Showing papers by "Arduino A. Mangoni published in 2018"

Neutrophil to lymphocyte ratio and clinical outcomes in COPD: recent evidence and future perspectives.

Abstract: Chronic obstructive pulmonary disease (COPD) is a disabling condition that is characterised by poorly reversible airflow limitation and inflammation Acute exacerbations of COPD are a common cause of hospitalisation and death among COPD patients Several biochemical markers have been studied as outcome predictors in COPD; however, their measurement often requires significant time and resources Relatively simple biomarkers of inflammation calculated from routine complete blood count tests, such as the neutrophil to lymphocyte ratio (NLR), might also predict COPD progression and outcomes This review discusses the available evidence from studies investigating the associations between the NLR, COPD exacerbations and death in this patient group

A Potential Link Between Oxidative Stress and Endothelial-to-Mesenchymal Transition in Systemic Sclerosis.

Abstract: Systemic sclerosis (SSc) is an autoimmune disease characterized by an aberrant immune system response, progressive fibrosis and microvasculature damage that affects organs and systems including skin, lungs, heart, digestive system, kidneys, muscles, joints, and nervous system. Several factors, including genetic and environmental, are involved in the SSc pathogenesis by leading to a pathological autoimmune response, exacerbated extracellular deposition and abnormal vascular restructuring. SSc-associated fibrosis and vascular damage can be caused by the altered secretion of growth factor and profibrotic cytokines, including transforming growth factor-beta (TGF-beta), interleukin-4 (IL-4), platelet-derived growth factor (PDGF), and connective-tissue growth factor. Such massive inflammatory response activates different biological events, including endothelial cells phenotypic conversion into activated myofibroblasts, a process known as endothelial to mesenchymal transition or EndMT. Among the multitude of proinflammatory factors involved in SSs-associated fibrosis and vascular derangement, reactive oxygen species (ROS) are paramount effectors. In this context, ROS-induced oxidative stress has been found implicated in mediating and/or activating TGF-β -induced EndMT in various diseases molecular models, suggesting the idea that a similar mechanism can be potentially involved in SSc. In this review, we collected and critically analyzed all the PubMed's articles providing experimental correlations between increased ROS generation and EndMT, as well as of the presence of the EndMT process in SSc, highlighting a potential link between oxidative stress and EndMT in this disease.

Evaluation of oxidative stress biomarkers in idiopathic pulmonary fibrosis and therapeutic applications: a systematic review

Abstract: Idiopathic pulmonary fibrosis (IPF), a fatal lung disease of unknown origin, is characterized by chronic and progressive fibrosing interstitial pneumonia which progressively impairs lung function. Oxidative stress is one of the main pathogenic pathways in IPF. The aim of this systematic review was to describe the type of markers of oxidative stress identified in different biological specimens and the effects of antioxidant therapies in patients with IPF. We conducted a systematic search of publications listed in electronic databases (Pubmed, Web of Science, Scopus and Google Scholar) from inception to October 2017. Two investigators independently reviewed all identified articles to determine eligibility. After a substantial proportion of the initially identified articles (n = 554) was excluded because they were duplicates, abstracts, irrelevant, or did not meet the selection criteria, we identified 30 studies. In each study, we critically appraised the type, site (systemic vs. local, e.g. breath, sputum, expired breath condensate, epithelial lining fluid, bronchoalveolar lavage, and lung tissue specimens), and method used for measuring the identified oxidative stress biomarkers. Furthermore, the current knowledge on antioxidant therapies in IPF was summarized. A number of markers of oxidative stress, with individual advantages and limitations, have been described in patients with IPF. Nevertheless, trials of antioxidant treatments have been unable to demonstrate consistent benefits, barring recent pharmacogenomics data suggesting different results in specific genotype subgroups of patients with IPF.

