69) to 0.73 (0.67-0.79), which was significantly higher (p < 0.05). In patients with ≥ 2 RFs, the addition of LVH and EAT did not significantly improve prediction of CPs. This study shows that the presence of LVH and higher EAT thickness together improves prediction of CPs in hypertensive patients with 0-1 risk factor and that those with ≥ 2 RFs show high prevalence of CPs independently of LVH and/or EAT.

Purpose: The therapeutic choice for patients with lung adenocarcinoma depends on the presence of EGF receptor (EGFR) mutations. In many cases, only cytologic samples are available for molecular diagnosis. Bronchoalveolar lavage (BAL) and pleural fluid, which represent a considerable proportion of cytologic specimens, cannot always be used for molecular testing because of low rate of tumor cells., Experimental Design: We tested the feasibility of EGFR mutation analysis on BAL and pleural fluid samples by next-generation sequencing (NGS), an innovative and extremely sensitive platform. The study was devised to extend the EGFR test to those patients who could not get it due to the paucity of biologic material. A series of 830 lung cytology specimens was used to select 48 samples (BAL and pleural fluid) from patients with EGFR mutations in resected tumors. These samples included 36 cases with 0.3% to 9% of neoplastic cells (series A) and 12 cases without evidence of tumor (series B). All samples were analyzed by Sanger sequencing and NGS on 454 Roche platform. A mean of 21,130 ± 2,370 sequences per sample were obtained by NGS., Results: In series A, EGFR mutations were detected in 16% of cases by Sanger sequencing and in 81% of cases by NGS. Seventy-seven percent of cases found to be negative by Sanger sequencing showed mutations by NGS. In series B, all samples were negative for EGFR mutation by Sanger sequencing whereas 42% of them were positive by NGS., Conclusions: The very sensitive EGFR-NGS assay may open up to the possibility of specific treatments for patients otherwise doomed to re-biopsies or nontargeted therapies.

Epicardial adipose tissue (EAT) is an emerging cardiometabolic risk factor, and its thickness can be measured using echocardiography. The relation of EAT to the metabolic syndrome (MS) is still unclear. A meta-analysis of published reports was performed to provide comprehensive insight on the association of EAT thickness as assessed by echocardiography and the MS. A systematic search was conducted for reports on echocardiographic EAT thickness in patients with and without the MS. Nine studies were identified. The pooled population consisted of 2,027 subjects, of whom 1,030 had the MS. EAT thickness was significantly higher in patients with the MS than in those without (standardized difference in means 1.15 mm, 95% confidence interval 0.78 to 1.53, p = 0.0001). Subgroup meta-analysis showed no difference between patients with and those without the MS by MS criteria used and echocardiographic cardiac cycle of measurement but did show a significant difference by ethnicity, with a greater difference in Caucasian subjects (standardized difference in means 1.75 mm, 95% confidence interval 1.43 to 2.07) than in other ethnic groups. In conclusion, echocardiographic EAT thickness is significantly higher in patients with the MS than in those without, but differences exist by ethnicity., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Cardiac outcome in patients with atherosclerotic renal artery stenosis (ARAS) undergoing percutaneous transluminal renal angioplasty (PTRA) or medical therapy is not yet completely clear. The aim of this study was to perform a meta-analysis of randomized controlled trials to compare the effect of PTRA and medical therapy on nonfatal myocardial infarction in patients with ARAS., Methods: We searched for articles reporting cardiovascular outcome, including nonfatal myocardial infarction, in patients with renal artery stenosis randomized to PTRA with/without stenting or medical therapy., Results: Five studies were identified. The pooled population consisted of 1,159 subjects who experienced 56 nonfatal myocardial infarctions. When compared with medical therapy, the overall relative risk (RR) was 0.85 (95% confidence interval (CI) 0.51-1.42), P = 0.55, for PTRA. There was no significant difference between PTRA and medical therapy according to procedural characteristics (with/without stent placement), mean serum creatinine at follow-up (higher or lower than 2.0 mg/dl), and maximum follow-up length (> or <2 years)., Conclusions: In patients with ARAS and hypertension, there is a lack of evidence supporting the superiority of PTRA over medical therapy in prevention of nonfatal myocardial infarction. Awaiting for results of ongoing trials, our data and previous data suggest that PTRA and drug therapy have a similar impact on cardiovascular risk reduction in patients with renal artery stenosis and hypertension.

