Showing papers by "Arduino A. Mangoni published in 2013"

Asymmetric dimethylarginine: a possible link between vascular disease and dementia.

Abstract: There is good epidemiological evidence that vascular disease predisposes to cognitive decline and dementia. The impact of vascular disease on dementia is likely to increase further because of the poor diagnosis and management of vascular risk factors, the increase in life expectancy, and the improved survival following major cardiovascular events, e.g. acute stroke. It is estimated that the adequate management of vascular risk factors, with pharmacological and/or nonpharmacological interventions, might result in a 50% reduction in the forecasted dementia prevalence. The exact mechanisms by which vascular risk factors and vascular disease adversely affect brain function remain unclear, but it is hypothesized that endothelial dysfunction plays an important role. Reduced synthesis and availability of endothelial nitric oxide (NO) may contribute to the development of dementia by at least two mechanisms: (1) favoring the onset and progression of atherosclerosis, vasoconstriction, and impaired cerebral blood flow regulation; and (2) reduced neuroprotection.Several studies have shown that asymmetric dimethylarginine (ADMA), an endogenous methylated form of the amino acid L-arginine, inhibits NO synthesis and favors oxidative stress and vascular damage. Unlike NO, ADMA concentrations are relatively stable and can be accurately measured in plasma. There is good evidence that higher plasma ADMA concentrations favor atherosclerosis and independently predict adverse cardiovascular and cerebrovascular outcomes in several patient groups. ADMA might represent a unifying pathophysiological pathway linking the presence of vascular risk factors with the onset and progression of cognitive decline and dementia. This review discusses the biological role of ADMA, its potential contribution to the onset and progression of dementia through vascular disease and atherosclerosis, the available evidence linking ADMA with cognitive impairment and dementia, and the strategies to characterize the predictive role of ADMA in cognitive impairment in epidemiological studies. Therapeutic implications and suggestions for future research directions are also discussed.

Prescribing patterns of proton pump inhibitors in older hospitalized patients in a Scottish health board

Abstract: Aim:Proton-pump inhibitors (PPI) are extensively prescribed worldwide. However, little information is available on PPI prescribing patterns, associated clinical and demographic factors, and potential drug-drug interactions in frail older patients.Methods:Data on clinical and demographic characterist

Under-representation of older adults in pharmacokinetic and pharmacodynamic studies: a solvable problem?

Abstract: The impact of advancing age, with or without the presence of structural and/or functional organ impairment, on the disposition and effects of drugs, demands adequate representation of older adults in pharmacokinetic and pharmacodynamic studies. Currently, however, this group remains poorly represented both in pre- and post-marketing studies. This review discusses recent data on the participation of older adults in pharmacokinetic/pharmacodynamic studies using established databases, the potential barriers to study recruitment and retention and possible strategies to enhance participation in this group. The article also provides a critical appraisal of current regulatory documents on the conduct of such studies.

Associations between different measures of anticholinergic drug exposure and Barthel Index in older hospitalized patients

Abstract: Objective:To compare associations between four measures of anticholinergic exposure (anticholinergic risk scale, ARS; anticholinergic drug burden, DBAC; number and use versus no use of anticholiner...

Serum thiols and cardiovascular risk scores: a combined assessment of transsulfuration pathway components and substrate/product ratios

Abstract: Serum thiols have shown associations with surrogate markers of cardiovascular disease. However, little information is available on their combined association with validated cardiovascular risk scores for primary prevention at population level. We sought to determine whether individual serum thiol concentrations and substrate/product ratios within the transsulfuration pathway are independently associated with such scores. Data on clinical and demographic characteristics, serum thiols (homocysteine, cysteine, taurine, glutamylcysteine, total glutathione and cysteinylglycine) and high-sensitivity C-reactive protein (CRP) were collected from a sample of the Hunter Community Study without previous cardiovascular events [n=350, median age (IQR) = 62 (59–66) years]. Five-year absolute cardiovascular risk score for each subject was calculated using the Framingham Risk Equation. Median risk score was 7% (IQR 4–10). After adjusting for body mass index, estimated glomerular filtration rate and physical activity regression analysis showed independent associations between cardiovascular risk scores and a) higher serum homocysteine (B 0.066, 95% CI 0.040 to 0.091, P<0.001) and lower cysteine (B −0.003, 95% CI −0.005 to −0.001, P=0.003) and glutathione (B −0.029, 95% CI −0.056 to −0.003, P=0.03) concentrations; and b) higher homocysteine/cysteine (B 0.114, 95% CI 0.066 to 0.161, P<0.001) and lower glutathione/cysteinylglycine (B −1.145, 95% CI −2.030 to −0.260, P=0.011) ratios. No significant associations were observed between cardiovascular risk scores, taurine and CRP. Serum homocysteine, cysteine and glutathione are independently associated with cardiovascular risk scores at population level. Enzymatic pathways involved in reduced bioconversion of homocysteine into cysteine and increased glutathione degradation might play an important role in such associations.