Protective effects of hydroxychloroquine against accelerated atherosclerosis in systemic lupus erythematosus

Abstract: Cardiovascular (CV) morbidity and mortality are a challenge in management of patients with systemic lupus erythematosus (SLE). Higher risk of CV disease in SLE patients is mostly related to accelerated atherosclerosis. Nevertheless, high prevalence of traditional cardiovascular risk factors in SLE patients does not fully explain the increased CV risk. Despite the pathological bases of accelerated atherosclerosis are not fully understood, it is thought that this process is driven by the complex interplay between SLE and atherosclerosis pathogenesis. Hydroxychloroquine (HCQ) is a cornerstone in treatment of SLE patients and has been thought to exert a broad spectrum of beneficial effects on disease activity, prevention of damage accrual, and mortality. Furthermore, HCQ is thought to protect against accelerated atherosclerosis targeting toll-like receptor signaling, cytokine production, T-cell and monocyte activation, oxidative stress, and endothelial dysfunction. HCQ was also described to have beneficial effects on traditional CV risk factors, such as dyslipidemia and diabetes. In conclusion, despite lacking randomized controlled trials unambiguously proving the protection of HCQ against accelerated atherosclerosis and incidence of CV events in SLE patients, evidence analyzed in this review is in favor of its beneficial effect.

Homoarginine and inhibition of human arginase activity: Kinetic characterization and biological relevance

Abstract: The inhibition of arginase, resulting in higher arginine (ARG) availability for nitric oxide synthesis, may account for the putative protective effect of homoarginine (HOMOARG) against atherosclerosis and cardiovascular disease. However, uncertainty exists regarding the significance of HOMOARG-induced arginase inhibition in vivo. A novel UPLC-MS method, measuring the conversion of ARG to ornithine (ORN), was developed to determine arginase 1 and arginase 2 inhibition by HOMOARG, lysine (LYS), proline (PRO), agmatine (AG), asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and NG-Monomethyl-L-arginine (L-NMMA). Plasma HOMOARG, ARG and ORN concentrations were further measured in 50 healthy older adults >65 years (27 males and 23 females). HOMOARG inhibited arginase 1 with IC50 and Ki values of 8.14 ± 0.52 mM and 6.1 ± 0.50 mM, and arginase 2 with IC50 and Ki values of 2.52 ± 0.01 mM and 1.73 ± 0.10 mM, respectively. Both arginase isoforms retained 90% activity vs. control when physiological HOMOARG concentrations (1–10 µM) were used. In partial correlation analysis, plasma HOMOARG was not associated with ARG (P = 0.38) or ARG/ORN ratio (P = 0.73) in older adults. Our results suggest that arginase inhibition is unlikely to play a significant role in the reported cardio-protective effects of HOMOARG.

The neutrophil-to-lymphocyte ratio as a marker of chronic obstructive pulmonary disease and its exacerbations: A systematic review and meta-analysis.

Abstract: INTRODUCTION The main white blood cell populations, neutrophils and lymphocytes, are involved in the pathophysiology of chronic obstructive pulmonary disease (COPD). We conducted a systematic review and meta-analysis of studies investigating the relationship between the neutrophil to lymphocyte ratio (NLR, a marker of subclinical inflammation), presence of COPD, and its exacerbations. METHODS A comprehensive literature search was conducted in Pubmed, Web of Science and Scopus databases; two investigators independently reviewed suitable studies. RESULTS Nine studies, from 247 initially identified, were included in the meta-analysis. Seven studies, in 775 COPD patients with stable disease and 496 healthy controls, showed a significant increase in NLR values in stable COPD (standardised mean difference, SMD, 0.773, 95% CI 0.410-1.136; P < 0.001). Furthermore, in six studies in 527 COPD patients with acute exacerbation and 620 COPD patients with stable disease, NLR values were significantly higher in patients with exacerbations (random effects SMD 0.850, 95% CI 0.549-1.151; P < 0.001). CONCLUSIONS Our meta-analysis showed that NLR values are significantly higher in stable COPD patients when compared to healthy individuals, although the magnitude of the difference is reduced after trim and fill adjustment, and in patients with COPD exacerbations when compared to patients with stable disease. Further studies, in larger cohorts, are needed to confirm whether the NLR is a useful tool in discriminating between COPD patients with stable disease, those with acute exacerbations, and subjects without the disease.

Homoarginine and all-cause mortality: A systematic review and meta-analysis.

