Effect of prolonged treatment with phosphodiesterase-5-inhibitors on endothelial dysfunction in vascular diseases and vascular risk conditions: A systematic review analysis and meta-analysis of randomized double-blind placebo-controlled trials.

OBJECTIVE To challenge the argument that continuous use of phosphodiesterase-5-selective inhibitors may reduce endothelial cell dysfunction in patients with vascular diseases or vascular risk conditions. DESIGN This study included systematic reviews and meta-analysis of randomized double-blind placebo-controlled trials dealing with the prolonged use of phosphodiesterase-5-selective inhibitors. The risk of bias and quality of trials were assessed by the Cochrane algorithm. Fixed or random effect models, standardised mean differences and heterogeneity were estimated in the study. DATA SOURCES Systematic search for randomized double-blind placebo-controlled trials was done in PubMed, Scopus, CINAHL, Science direct and the Cochrane Library. ELIGIBILITY CRITERIA FOR SELECTING STUDIES Randomized double-blind placebo-controlled trials reporting measures of endothelial cell dysfunction and/or endothelial cell activation were included. RESULTS On the whole, 469 subjects were allocated to the phosphodiesterase-5-selective inhibitor group, while 463 were assigned to the placebo group in 13 randomized double-blind placebo-controlled trials. Flow-mediated dilation of the brachial artery was found to improve after the administration of phosphodiesterase-5-selective inhibitors (P < 0.0001). The results were questioned by the elevated and uncorrectable heterogeneity (I2 = 92%) and the asymmetry of the funnel plot suggested a publication bias. Phosphodiesterase-5-selective inhibitors have no effect on endothelial cell dysfunction, as assessed in the resistance vessels by digital arterial tonometry. The blood level of endothelin-1 was observed to be decreased in phosphodiesterase-5-selective inhibitors arm (P = 0.03), although the effect disappeared once the publication bias and heterogeneity were corrected. The effect of phosphodiesterase-5-selective inhibitors on biomarkers of endothelial cell activation was found to be inconsistent. CONCLUSIONS The results on the benefits of a prolonged use of phosphodiesterase-5-selective inhibitors, with the objective of lowering endothelial cell dysfunction in patients with vascular diseases or vascular risk conditions are not convincing. This is because of the overall low quality of evidence, giving an unclear scientific support to this treatment. Systematic review registration: PROSPERO registration: CRD42017055399

Different Effects of Angiotensin Converting Enzyme Inhibitors on Endothelin-1 and Nitric Oxide Balance in Human Vascular Endothelial Cells: Evidence of an Oxidant-Sensitive Pathway

Angiotensin converting enzyme inhibitors (ACE-I) are able to reduce the formation of the potent vasoconstrictor endothelin-1 and increase nitric oxide bioavailability in human vascular endothelial cells (HUVECs). We tested the effects of two sulfhydryl-containing ACE-I, zofenoprilat, and captopril, and two nonsulfhydryl containing ACE-I, enalaprilat and lisinopril, on endothelin-1/nitric oxide balance and oxidative stress in HUVECs. All the four tested ACE-I reduced endothelin-1 secretion and increased nitric oxide metabolite production by HUVECs. However, zofenoprilat (−42% after 8 hours of incubation) was more effective (P < .05) than enalaprilat (−25%), lisinopril (−21%), and captopril (−30%) in reducing endothelin-1 secretion. Similarly, zofenoprilat (+110% after 8 hours of incubation) was more effective (P < .05) than enalaprilat (+64%), lisinopril (+63%), and captopril (+65%) in increasing nitric oxide metabolite production. The effect of ACE-I on endothelin-1 and nitric oxide metabolite production is mediated by the activation of bradykinin B2 receptor being counteracted, at least in part, by a specific antagonist. Zofenoprilat and, to a lesser extent, captopril also reduced oxidative stress in HUVECs. In conclusion, among the four tested ACE-I, zofenoprilat was more effective in improving endothelin-1/nitric oxide balance in HUVECs likely because of its greater antioxidant properties