Aldosterone glucuronidation inhibition as a potential mechanism for arterial dysfunction associated with chronic celecoxib and diclofenac use in patients with rheumatoid arthritis.

Abstract: OBJECTIVES Adverse cardiovascular (CV) effects of non-steroidal anti-inflammatory drugs (NSAIDs) are largely independent of their cyclooxygenase (COX) enzyme selectivity, but could be a consequence of aldosterone 18s-glucuronidation inhibition (AGI), which varies between NSAIDS. This study assesses the chronic effects of celecoxib (selective COX-2 inhibitor) versus diclofenac (non-selective NSAID) therapy on arterial dysfunction in patients with rheumatoid arthritis (RA). METHODS AGI was assessed in vitro using human kidney cortical microsomes. Arterial function was measured clinically as the extent (augmentation index, AIX%) and timing (reflected wave transit time, RWTT, msec) of arterial wave reflection using radial applanation pulse wave analysis (SphygmoCor PWA device) in 39 RA patients without overt CV disease aged 40-65. A higher AIX% (and lower RWTT) indicates arterial dysfunction. Clinical assessment on a single occasion included a fasting blood sample, patient questionnaire and medical record review. Multivariable analysis was used to adjust for sex, mean blood pressure, arthritis duration, cumulative ESR-years and current DMARD therapy. RESULTS The inhibition constant (Ki) for celecoxib was lower than that of diclofenac (Ki, 3.5 vs. 8.4 μM). Chronic celecoxib use was associated with a higher AIX% (34.8 vs. 32.3) and lower RWTT (130.1 vs. 132.7 msec) compared with diclofenac. Adjusted mean differences were AIX% 4.7 (95%CI 0.6 to 8.9; p=0.03) and RWTT -3.6 (95%CI -10.0 to 2.7; p=0.26). CONCLUSIONS Celecoxib has a greater potency for AGI than diclofenac and its use is associated with a significantly higher AIX%. Our findings support AGI as a plausible mechanism for the CV toxicity of NSAIDs.

Serum methylarginines and spirometry-measured lung function in older adults.

Abstract: Funding: Funding provided by the University of Newcastle Strategic Initiative Fund. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Acknowledgments We are grateful to The University of Newcastle for funding and to the men and women of the Hunter region who provided the information recorded.

Routine pharmacological venous thromboembolism prophylaxis in frail older hospitalised patients: where is the evidence?

Abstract: It has been claimed that there are over 25,000 preventable in-hospital deaths from venous thromboembolism annually in the UK. NICE and SIGN guidelines therefore recommend that all hospitalised patients are risk assessed for venous thromboembolism. The guidelines would recommend using pharmacological thromboprophylaxis for all patients aged 60 and above with reduced mobility and acute medical illness unless obvious contra-indications exist. Meta-analysis data regarding pharmacological thromboprophylaxis for medical patients demonstrate reductions in asymptomatic deep vein thrombosis (DVT) rather than fatal pulmonary embolism and mortality. There is also the potential for increased bleeding risk with this approach. Evidence for older medical in-patients, particularly those aged over 75, is more limited being derived from subgroup analyses of larger clinical trials. In addition, based on exclusion criteria such as increased bleeding risk, frailer older adults were unlikely to have been included within such trials. This commentary will (i) critically appraise available data on the incidence of DVT and PE in older hospitalised patients; (ii) review the evidence available from meta-analyses and subgroup analyses in older medical in-patients for the use of venous thromboembolism prophylaxis; (iii) discuss those situations out-with the guidelines where venous thromboprophylaxis may not be appropriate and even potentially harmful in this patient group and (iv) suggest future research directions.