We have here investigated possible occurrence of bicarbonate-dependent, carbonate radical anion (CO(3)(•-))-driven tocopherol-mediated human LDL peroxidation (TMP) in vitro and in vivo. CO(3)(•-), generated in vitro by the SOD1/H(2)O(2)/bicarbonate system, readily promoted TMP, which was dependent on α-tocopherol and bicarbonate concentrations, and was inhibited by the CO(3)(•-) scavenger ethanol; moreover, TMP induced in vitro by the SOD1/H(2)O(2)/bicarbonate system occurred in the presence of α-tocopherol that typically underwent slow oxidative consumption. In the in vivo clinical setting, we showed that, compared to controls, hypertensive patients with diuretic-induced metabolic alkalosis and heightened blood bicarbonate concentration had lipid hydroperoxide burden and decreased α-tocopherol content in the LDL fraction, with direct significant correlation between the LDL levels of α-tocopherol and those of lipid hydroperoxides; remarkably, after resolution of metabolic alkalosis, together with normalization of blood bicarbonate concentration, the LDL content of lipid hydroperoxides was decreased and that of α-tocopherol augmented significantly. These findings suggest bicarbonate-dependent, CO(3)(•-)-driven LDL TMP in vivo. In conclusion, the present study highlights the occurrence of bicarbonate-dependent, CO(3)(•-)-driven human LDL TMP, the role of which in pathological conditions such as atherosclerosis warrants, however, further investigation.

Multidrug resistance (MDR) to anticancer chemotherapy is often mediated by the overexpression of the plasma membrane drug transporter P-glycoprotein (Pgp) encoded by multidrug resistance gene (MDR1). Various chemosensitizing agents are able to inhibit Pgp activity but their clinical application is limited by their toxicity. Furthermore, hepatotoxicity related to chemotherapy causes delays of treatment in cancer patients and often requires supplementation of anti-tumour therapy with hepatoprotective agents. In this in vitro study, we investigated the effectiveness of an endogenous hepatoprotective agent, S-adenosylmethionine (SAMe), and a natural hepatoprotective compound, Cynarin (Cyn), to inhibit Pgp activity in order to evaluate their potential use as chemosensitizing agents. Human doxorubicin (doxo) resistant uterine sarcoma cells (MES-SA/Dx5) expressing high levels of Pgp were treated with two hepatoprotectors at various concentrations (1, 5 and 10 microM) that are clinically achievable, in the presence or absence of three different concentrations of doxo (2, 4 and 8 microM). In order to evaluate the effects of both hepatoprotectors, we measured the intracellular accumulation and cytotoxicity of doxo, the cellular GSH level, ROS production and catalase (CAT) activity. We found that treatment with 2, 4 and 8 microM doxo in the presence of SAMe or Cyn significantly increased the doxo accumulation and cytotoxicity on MES-SA/Dx5 cells, when compared to control cells receiving doxo alone. Moreover, treatment with SAMe or Cyn significantly increased GSH content, greater than 80 percent and 60 percent, respectively) and CAT activity greater than 60 and 150 percent, respectively) in resistant cancer cells, while ROS production was below the values of corresponding untreated control cells. Our in vitro findings provide a rationale for the potential clinical use of these hepatoprotectors both as chemosensitizing agents, to reverse Pgp-mediated MDR, and as antioxidants to protect normal cells from chemotherapy-induced cytotoxixity.