Abstract: BACKGROUND Homoarginine, a basic amino acid and analogue of L-arginine, has been shown to exert salutary effects on vascular homoeostasis, possibly through interaction with the enzymes nitric oxide synthase and arginase. This might translate into improved survival outcomes, particularly in subjects with moderate-high cardiovascular risk. We conducted a systematic review and meta-analysis to investigate the association between circulating homoarginine concentrations and all-cause mortality in observational studies of human cohorts. MATERIALS AND METHODS Studies reporting baseline circulating homoarginine concentrations and all-cause mortality as outcome were searched using the MEDLINE, Scopus and Cochrane databases until January 2018. Hazard ratios (HRs) with 95% confidence intervals (CIs) derived from multivariate Cox's proportional-hazards analysis were extracted from individual studies. RESULTS A total of 13 studies in 11 964 participants were included in the final analysis. Homoarginine concentrations were inversely associated with all-cause mortality (HR 0.64, 95% CI 0.57-0.73). This association remained significant in participant sub-groups with predominant cardiovascular disease (HR 0.64, 95% CI 0.55-0.76) and renal disease (HR 0.60, 95% CI 0.46-0.68). CONCLUSIONS This meta-analysis of observational studies showed an inverse association between circulating homoarginine concentrations and all-cause mortality. Further research is warranted to investigate the direct effects of homoarginine on cardiovascular homoeostasis, the associations between homoarginine and all-cause mortality in other population groups, and the effects of interventions on homoarginine concentrations on clinical outcomes.

Coronary flow reserve in systemic rheumatic diseases: a systematic review and meta-analysis

Abstract: Coronary flow reserve (CFR), a measure of both obstructive coronary artery disease and microvascular dysfunction, has been evaluated in systemic rheumatic diseases (RDs), but a comprehensive critical appraisal of the available evidence is lacking. The objective of this study is to conduct a systematic review and meta-analysis of studies with small sample size investigating the associations between the presence of RDs and CFR to increase statistical power and accuracy. PubMed, Web of Science, Scopus, and Google Scholar, from inception to March 2018, were searched for studies reporting on CFR in RDs in comparison to healthy subjects. Standardized mean differences (SMD) with 95% confidence intervals (CI) were calculated. Meta-regressions and sensitivity analyses assessed study heterogeneity by type of RDs, age, traditional cardiovascular risk factors, systemic inflammation, and methodology used to evaluate CFR. Twenty-one studies (709 RDs patients and 650 healthy controls) were included in the meta-analysis. Pooled results showed that CFR values were significantly lower in patients with RDs than in healthy controls (SMD = − 1.51, 95% CI − 1.91, − 1.11; p < 0.001; I2 = 90.1%, p < 0.001). The between-group differences in CFR were not associated with inflammatory burden, age, lipids, body mass index, blood pressure, or assessment methods. Patients with prevalent autoimmune features (e.g., systemic lupus erythematosus) showed a significantly lower CFR when compared to patients with mixed autoimmune and autoinflammatory features (e.g., psoriatic arthritis). This meta-analysis showed a significant impairment in CFR in patients with RDs with respect to the general population. Differences in pathogenetic mechanisms may influence the severity of CFR impairment in RDs.

Prevalence and Determinants of Peripheral Microvascular Endothelial Dysfunction in Rheumatoid Arthritis Patients: A Multicenter Cross-Sectional Study.

Abstract: Objectives To define the prevalence and determinants of peripheral microvascular endothelial dysfunction (ED) in a large series of rheumatoid arthritis (RA) patients free of previous cardiovascular events Materials and Methods Data from 874 RA patients enrolled in the EDRA study (Endothelial Dysfunction Evaluation for Coronary Heart Disease Risk Estimation in Rheumatoid Arthritis—ClinicalTrialsgov: and OR (95% CI) = 1005 (1002–1009), , respectively] Multiple regression analysis showed a positive correlation between Ln-RHI values and systolic blood pressure and HDL cholesterol levels; furthermore, higher values of Ln-RHI were associated with ACPA positivity, while smoking habit was associated with lower Ln-RHI values Conclusions This study demonstrates for the first time a high prevalence of peripheral microvascular ED in patients with RA free of previous cardiovascular events that appear to be only partially driven by traditional cardiovascular risk factors The association between ACPA negativity and ED warrants further exploration