C677T Methylenetetrahydrofolate Reductase Homozygosis and Vitamin Supplement in Migraineur Children

Purpose: Methylenetetrahydrofolate reductase (MTHFR) variant C677T has been associated with an increased genetic risk in migraine susceptibility. Individuals with the homozygous genotype show higher levels of plasma homocysteine (Hcy) [1,2,3]. Methods: Open-label study evaluating clinical trial was performed on 148 children migraineurs among 236 children suffering from headache, admitted to the Headache Regional Centre in l'Aquila (Italy)-Neuropsychiatric clinic, recruited and observed sequentially during the years 2015-2017. 31 patients (16,6% of all the sample) MTHFR homozygous were selected and underwent clinical evaluation of migraine characteristics (frequency, severity of pain and use of acute treatment) at baseline and after a 12 month-period of daily supplement of vitamins B9(2 mg), B6(25 mg), B12(400 mcg). In 20 patients with hyper Hcy (>95° percentile for age) the second collection of blood sample was obtained for Hcy assessment. Diagnosis of headache according to ICHD-III criteria. Statistical analysis is made by Wilcoxon test. Results: 20 children suffer from Migraine without aura (MwoA) and 11 from Migraine with aura (MA). 86% of children aged >10 years had significantly higher Hcy values compared with controls (p 95°percentile. In all the sample the vitamin supplementation was effective in producing significant reduction in Hcy levels (p=0.0001) and a significant improvement of migraine disability of frequency (p<0.0001), severity of pain (p<0.0003) and use of acute treatment (p<0.0001). Conclusions: The study results are encouraging and emphasize the importance of a comprehensive therapy in paediatric migraines

Association between female reproductive health and mancozeb: systematic review of experimental models

Abstract: Mancozeb is a widely used fungicide approved for use in agriculture in many countries with long persistence in the environment and consequent bioaccumulation in tissues and biological fluids. Despite the large amount of studies published in recent years, the relationship between mancozeb exposure and female reproductive health is not fully elucidated. In order to summarize current evidence on mancozeb exposure and female reproductive disease, we performed a systematic review of literature. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used to make this review. An adapted version of the National Toxicology Program’s Office of Health and Assessment and Translation (OHAT) framework was used to evaluate the risk of bias. Electronic search on two databases (PubMed and Scopus) was used to find experimental studies (in vitro and in vivo) on mancozeb exposure. The database search identified 250 scientific articles, 20 of which met our inclusion criteria. Selected data were then reviewed and summarized in tables. Overall, mancozeb represents a hazard for female reproductive health, with different mechanisms of action. Undoubtedly more experimental and epidemiological studies are required to definitively validate mancozeb as reproductive toxicant

Clostridium difficile outbreak: epidemiological surveillance, infection prevention and control

INTRODUCTION: Clostridium difficile infection (CDI) is currently considered the most common cause of health care-associated infections. The aim is to describe the trend of CDI in an Italian hospital and to assess the efficacy of the measures adopted to manage the burden. METHODS: we looked at CDI from 2016 to 2018. The incidence rate of CDIs was calculated as the number of new infected persons per month by the overall length of stay (incidence per 10,000 patient-days). Changes in the CDI rate during the period considered were analysed using a joinpoint regression model. RESULTS: thanks to the monitoring activity it was possible to adopt a new protocol, in order to manage CDI: the CDI episodes decreased from 85 in 2017 to 31 in 2018 (63% decrease). The joinpoint regression model was a useful tool to identify an important decrement during 2017, statistically significant (slope=-15.84; p= 0.012). CONCLUSIONS: reports based on routine laboratory data can accurately measure population burden of CDI with limited surveillance resources. This acitivity can help target prevention programs and evaluate their effect

Microfracture versus microfracture and platelet-rich plasma: arthroscopic treatment of knee chondral lesions. A two-year follow-up study.