Background: Venous thromboembolism (VTE) often complicates the clinical course of cancer disease. The risk is further increased by chemotherapy but the safety and efficacy of primary thromboprophylaxis in cancer patients treated with chemotherapy is uncertain., Objectives: To assess the efficacy and safety of primary thromboprophylaxis in ambulatory cancer patients receiving chemotherapy., Search Methods: The Cochrane Peripheral Vascular Diseases Group searched their Specialised Register (last searched 3 May 2011) and CENTRAL (2011, Issue 2). The authors searched clinical trials registries and reference lists of relevant studies., Selection Criteria: Randomised controlled trials (RCTs) comparing unfractionated heparin (UFH), low molecular weight heparin (LMWH), vitamin K antagonists (VKA), direct thrombin inhibitors, direct factor Xa inhibitors or mechanical intervention to no intervention or placebo; or comparing two different anticoagulants., Data Collection and Analysis: Data were extracted on methodological quality, patients, interventions and outcomes including symptomatic VTE and major bleeding as the primary effectiveness and safety outcomes, respectively., Main Results: Nine RCTs with a total of 3538 patients were considered. None of the RCTs tested UFH, fondaparinux, direct factor Xa inhibitors or mechanical interventions. Overall, the risk of bias was low in most of the studies. LMWH, when compared with inactive control, significantly reduced the incidence of symptomatic VTE (risk ratio (RR) 0.62, 95% confidence interval (CI) 0.41 to 0.93) with no evidence of heterogeneity (I(2) = 0%). The number needed to treat to prevent a symptomatic VTE was 60. LMWH was associated with a 60% increase in major bleeding when compared with inactive control, although this was not statistically significant (RR 1.57, 95% CI 0.69 to 3.60; I(2) = 10%). There was a 45% reduction in overall VTE (RR 0.55, 95% CI 0.34 to 0.88; I(2) = 0%) while for symptomatic pulmonary embolism, asymptomatic VTE, minor bleeding and one-year mortality the differences between the LMWH and control groups were not statistically significant. The effect of the vitamin K antagonist warfarin on preventing symptomatic VTE, measured in only one study, was not statistically significant (RR 0.15, 95% CI 0.02 to 1.20). In one RCT of patients with myeloma, LMWH was associated with a 67% reduction in symptomatic VTE (RR 0.33, 95% CI 0.14 to 0.83) compared with warfarin, with no differences in major bleeding. Antithrombin, evaluated in one study on paediatric patients, had no significant effect on VTE nor major bleeding when compared with inactive control., Authors' Conclusions: Primary thromboprophylaxis with LMWH significantly reduced the incidence of symptomatic VTE in ambulatory cancer patients treated with chemotherapy. However, the lack of power hampers definite conclusions on the effects on major safety outcomes, which mandates additional studies to determine the risk to benefit ratio of LMWH in this setting.

Microdeletions at exon 19 are the most frequent genetic alterations affecting the Epidermal Growth Factor Receptor (EGFR) gene in non-small cell lung cancer (NSCLC) and they are strongly associated with response to treatment with tyrosine kinase inhibitors. A series of 116 NSCLC DNA samples investigated by Sanger Sequencing (SS), including 106 samples carrying exon 19 EGFR deletions and 10 without deletions (control samples), were subjected to deep next generation sequencing (NGS). All samples with deletions at SS showed deletions with NGS. No deletions were seen in control cases. In 93 (88%) cases, deletions detected by NGS were exactly corresponding to those identified by SS. In 13 cases (12%) NGS resolved deletions not accurately characterized by SS. In 21 (20%) cases the NGS showed presence of complex (double/multiple) frameshift deletions producing a net in-frame change. In 5 of these cases the SS could not define the exact sequence of mutant alleles, in the other 16 cases the results obtained by SS were conventionally considered as deletions plus insertions. Different interpretative hypotheses for complex mutations are discussed. In 46 (43%) tumors deep NGS showed, for the first time to our knowledge, subpopulations of DNA molecules carrying EGFR deletions different from the main one. Each of these subpopulations accounted for 0.1% to 17% of the genomic DNA in the different tumors investigated. Our findings suggest that a region in exon 19 is highly unstable in a large proportion of patients carrying EGFR deletions. As a corollary to this study, NGS data were compared with those obtained by immunohistochemistry using the 6B6 anti-mutant EGFR antibody. The immunoreaction was E746-A750del specific. In conclusion, NGS analysis of EGFR exon 19 in NSCLCs allowed us to formulate a new interpretative hypothesis for complex mutations and revealed the presence of subpopulations of deletions with potential pathogenetic and clinical impact.