Red blood cell distribution width in pregnancy: a systematic review

Abstract: Anisocytosis has been associated with the severity and prognosis of several acute and chronic diseases, as well as physiological conditions such as pregnancy. Anisocytosis is quantified by the red blood cell distribution width (RDW), expressed as the ratio, multiplied by 100, between the standard deviation (SD) of red blood cell volumes and the mean corpuscular volume, or as the SD of erythrocyte volumes (RDW-SD). The aim of the present review was to report the state of the art on the physiological values and the putative diagnostic and prognostic roles of RDW in complicated pregnancy. Literature research for articles published in the last ten years was conducted in Pubmed, Web of Science, ClinicalTrials.gov, and Scopus databases. Abstracts were independently screened by two investigators. If relevant, full articles were retrieved. References, in these articles, citing relevant reviews or original studies were also accessed to identify additional eligible studies. Any disagreement between the reviewers was resolved by a third investigator. A total of 28 studies were included in the review. These studies reported changes in RDW values during physiological pregnancy, and associations between the RDW and several pregnancy complications including anaemia, preeclampsia, gestational diabetes, and recurrent miscarriage. This review provides background information for establishing physiological and pathological RDW values in pregnancy for diagnostic and prognostic use in clinical practice.

Circulating malondialdehyde concentrations in patients with stable chronic obstructive pulmonary disease: a systematic review and meta-analysis.

Abstract: The aim of this meta-analysis was to review the available evidence regarding the blood concentrations of the oxidative stress marker malondialdehyde (MDA) in chronic obstructive pulmonary disease (COPD) patients in comparison to healthy individuals. 14 studies were included in the meta-analysis (from inception to October 2017) with a total of 817 COPD patients and 530 healthy controls. Pooled MDA concentrations were significantly higher in patients with COPD than controls (standardized mean differences = 2.39 μmol/l, 95% CI: 1.50-3.28 μmol/l; p < 0.001). Our meta-analysis showed that the blood concentrations of MDA are consistently higher in patients with COPD when compared with healthy controls, suggesting an important role of lipid peroxidation, and thus oxidative stress, in the pathogenesis of COPD.

Oxidative stress-linked biomarkers in idiopathic pulmonary fibrosis: a systematic review and meta-analysis.

Abstract: Aim The aim of this meta-analysis was to investigate associations between idiopathic pulmonary fibrosis (IPF) and markers of oxidative stress (OS) measured in different biological samples. Methods A systematic search of publications listed in PubMed, Web of Science, Scopus and Google Scholar from inception to December 2017 was conducted. Results Significant differences between IPF patients and controls were observed for all biomarkers (thiobarbituric acid reactive substances, hydroperoxides and glutathione), barring systemic isoprostanes. Conclusion This meta-analysis showed a consistent increase in the concentrations of OS markers or a reduction in antioxidant markers, in patients with IPF, independent of the type of biological sample. Pending the results of further studies, OS biomarkers might be useful for the diagnosis and monitoring of IPF.

Inflammatory cell indexes as preoperative predictors of hospital stay in open elective thoracic surgery.

Abstract: BACKGROUND Shorter and safer hospital stay (HS) is a desired outcome for patients undergoing thoracic surgery. The aim of the present study was to evaluate the predictive capacity of a series of pre-defined inflammatory cell indexes based on preoperative complete blood counts, towards length of HS in open elective thoracic surgery. METHODS We retrospectively studied 157 consecutive patients undergoing open elective thoracic surgery. Preoperative neutrophil to lymphocyte, platelet to lymphocyte and lymphocyte to monocyte ratios were calculated, and the red cell distribution width and mean platelet volume were registered. In addition, the systemic inflammation response index (SIRI) and a further derivative index, the aggregate inflammation systemic index (AISI) were calculated. RESULTS Statistically significant and positive correlations were observed between HS and SIRI, and between HS and AISI. In multiple logistic regression analysis, after dividing the patients in groups with normal and prolonged HS and adjusting for several confounders, only AISI was independently associated with HS. CONCLUSIONS Our results suggest that simple, inexpensive and widely available inflammatory cell indexes like SIRI and, particularly AISI, can be useful for the early identification of patients at risk of prolonged HS in open elective thoracic surgery.