Purpose: the aim of this study was to describe and compare the clinical results obtained in patients affected by chondral lesions of the knee submitted to an arthroscopic treatment with the microfracture technique or microfracture + intraoperative autologous platelet-rich plasma (PRP) injection. Methods: a prospective observational study was performed in patients affected by chondral lesions of the knee (classed as grade III-IV according to Outer-bridge's classification) and early osteoarthritis (classed as grade 1-2 according to the Kellgren-Lawrence classification). Their mean age was 52.4 years. Thirteen patients were treated with the microfracture technique according to Steadman (Group A), while 14 were treated with microfracture + PRP injection (Group B). Both groups were assessed using series of measures (a visual analog scale for pain, the 36-Item Short Form Health Survey and the International Knee Documentation Committee Subjective Knee Form) to compare pre-operative and postoperative values at 3, 6, 12 and 24 months. Statistical analysis was conducted using a two-factor ANOVA for repeated measures. Results: the VAS score decreased from a pre-operative value of 6.62±1.26 to 3.54 ±2.26 at 24 months in Group A (p&lt;0.001), and from 6.43±1.91 to 3.36±2.84 in Group B (p&lt;0.001). The IKDC subjective score increased from a pre-operative value of 37.02±12.00 to 62.13±19.00 at two years in Group A (p&lt;0.001) and from 34.63±15.00 to 67.11±26.74 in Group B (p&lt;0.001); the SF-36 scores showed a similar trend. Although an improvement was recorded over time in both groups, in the short term the IKDC subjective score improvement seemed to be better in Group B; a similar trend was shown by the SF-36 and VAS scores. At two years, the IKDC Subjective Scale, VAS and SF-36 scores seemed to be similar in the two groups. Over time, no significant differences were found between the two groups in any of the three outcomes. Conclusions: the use of autologous PRP in association with the microfracture technique seems to give better clinical and functional results in short-term follow-up, above all as regards pain. At two-year follow-up, however, the clinical results of the two groups were similar. Level of evidence: Level II, prospective cohort study

Measles-Related Hospitalizations in Italy, 2004–2016: The Importance of High Vaccination Coverage

Background: Measles is a highly contagious human infectious disease. It can lead to serious complications and often requires hospitalization. In Italy, as in other European countries, the goal of measles elimination in 2015 failed. To reach this target, identifying susceptible individuals, closing any immunity gaps and reaching adequate vaccination coverage is necessary. Objective: To contribute to these purposes, a retrospective observational study on measles-related hospitalization between 2004 and 2016 in Italy was conducted, using the national hospital discharge database as informational flow. Methods: Admission frequencies and hospitalization rates were compared between regions with low (90% led to a halving of measles hospitalizations, but it is insufficient for the elimination: ≥95% coverage continues to be the target to be reached

Serum Uric Acid Levels Are Associated with the Echogenic Features of Carotid Plaque Vulnerability in Elderly Patients with Atherosclerotic Disease

Uric acid is a marker of inflammation and a risk factor for atherosclerosis that has been suggested to play a role in carotid plaque instability. Reduced atherosclerotic plaque echogenicity at ultrasound examination is associated with alarming histopathological features and inflammation. In this study, we investigated the relationship between serum uric acid (SUA) levels and echogenic patterns of plaque instability in elderly subjects with carotid atherosclerosis. Since uric acid metabolism largely depends on renal function, SUA levels were indexed for serum creatinine levels (SUA/SCr). We enrolled 108 patients aged 65 years or more (72.7 ± 5.9 years; 50 females and 58 males) who underwent carotid duplex ultrasound to evaluate plaque echogenicity by greyscale median (GSM). The regression analysis demonstrated a significant inverse association between the GSM and the SUA/SCr ratio (β: -0.567; 95% CI -0.751 to -0.384 and p < 0.0001). Stepwise multivariate regression showed that the SUA/SCr ratio explained 30.3% of GSM variability (β: -0.600; 95% CI -0.777/-0.424, p < 0.0001, and semi-partial correlation 0.303). After a mean period of 3.5 ± 0.5 years, 48 patients were reevaluated according to the same baseline study protocol. The regression analysis demonstrated a still significant inverse association between the GSM and the SUA/SCr ratio (β: -0.462; 95% CI -0.745 to -0.178 and p = 0.002). Stepwise multivariate regression showed that the SUA/SCr ratio explained 28.0% of GSM variability (coefficient -0.584, 95% CI -0.848/-0.319, p < 0.0001, and semi-partial R$^{2}$ 0.280). In conclusion, this study demonstrates that SUA levels indexed for serum creatinine are associated with the echogenic features of carotid plaque vulnerability in elderly patients with atherosclerotic disease. These data could suggest an influential role for uric acid metabolism in carotid plaque biology