Background: Metabolic syndrome (MetS) is a cluster of risk factors, related to visceral adiposity, which is frequently observed in overweight patients. However, it has also been reported in normal weight subjects. Epicardial adipose tissue (EAT) is a visceral fat. The aim of the study was to evaluate whether EAT is associated with MetS in hypertensive patients with normal weight and waist., Methods: We studied 174 Caucasian hypertensive patients, aged ≥40 years, with body mass index (BMI) <25 kg/m(2) and waist circumference <102 cm in men and 88 cm in women. MetS was defined according to NCEP ATP III criteria, not including waist circumference. EAT was measured by echocardiography above the free wall of the right ventricle, at end diastole., Results: MetS was present in 21 (12%) patients. EAT was significantly higher in patients with MetS than in those without MetS, 4.0 ± 0.8 vs 2.5 ± 0.9 mm, P < 0.01, respectively, but BMI and waist circumference were not. Multivariate analysis showed that EAT was independently associated with MetS. Receiver operating characteristic (ROC) curve analysis showed that EAT significantly improved prediction of MetS when added to BMI and waist circumference. Indeed, the area under the curve improved from 0.63 (0.50-0.76) to 0.91 (0.87-0.96), and resulted significantly higher (P < 0.01). ROC curve for EAT alone indicated that the cutoff value of 3.1 mm had the best performance in predicting MetS, that is, 100% sensitivity and 79% specificity., Conclusion: EAT thickness is associated with MetS in hypertensive patients with normal weight and waist.

It is debated whether subjects with concentric remodeling (CR, normal left ventricular mass index (LVMI) and increased relative wall thickness (RWT)) are at higher cardiovascular risk than those with normal geometry (NG, normal LVMI and RWT). The aim of this study was to perform a meta-analysis of studies evaluating cardiovascular events in subjects with CR and NG according to baseline classification. We searched for articles evaluating cardiovascular outcome in subjects with CR compared with those with NG, and reporting adjusted hazard ratio (HR) and 95% confidence interval (CI). Six studies were included in the meta-analysis. The pooled population consisted of 7465 subjects with CR and NG. During the follow-up, they experienced 852 events. When compared with NG, the overall adjusted HR was 1.36 (95% CI 1.03-1.78) for CR, P<0.03. There was some heterogeneity between studies. Subgroup meta-analysis showed that increased cardiovascular risk in subjects with CR was more relevant in studies evaluating hypertensive and Caucasian subjects and reporting both fatal and non-fatal events. Cardiovascular risk is significantly higher in subjects with CR than in those with NG. This aspect is more evident in studies including hypertensive patients and Caucasian populations and reporting global cardiovascular risk.

Thrombophilia has been associated with pregnancy complications and recurrent miscarriage. The aim of this systematic review was to evaluate the controversial association between thrombophilia and failures of assisted reproduction technology (ART). A systematic search of the literature for studies reporting on thrombophilia in women undergoing ART up to April 2011 yielded 33 studies (23 evaluating anti-phospholipid antibodies, 5 inherited thrombophilia, and 5 both) involving 6092 patients. Overall, methodologic quality of the studies was poor. Combined results from case-control studies showed that factor V Leiden was significantly more prevalent among women with ART failure compared with fertile parous women or those achieving pregnancy after ART (odds ratio = 3.08; 95% confidence interval, 1.77-5.36). The prothrombin mutation, methylenetetrahydrofolate reductase mutation, deficiency of protein S, protein C, or anti-thrombin were all not associated with ART failure. Women with ART failure tested more frequently positive for anti-phospholipids antibodies (odds ratio = 3.33; 95% confidence interval, 1.77-6.26) with evidence of high degree of between-study heterogeneity (I(2) = 75%; P < .00001). Prospective cohort studies did not show significant associations between thrombophilia and ART outcomes. Although case-control studies suggest that women experiencing ART failures are more frequently positive for factor V Leiden and anti-phospholipid antibodies, the evidence is inconclusive and not supported by cohort studies.