Repurposing existing drugs for cardiovascular risk management: a focus on methotrexate

Abstract: About 20% of patients with a history of atherosclerotic cardiovascular disease will experience further cardiovascular events despite maximal pharmacological treatment with cardioprotective drugs. This highlights the presence of residual cardiovascular risk in a significant proportion of patients and the need for novel, more effective therapies. These therapies should ideally target different pathophysiological pathways involved in the onset and the progression of atherosclerosis, particularly the inflammatory and immune pathways. Methotrexate is a first-line disease-modifying antirheumatic drug that is widely used for the management of autoimmune and chronic inflammatory disorders. There is some in vitro and in vivo evidence that methotrexate might exert a unique combination of anti-inflammatory, blood pressure lowering, and vasculoprotective effects. Pending the results of large prospective studies investigating surrogate end-points as well as morbidity and mortality, repurposing methotrexate for cardiovascular risk management might represent a cost-effective strategy with immediate public health benefits. This review discusses the current challenges in the management of cardiovascular disease; the available evidence on the effects of methotrexate on inflammation, blood pressure, and surrogate markers of arterial function; suggestions for future research directions; and practical considerations with the use of methotrexate in this context.

Evaluation of modafinil as a perpetrator of metabolic drug-drug interactions using a model informed cocktail reaction phenotyping trial protocol.

Abstract: Aim To evaluate the capacity for modafinil to be a perpetrator of metabolic drug–drug interactions by altering cytochrome P450 activity following a single dose and dosing to steady state. Methods A single centre, open label, single sequence cocktail drug interaction trial. On days 0, 2 and 8 participants were administered an oral drug cocktail comprising 100 mg caffeine, 30 mg dextromethorphan, 25 mg losartan, 1 mg midazolam and 20 mg enteric-coated omeprazole. Timed blood samples were collected prior to and for up to 6 h post cocktail dosing. Between days 2 and 8 participants orally self-administered 200 mg modafinil each morning. Results Following a single 200 mg dose of modafinil mean (± 95% CI) AUC ratios for caffeine, dextromethorphan, losartan, midazolam and omeprazole were 0.95 (± 0.08), 1.01 (± 0.35), 0.97 (± 0.10), 0.98 (± 0.10) and 1.36 (± 0.06), respectively. Following dosing of modafinil to steady state (200 mg for 7 days), AUC ratios for caffeine, dextromethorphan, losartan, midazolam and omeprazole were 0.90 (± 0.16), 0.79 (± 0.09), 0.98 (± 0.11), 0.66 (± 0.12) and 1.90 (± 0.53), respectively. Conclusions These data support consideration of the risk of clinically relevant metabolic drug–drug interactions perpetrated by modafinil when this drug is co-administered with drugs that are primarily cleared by CYP2C19 (single modafinil dose or steady state modafinil dosing) or CYP3A4 (steady state modafinil dosing only) catalysed metabolic pathways.

Plasma Proteomic Signatures in Early Chronic Obstructive Pulmonary Disease.

Abstract: Purpose Chronic obstructive pulmonary disease (COPD) is characterized by progressive airflow limitation and abnormal inflammatory response of the lungs to inhaled noxious particles or gases. We used a proteomic approach with 2-DE followed by MALDI TOF-MS analyses in order to identify potential biomarkers in the early stages of the disease: global initiative for chronic obstructive pulmonary disease (GOLD) stage mild and moderate. Experimental design Blood plasma was collected from 43 patients with mild and moderate COPD as well as from 43 age- and sex-matched control subjects. Proteome analysis was based on 2D-Page followed by MALDI-TOF MS identifications. Validation was made on two significant proteins by western blotting. Results The analyses revealed 29 between-group differences in expressed spots, belonging to 20 unique proteins. These proteins are involved in inflammation (haptoglobin, Ig alpha-1 chain C), blood coagulation and complement pathways (prothrombin, complement 4-B, ApoH), oxidative stress (ceruloplasmin, vitamin D binding protein, and serotransferrin), and lipoprotein/lipid metabolism (apolipoprotein A-I, and apolipoprotein E). Conclusion and clinical relevance These results indicate that specific proteomic signatures can be detected and useful in terms of treatment selection and in early COPD patient monitoring.

Increased kynurenine plasma concentrations and kynurenine-tryptophan ratio in mild-to-moderate chronic obstructive pulmonary disease patients.