Enhanced Carotid Plaque Echolucency Is Associated with Reduced Cognitive Performance in Elderly Patients with Atherosclerotic Disease Independently on Metabolic Profile

Vulnerable carotid atherosclerotic plaques are related to an increased risk of cognitive impairment and dementia in advanced age. In this study, we investigated the relationship between the echogenicity of carotid plaques and cognitive performance in patients with asymptomatic carotid atherosclerotic plaques. We enrolled 113 patients aged 65 years or more (72.4 ± 5.9 years) who underwent carotid duplex ultrasound to evaluate plaque echogenicity by grey-scale median (GSM) and neuropsychological tests to assess cognitive function. The GSM values at baseline were inversely correlated with the number of seconds required to complete Trail Makin Test (TMT) A (rho: -0.442; p < 0.0001), TMT B (rho: -0.460; p < 0.0001) and TMT B-A (rho: -0.333; p < 0.0001) and directly correlated with Mini Mental State Examination (MMSE) and Verbal Fluency Test (VFT) score (rho: 0.217; p = 0.021 and rho: 0.375; p < 0.0001, respectively) and the composite cognitive z-score (rho: 0.464; p < 0.0001). After a mean period of 3.5 ± 0.5 years, 55 patients were reevaluated according to the same baseline study protocol. Patients with baseline GSM value higher than the median value of 29 did not show any significant variation in the z-score. Instead, those with GSM ≤ 29 showed a significant worsening of z-score (-1.2; p = 0.0258). In conclusion, this study demonstrates the existence of an inverse relationship between the echolucency of carotid plaques and cognitive function in elderly patients with atherosclerotic carotid disease. These data suggest that the assessment of plaque echogenicity if used appropriately, might aid in identifying subjects at increased risk for cognitive dysfunction

Pertussis in Italy: how to protect the “unprotectable”?

Whooping cough continues to be an important public health issue despite high levels of vaccination coverage with acellular pertussis vaccine. Young unimmunized infants represent the most vulnerable group with the highest rates of complications and death. As infant-specific pertussis epidemiologic data, especially among neonates, in Italy were limited, a retrospective observational study of hospitalizations for whooping cough in Italian infants aged <12 months between 2007 and 2018 was conducted to address this knowledge gap. The temporal trend of rates, also stratified for age classes according to the expected age for the administration of vaccine doses, were analyzed by the slope of the regression line. The mean age at the time of admission was 92 d (±64). A clear seasonal pattern in the occurrence of pertussis hospitalizations with a summer peak was observed. Infants younger than 3 months old had the highest hospitalization rates (169 x 100000 infants on average), with a significant rising trend of 9 x 100000 infants on average per year. Limiting the analysis to Bordetella pertussis-related hospitalizations such trend was even more evident. In the other age classes, hospitalization rates were considerably lower and gradually decreased with increasing age. This study demonstrated that pediatric populations, too young to be protected by vaccination, had a greater risk of contracting pertussis. Thus, it is necessary to promote additional immunization strategies besides one booster dose in adolescents, including vaccination during pregnancy