Background: Iron deficiency anemia (IDA) is a frequently encountered condition in clinical practice. After conventional endoscopy, the cause of anemia remains unknown in up to 40% of patients., Objective: To evaluate prospectively the diagnostic efficacy of a systematic endoscopic approach to IDA and to compare the diagnostic yield of videocapsule endoscopy (VCE) and CT-enteroclysis in endoscopy-negative patients., Design: Consecutive patients with IDA were enrolled prospectively., Setting: Open-access endoscopy within an academic hospital., Patients: This study involved 189 patients with IDA, including 98 women and 91 men; mean (±standard deviation) age 68 years±16.6 years., Intervention: Patients with IDA underwent gastroscopy and colonoscopy plus ileoscopy. Endoscopy-negative patients were further blindly evaluated by both CT-enteroclysis and VCE., Main Outcome Measurements: Diagnostic yield of conventional endoscopy; diagnostic yield of VCE versus CT-enteroclysis., Results: Endoscopy results were positive in 144 of 189 patients (76.2%). CT-enteroclysis and VCE allowed a diagnosis in 37 of 45 endoscopy-negative patients (82.2%). Overall, VCE was superior to CT-enteroclysis (77.8% vs 22.2%; P<.001), in particular when flat lesions were found., Limitations: Single-center study., Conclusion: A systematic approach to IDA, which includes standard endoscopy, VCE, and CT-enteroclysis allows an overall diagnostic rate of 95.7%; however, CT-enteroclysis should be limited to cases of nondiagnostic VCE., (Copyright © 2011 American Society for Gastrointestinal Endoscopy. Published by Mosby, Inc. All rights reserved.)

Multidrug resistance (MDR) to cancer therapy is frequently associated with the over-expression of the multidrug transporter MDR1 gene product P-glycoprotein (Pgp) in several types of human tumours. Various chemosensitizers have been used to inhibit Pgp activity but toxicity limits their clinical application. Di(2-ethylhexyl)phthalate (DEHP) is a plasticizer that is released from polyvinyl chloride (PVC) medical devices. Therefore, cancer patients undertaking chemotherapy are exposed to a clinically important amount of DEHP through blood and blood component transfusions, apheresis products, intravenous chemotherapy, parenteral nutrition and other medical treatments. The present study was designed to investigate the effects of DEHP on transport activity and expression of Pgp in order to evaluate its potential use as a chemosensitizer in cancer therapy. Human doxorubicin (doxo) resistant sarcoma cells (MES-SA/Dx5) that over-express Pgp were treated with different doses of doxo (2, 4 and 8 μM) in the presence or absence of various concentrations of DEHP (3, 6 and 12 μM) that were clinically achievable in vivo. Our results show that co-treatment with 2, 4 and 8 μM doxo in the presence of the lowest concentration of DEHP (3 μM) enhanced significantly doxo accumulation in MES-SA/Dx5 cells and, consistently increased the sensitivity to doxo, when compared to controls receiving only doxo. In contrast, higher DEHP concentrations (6 and 12 μM) induced MES-SA/Dx5 to extrude doxo decreasing doxo cytotoxicity toward resistant cells below control values. These results are consistent with the increase in Pgp expression levels in parental MES-SA cells treated with 3, 6 and 12 μM DEHP for 24 h and compared to untreated controls. All in all, these findings suggest a potential clinical application of DEHP as a chemosensitizer to improve effectiveness of the antineoplastic drugs in MDR human tumours.

Background: Both obesity and the decline in muscle strength, which often occur with aging, are accompanied by functional and metabolic changes that may affect the risk of thrombosis. This study evaluated whether obesity and poor muscle strength are associated with venous thromboembolism (VTE)., Methods: Objectively confirmed VTEs were assessed at baseline and more than a 6-year follow-up in 1,045 participants more than or equal to 60 years enrolled in the InCHIANTI study., Results: At baseline, 97 participants had a positive history of VTE. Obese participants were almost twice more likely (odds ratio 1.76; 95% confidence interval 1.03-3.01) and obese with poor muscle strength were threefold more likely (odds ratio 2.99; 95% confidence interval 1.56-5.73) to have VTE compared with lean participants with normal strength. Fifty-five VTEs occurred during follow-up. History of VTE, obesity, and/or poor strength independently predicted new VTE events. In participants with previous VTE, the odds ratio (95% confidence interval) for thrombosis was 6.64 (1.92-22.95) with poor strength, 9.69 (3.13-30.01) in the obese, and 14.57 (5.16-41.15) in the obese with poor strength as compared with lean participants with normal strength., Conclusion: Obesity with or without poor muscle strength is a risk factor for VTE among older persons and significantly amplifies the risk of recurrent thrombosis.