Methylated arginines and nitric oxide in end-stage renal disease: impact of inflammation, oxidative stress and haemodialysis.

Abstract: Objectives: To determine whether inflammation (C-reactive protein, CRP), oxidative stress (malondialdehyde, MDA) or haemodialysis (HD) affect associations between asymmetric (ADMA), symmetric (SDMA) dimethylarginine, NG-monomethyl-L-arginine (L-NMMA) and nitrite/nitrate (NOx) in end-stage renal disease (ESRD).Method: Metabolites were measured pre-HD, after 1 hour and end-HD in 40 ESRD patients (age 63 ± 14 years).Results: Positive associations between NOx and ADMA (p = 0.04), SDMA (p < 0.001) and L-NMMA (p = 0.04) were observed pre-HD. Associations weakened during HD but were not significantly influenced by CRP or MDA.Conclusions: HD, oxidative stress or inflammation did not significantly affect the positive associations between methylated arginines and NOx in ESRD.

Transsulfuration pathway thiols and methylated arginines: the hunter community study

Abstract: Background Serum homocysteine, when studied singly, has been reported to be positively associated both with the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine [ADMA, via inhibition of dimethylarginine dimethylaminohydrolase (DDAH) activity] and with symmetric dimethylarginine (SDMA). We investigated combined associations between transsulfuration pathway thiols, including homocysteine, and serum ADMA and SDMA concentrations at population level.

Health services research

Abstract: Scope: Sedentary behaviour and bed rest in hospital are associated with multiple complications and worse health outcomes in older people. There is evidence that early mobilisation of those patients improves not only health outcomes but also general wellbeing and satisfaction with healthcare. This aspect of care is frequently compromised due to the time pressures experienced by clinical staff. We undertook a systematic literature review of studies that included volunteers helping mobilise older inpatients. Search methods: We searched Cochrane, Medline, Embase, CINNAHL, Amed and Google databases using MeSH headings and keywords within six key themes: inpatients, older, exercise, delirium, falls and volunteers. The abstracts were screened first independently then jointly by two reviewers. Full texts of relevant articles were retrieved. Reference lists were reviewed. Hospital based studies, projects or programmes in which volunteers (+/staff members) were used to assist mobilisation in medical inpatients aged over 65 were included. Multi – intervention trials were included if mobilisation was part of the protocol. We excluded studies limited to a single disease such as stroke or Parkinson’s disease. Results: 1677 papers were identified and the titles and abstracts were screened. Only four studies fulfilled the search criteria and were included in the final review. Multiple scientific abstracts related to one controlled study which included volunteer assisted mobilisation as part of the delirium prevention multi-intervention (HELP).Three observational studies were identified only on Google but were poorly evaluated or still on-going. The data available indicated a positive effect of volunteers on patient and staff satisfaction with care. Conclusions: There is a lack of randomised controlled trials of volunteer assisted mobilisation of older inpatients. When adopted as part of delirium prevention programme volunteers contributed to improved outcomes. There is insufficient evidence to provide guidance on the use of volunteers specifically to deliver mobility assistance to older inpatients.

Effects of red wine on established markers of arterial structure and function in human studies: current knowledge and future research directions.

Abstract: Evidence from observational studies suggests that mild-to-moderate consumption of red wine is associated with reduced cardiovascular morbidity and mortality. Various individual chemical components of red wine also show salutary effects on vascular homeostasis, that is, enhanced endothelial function and arterial distensibility, both in vitro and in animal studies. However, testing the beneficial potential of red wine in primary and secondary cardiovascular prevention on established surrogate cardiovascular markers requires further study with longer term intervention trials. This report reviews and critically appraises the published evidence for the effects of red wine on endothelium-dependent vasodilation, arterial stiffness and arterial wave reflections in healthy subjects and in patients with cardiovascular disease. Suggestions for future research directions are also provided.