Abstract: Aim Since an increase in kynurenine (Kyn) plasma concentrations has been proposed as marker of immune system activation, we studied the associations between the Kyn levels and presence and severity of chronic obstructive pulmonary disease (COPD). Methods & results Plasma Kyn, tryptophan (Trp) and Kyn/Trp ratio were measured in 43 COPD patients with clinically defined mild (n = 29) or moderate (n = 14) disease and 43 age- and sex-matched healthy controls. When compared with controls, COPD patients had significantly higher plasma Kyn concentrations and Kyn/Trp ratios. In multiple logistic regression analysis, after adjusting for clinical and demographic confounders, the Kyn/Trp ratio was independently associated with COPD severity. Discussion & conclusion Kyn and Kyn/Trp ratio might represent a new, sensitive, biomarker of systemic inflammation in COPD patients.

Systemic concentrations of asymmetric dimethylarginine (ADMA) in chronic obstructive pulmonary disease (COPD): state of the art.

Abstract: Experimental evidence suggests that oxidative stress (OS) may increase the activity of arginine methylating enzymes that produce the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA). In addition, it is well documented that OS can significantly decrease the synthesis and/or activity of ADMA degrading enzymes, thus causing ADMA accumulation in biological fluids. Recent reports have focused on circulating methylated arginine concentrations in chronic obstructive pulmonary disease, a disease characterized by a significant increase in OS. This review discusses the results of these studies and the opportunities for further research in this area.

Sex Differences in the Associations between L-Arginine Pathway Metabolites, Skeletal Muscle Mass and Function, and their Responses to Resistance Exercise, in Old Age.

Abstract: The current study was designed to explore the associations between L-arginine metabolites and muscle mass and function in old age, which are largely unknown. The study used a randomised, double-blind, placebo-controlled design. The study was carried out in a laboratory setting. 50 healthy older adults [median age 70 years (IQR 67-73); 27 males]. Participants undertook an 18-week resistance exercise program, and a nutritional intervention (fish oil vs. placebo). Serum homoarginine, ornithine, citrulline, asymmetric dimethylarginine (ADMA), NG-monomethyl-L-arginine (L-NMMA), and symmetric dimethylarginine (SDMA), maximal voluntary contraction (MVC) and isokinetic torque of the knee extensors at 30° s-1 (MIT), muscle cross sectional area (MCSA) and quality (MQ) were measured at baseline and after the intervention. No significant exercise-induced changes were observed in metabolite concentrations. There were significant sex differences in the associations between metabolites and muscle parameters. After adjusting for age, glomerular filtration rate and fish oil intervention, citrulline (P=0.002) and ornithine (P=0.022) were negatively associated with MCSA at baseline in males but not females. However, baseline citrulline was negatively correlated with exercise-induced changes in MVC (P=0.043) and MQ (P=0.026) amongst females. Furthermore, amongst males, baseline homoarginine was positively associated with exercise-induced changes in MVC (P=0.026), ADMA was negatively associated with changes in MIT (P=0.026), L-NMMA (p=0.048) and ornithine (P<0.001) were both positively associated with changes in MCSA, and ornithine was negatively associated with changes in MQ (P=0.039). Therefore, barring citrulline, there are significant sex differences in the associations between L-arginine metabolites and muscle mass and function in healthy older adults. These metabolites might enhance sarcopenia risk stratification, and the success of exercise programs, in old age.

The effect of vitamin B12 and folic acid supplementation on routine haematological parameters in older people: an individual participant data meta-analysis.

Abstract: Low vitamin B12 and folate levels in community-dwelling older people are usually corrected with supplements. However, the effect of this supplementation on haematological parameters in older persons is not known. Therefore, we executed a systematic review and individual participant data meta-analysis of randomised placebo-controlled trials (RCTs). We performed a systematic search in PubMed, EMBASE, Web of Science, Cochrane and CENTRAL for RCTs published between January 1950 and April 2016, where community-dwelling elderly (60+ years) who were treated with vitamin B12 or folic acid or placebo. The presence of anaemia was not required. We analysed the data on haematological parameters with a two-stage IPD meta-analysis. We found 494 full papers covering 14 studies. Data were shared by the authors of four RCTs comparing vitamin B12 with placebo (n = 343) and of three RCTs comparing folic acid with placebo (n = 929). We found no effect of vitamin B12 supplementation on haemoglobin (change 0.00 g/dL, 95% CI: −0.19;0.18), and no effect of folic acid supplementation (change −0.09 g/dL, 95% CI: −0.19;0.01). The effects of supplementation on other haematological parameters were similar. The effects did not differ by sex or by age group. Also, no effect was found in a subgroup of patients with anaemia and a subgroup of patients who were treated >4 weeks. Evidence on the effects of supplementation of low concentrations of vitamin B12 and folate on haematological parameters in community-dwelling older people is inconclusive. Further research is needed before firm recommendations can be made concerning the supplementation of vitamin B12 and folate.