Background: The prognostic relevance of white-coat hypertension (WCH) and masked hypertension (MH) is controversial. The aim of this study was to perform an updated meta-analysis on the prognostic value of WCH and MH diagnosed by ambulatory monitoring in initially untreated subjects., Methods: We searched for articles evaluating cardiovascular outcome in WCH or MH or sustained hypertension (SH) in comparison with normotension, investigating untreated subjects at baseline or performing separate analysis for untreated or treated subjects, and reporting adjusted hazard ratio (HR) and 95% confidence interval (CI)., Results: Eight studies were identified. Five whole studies and untreated groups of three others were included in the meta-analysis. The pooled population consisted of 7,961 subjects who experienced 696 events. When compared with normotension, the overall adjusted HR was 0.96 (95% CI 0.65-1.42) for WCH (P = 0.85), 2.09 (1.55-2.81) for MH (P = 0.0001), and 2.59 (2.0-3.35) for SH (P = 0.0001). There was no significant difference between WCH and normotension according to normotensive subjects source (same or different study population) and follow-up length. Where reported, prevalence of drug therapy was higher in subjects with WCH than in those with normotension at follow-up., Conclusions: Cardiovascular risk is not significantly different between WCH and normotension, regardless of normotensive population type and follow-up length. However, at follow-up drug therapy was more frequent in WCH than in normotension and its possible impact on outcome should be evaluated in future studies. MH shows significantly higher risk than normotension, although the best way for its detection and treatment remains to be established.

Objectives: To investigate the association of serum albumin (SA) with oxidative damage of human atherosclerotic plaques and the severity of atherosclerosis., Design and Methods: Correlation of the levels of SA with those of lipid and protein oxidation of endarterectomy-removed carotid atherosclerotic plaques; SA and plaque oxidative biomarkers comparison between 2 groups of patients with different severity of atherosclerotic carotid stenosis, i.e. <90% (group I) or ≥90% (group II)., Results: SA was strongly inversely correlated with plaque oxidative damage; SA was lower and plaque oxidative damage higher in group II than group I., Conclusions: Lowered SA is associated with oxidative damage of atherosclerotic plaques and the severity of atherosclerosis., (Copyright © 2010 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

While the association between cancer and symptomatic venous thromboembolism (VTE) is well established, the incidence and risk factors for incidental VTE in cancer patients remain unclear. The medical records of 1,921 consecutive cancer patients starting chemotherapy from January 2003 up to March 2009 were identified. Patients with a positive history of VTE were excluded. Pre-existing signs of VTE, kind and stage of malignancy, first and subsequent lines of chemotherapy, and all follow-up computed tomography (CT) scans were analysed. The primary outcome was incidental VTE. Overall, there were 101 (5.3%) VTE, 62 (3.2%) incidental and 39 (2.0%) symptomatic during a median of eight months (range 3-72). The incidence on CT scans was 0.58% (95%CI: 0.44-0.74). Incidental VTE included 24 pulmonary embolism, 28 deep venous thrombosis of the extremities, and 10 thromboses of the cava or splanchnic veins. Half of the incidental VTE occurred in the first 3-6 months of chemotherapy with a relatively higher incidence in gynecological and lung cancers. The presence of metastases, high leukocyte count, and platin-based chemotherapy increased the risk up to three-fold. All patients with incidental VTE regardless the location received half to full therapeutic doses of low-molecular-weight heparin for a minimum of three months. In summary, incidental VTE is a relative common finding in patients with solid tumours, especially in the first months of chemotherapy. Further research is needed to understand the natural history of incidental thrombosis in order to develop adequate management guidelines.

Background: The prognostic relevance of echocardiographic left ventricular hypertrophy (LVH) regression in hypertension is uncertain. The aim of this study was to perform an updated meta-analysis about the impact of LVH regression on the occurrence of cardiovascular events in hypertensive patients., Methods: We searched for studies on echocardiographic LVH regression and prognosis in hypertension that compared patients with or without LVH regression or groups including subjects with or without LVH regression and reported adjusted hazard ratio (HR) for calculating the overall effect size., Results: Five studies were identified (3,149 patients, mean age range 48-66 years, 58% men). Follow-up echocardiography was performed after a mean period ranging from 1 to 5 years. Entire follow-up duration ranged from 3 to 9 years. Globally, 333 cardiovascular events occurred. Three whole studies and subgroups of two others were included in the meta-analysis, comprising 2,449 patients, 1,900 (78%) with baseline LVH and 969 (51%) with LVH regression, who experienced 304 events. The overall adjusted HR of total cardiovascular events was 0.54, 95% confidence interval (CI) 0.35-0.84, P = 0.007, for LVH regression/persistent normal left ventricular (LV) mass vs. LVH persistence/LVH development. Heterogeneity was found between studies. Higher baseline prevalence of comorbid conditions and Japanese ethnicity seemed to be associated with lower benefit from LVH regression., Conclusions: This meta-analysis indicates that regression of echocardiographic LVH in hypertension, even after adjustment for various confounders, is associated with reduction of cardiovascular events. However, future studies are needed to evaluate whether LVH regression is of benefit for all hypertensive patients and ethnic groups.

Multidrug resistance (MDR) in cancer cells is often caused by the high expression of the plasma membrane drug transporter P-glycoprotein (Pgp) associated with an elevated intracellular glutathione (GSH) content in various human tumors. Several chemosensitizers reverse MDR but have significant toxicities. Sedatives are often used to control anxiety and depression in cancer patients. In this in vitro study we investigated the effects of three plant derived sedatives such as apigenin (Api), fisetin (Fis), flavonoids and honokiol (Hnk) on Pgp activity and cellular GSH content in order to evaluate their potential use as chemosensitizing agents in anticancer chemotherapy. Human doxorubicin (doxo) resistant uterine sarcoma cells (MES-SA/Dx5) that overexpress Pgp, were treated with each sedative alone (10 microM) or in combination with different doxo concentrations (2-8 microM). We measured the intracellular accumulation and cytotoxicity of doxo (MTT assay), the cellular GSH content (GSH assay) and ROS production (DFC-DA assay), in comparison with verapamil (Ver), a specific inhibitor for Pgp, used as reference molecule. We found that exposure at 2 and 8 microM doxo concentrations in the presence of Api, Fis and Hnk enhanced significantly doxo accumulation by 29+/-3.3, 20+/-4.8, 24+/-6.6 percent and 14+/-1.7, 8.3+/-4.2, 10.7+/-3.1 percent, respectively, when compared with doxo alone. These results were consistent with the increase of sensitivity towards doxo in MES-SA/Dx5, resulting in 1.7, 1.2, 1.4-fold and 1.2, 1.0 and 1.1-fold increases, respectively. Moreover, treatment with Api decreased markedly cellular GSH content (18 percent) and increased ROS production (greater than 20 percent) on MES-SA/Dx5 cells, while a significant reduction in ROS levels was observed in Hnk and Fis treated cells, when compared to untreated control. Our in vitro findings provide a rationale for innovative clinical trials to assess the use of natural sedatives or their derivatives as potential adjuvants to anticancer treatment for overcoming multidrug resistance Pgp-mediated in cancer patients.

We reviewed the literature on ambulatory blood pressure (BP) monitoring in type 2 diabetes mellitus (T2DM) (focusing on organ damage progression, prognosis, white coat hypertension, and masked hypertension) and metabolic syndrome (MetS). In the text we reported 21 articles about T2DM and 11 about MetS, part of which were included in meta-analyses. In T2DM, individual studies and meta-analyses indicate that 24-h pulse pressure and reduced night-time BP fall or reverse dipping predict organ damage progression, total cardiovascular events and all-cause mortality. Moreover, white coat hypertension seems to be less frequent in T2DM and its impact on cardiovascular complications remains controversial. In contrast, masked hypertension is more frequent in T2DM and seems to be associated with increased organ damage. Some studies reported higher ambulatory BP in patients with MetS, but these patients were older and had higher clinical BP than those without MetS. With regard to the circadian BP profile, contrasting data have been reported, although pooled data suggest a higher risk of nondipping in patients with MetS.