Genetic polymorphism of the methotrexate transporter ABCG2, blood pressure and markers of arterial function in patients with rheumatoid arthritis: repeated cross-sectional study

Abstract: Purpose Methotrexate (MTX) treatment is associated with lower blood pressure (BP) and arterial stiffness in rheumatoid arthritis (RA). We investigated associations between single-nucleotide polymorphism (SNP) of the ATP-binding cassette efflux transporter gene ABCG2 (rs2231142), BP, and arterial stiffness in RA patients treated with MTX. Patients and methods Clinical and 24-hour peripheral and central BP, arterial wave reflection (Augmentation Index, AIx), arterial stiffness (Pulse Wave Velocity, PWV), and intracellular MTX polyglutamate (MTXPGs) concentrations were assessed in 56 RA patients on stable treatment with MTX using a repeated cross-sectional study design with measurements at baseline and after 8 months. Results Majority of the RA patients were homozygotes for the normal allele (CC, n=46) whereas 10 were rs2231142 heterozygotes (AC, n=10). MTXPGs concentrations were non-significantly higher in AC when compared to CC (144.3 vs 116.3 nmol/L packed RBCs, P=0.10). At baseline, the AC group had significantly lower age-adjusted clinical systolic BP (SBP) (P=0.01), 24-hour peripheral SBP (P=0.003), and central SBP (P=0.02) when compared to the CC group. However, AIx and PWV values were not significantly different between the two groups. When data from both visits were combined in a single analysis, and additionally adjusted for visit, gender, body mass index, and Disease Activity Score 28, the trend in SBP differences between-groups persisted but was no longer significant. Conclusion Future studies are required to test the hypothesis that this genetic polymorphism is associated with lower BP, arterial stiffness, and possibly, cardiovascular risk, in RA patients treated with MTX.

Real-world incidence of patient-reported dyspnoea with ticagrelor:

Abstract: Dyspnoea, a common and multifactorial symptom in patients with acute coronary syndrome, has been associated with lower quality of life and hospital readmission. Prescriber preference for antiplatel...

Predictors of anti-VEGF drug-induced hypertension using different hypertension criteria: a secondary analysis of the COMPARZ study

Abstract: Background:There is inconsistency in the criteria used to define anti-vascular endothelial growth factor (VEGF) drug-induced hypertension (AVEGF-HT) in published studies. It is unknown whether spec...

Development of an LC⁻Tandem Mass Spectrometry Method for the Quantitative Analysis of Hercynine in Human Whole Blood.

Abstract: Given that the peculiar redox behavior of ergothioneine involves a rapid regeneration process, the measurement of its precursor and redox metabolite hercynine could be particularly useful in assessing its role in oxidative stress or other biological processes. Thus, a LC-MS/MS method for the determination of hercynine concentrations in whole blood was developed. After lysis of red blood cells by cold water, samples were filtered on micro concentrators at a controlled temperature of 4 °C. The clear filtered fluid was then treated with diethylpyrocarbonate to derivatize hercynine for the analysis by LC-MS/MS. The derivatized analyte was isocratically separated as a carbethoxy derivative on a C18 column with a mobile phase of an aqueous 0.1% v/v formic acid and acetonitrile (95:5). Effluents were monitored by MRM transitions at m/z 270.28→95 and 273.21→95 for hercynine and its deuterated counterpart, respectively. No cross-talk between MRM transitions was observed and a good linearity was found within a range of 35–1120 nmol/L. The LOD and LOQ were, respectively, 10.30 and 31.21 nmol/L with an intraday and intermediate precision below 7%. The average hercynine concentration in whole blood from 30 healthy male volunteers (aged 77 ± 12 years) was 178.5 ± 118.1 nmol/L. Overall, the method is easy to perform, allowing a rapid and accurate assessment of whole blood concentrations of hercynine.

Hercynine content in widely consumed commercial beverages

Abstract: Hercynine, the main biosynthetic precursor and oxidative metabolite of ergothioneine, was measured by an LC-ESI-MS/MS method in tea, coffee, beer, and wine samples. Results showed that hercynine was detectable and measurable in all beverage. Among teas, the higher concentration was in the black variety (170.45 ± 7.84 ng/mg of dry weight) followed by the white (130.63 ± 8.79 ng/mg of dry weight) and green ones (71.62 ± 6.13 and 47.43 ± 7.66 ng/mg of dry weight). Compared to teas, coffees had less amount of hercynine with more homogeneous levels that appear unlinked to the kind of mixture (100% Arabica 12.92 ± 1.01 ng/mg of dry weight, 50/50 Arabica/Robusta 10.52 ± 0.38 ng/mg of dry weight, and decaffeinated 8.59 ± 0.75 ng/mg of dry weight). Overall, the red wines had the highest values of hercynine compared to the whites (379.57 ± 238.15 vs. 575.51 ± 62.60 nmol/L). In the latter, hercynine concentrations showed a trend toward an increase with increasing pH values. Hercynine concentrations in the beers were similar to the levels in wines, and there was no difference between traditional and gluten-free sample (679.24 ± 0.92 vs. 570.58 ± 0.88 nmol/L). These data highlight the potential of hercynine as a possible marker of antioxidant activity of ergothioneine in beverages and food.

Comprehensive Geriatric Assessment and Personalized Medicine

Abstract: There is increasing evidence that personalized medicine, an evolving field where patient management is based on individual genetic, molecular or cellular characteristics, improves the outcome of several disease states, particularly cancer. However, the routine application of personalized medicine in the ever-growing cohort of frail older patients presents significant challenges because of the confounding impact of coexisting disease states, polypharmacy, and interindividual variability in homeostatic capacity and treatment response. Furthermore, the use of conventional, disease-specific, end points, typically investigated in clinical trials conducted in younger and/or healthier subjects, is also questionable in patients with poor functional status and limited life expectancy. In this patient group, the maintenance of independence is key to self-rated health. However, whether measures of independence and quality of life can be used to better select treatment strategies and improve outcomes in older patients remains to be investigated. The development of robust and validated tools to quantify key components of the comprehensive geriatric assessment provides opportunities to (a) design interventions that take into account measures of frailty and functional status and (b) investigate the role of patient-centred end points in monitoring the effects of such interventions. In this context, an age-adapted definition, patient-centred medicine, indicates a management approach primarily based on measures of frailty and quality of life, rather than more fundamental genetic or molecular factors. Research is warranted to investigate whether combining personalized medicine with patient-centred medicine leads to more effective and safe management strategies in old age.

Serum Methylarginines and Hearing Loss in a Population-based Cohort of Older Adults.

Abstract: Objective Age-related hearing loss is associated with endothelial dysfunction and increased cardiovascular risk, suggesting a vascular etiology. Methylarginines are endogenous nitric oxide synthase inhibitors that cause endothelial dysfunction and increase cardiovascular disease risk. This study is the first to examine the hypothesis that higher serum concentrations of methylarginines are associated with greater hearing loss prevalence. Study design/patients Cross-sectional audiometric data on hearing levels, and serum methylarginines were collected from a population-based sample of 630 older community-dwelling adults. Results Linear regression analysis showed a statistically significant association between higher serum concentrations of asymmetric dimethylarginine (ADMA) and L-arginine and greater degrees of hearing loss for males, particularly over 75 years. Higher body mass index and previous history of stroke were also associated with hearing loss. For females, ADMA concentration was not associated with hearing loss, but higher serum L-arginine concentrations were associated with reduced hearing loss prevalence in older females. Antihypertensive medication use was also associated with reduced hearing loss prevalence. LDL cholesterol and previous myocardial infarction were associated with greater hearing loss. Conclusion This study showed a significant association between serum concentrations of ADMA and hearing loss for males, consistent with the association between endothelial dysfunction and hearing loss. The opposite effect of L-arginine on hearing loss in males versus females might reflect a different role of this precursor toward nitric oxide versus methylated arginines synthesis. These findings are potentially clinically significant if the association between ADMA and hearing loss is causal, as serum methylarginine levels are modifiable through pharmacotherapeutic/lifestyle interventions.