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BACKGROUND AIMS: Nitric oxide, a major inhibitory nonadrenergic, noncholinergic neurotransmitter that relaxes smooth muscle, may be implicated in the pathophysiology of visceral hypersensitivity in irritable bowel syndrome (IBS). Impaired bioavailability of the nitric oxide precursor molecule L-arginine and higher concentrations of methylarginines (endogenous inhibitors of nitric oxide synthesis) are known to impair nitric oxide synthesis in numerous gastrointestinal cell types. We therefore examined serum concentrations of L-arginine and the methylarginines in a nested case-control study, to assess whether these factors are associated with adult IBS.Data on clinical characteristics, methylarginines, and L-arginine (measured using LC-MS/MS) were collected from a random population-based cohort of Australian adults (median age = 64 years; IQR = 60-70). Cases of IBS, defined according to Rome III criteria (N = 156), and controls (N = 332) were identified from within the cohort at the 5-year follow-up.In adjusted logistic regression analyses, L-arginine, asymmetric dimethylarginine, symmetric dimethylarginine, L-arginine/asymmetric dimethylarginine ratio, and Kessler-10 psychological distress scores were significantly associated with IBS (p 0.05). [Correction added on 18 September 2021, after first online publication: In the preceding sentence, the value (p 0.05) has been changed to (p 0.05)]. Similar results were found for IBS subtypes. Higher serum L-arginine concentration had the strongest association with IBS diagnosis, with an odds ratio of 9.03 for those with serum L-arginine at the 75th (84 μmol/L) versus 25th (46 μmol/L) percentile (95% CI: 5.99-13.62). L-arginine had the best discriminative ability with a bias-adjusted area under the receiver operator characteristic curve of 0.859.Higher serum concentrations of L-arginine and endogenous methylarginines are strongly associated with IBS in adults.

Aims This study aimed to explore the rapid effects of dapagliflozin in heart failure with reduced ejection fraction (HFrEF). Methods and results We studied the functional, echocardiographic, electrophysiological, lung ultrasound, ambulatory blood pressure (BP), microvascular and macrovascular function, and biochemical effects of 2 week treatment with dapagliflozin in 19 type 2 diabetic HFrEF patients in a double‐blind, crossover, placebo‐controlled trial. Dapagliflozin had no significant effect on clinical, functional, or quality of life parameters. Dapagliflozin reduced systolic BP [114 (105, 131) vs. 106 (98, 113) mmHg, P

OBJECTIVE While the global prevalence of antibiotic-resistant Helicobacter pylori (H. pylori) is increasing, there is much regional variation, and local data are required to guide eradication therapy. We performed a systematic review and meta-analysis to determine rates of H. pylori antibiotic resistance in Australia and New Zealand. STUDY DESIGN Random effects meta-analysis of data from 15 published studies and three published abstracts reporting prevalence of primary or secondary H. pylori antibiotic resistance in Australasia. DATA SOURCES PubMed, EMBASE, MEDLINE, PROSPERO, and the Cochrane Library were searched until August, 2020. DATA SYNTHESIS Fifteen published studies and three published abstracts were identified; one study was excluded due to high risk of bias. Seventeen studies conducted between 1996 and 2013 were included in the final analysis, 12 reporting primary and five reporting secondary antibiotic resistance. Prevalence of primary resistance was clarithromycin 7.4% (95% confidence interval [CI], 5.3-9.7%), metronidazole 50.0% (95%CI, 23.9-56.1%), fluoroquinolones 3.7% (95%CI, 0.004-14.8%), and both amoxicillin and tetracycline

Objective To evaluate the diagnostic accuracy of anticarbamylated protein antibodies (CarP), alone and in combination with traditional biomarkers (rheumatoid factor [RF] and anticitrullinated peptide antibodies [ACPA]), in established rheumatoid arthritis (RA). Methods A commercially available enzyme‐linked immunosorbent assay (ELISA) kit was used to assess CarP concentrations in serum samples of 200 established RA and 206 controls (115 healthy donors and 55 patients with other rheumatic diseases). Main outcome measures were sensitivity, specificity, and area under the curve (AUC; 95% confidence interval [CI]). Difference in accuracy was evaluated by comparison of the respective AUCs. Results A serum CarP cut‐off of 1.47 ng/ml or more differentiated patients with RA from controls with 30% sensitivity, 97.1% specificity, and good accuracy (AUC[95%CI] = 0.83[0.79‐0.86], P < 0.0001). However, it showed moderate diagnostic accuracy in seronegative RA patients: sensitivity 17.9%, specificity 96.9%, and AUC (95% CI) = 0.69 (0.63‐0.75). The diagnostic accuracy of CarP_ACPA and CarP_RF combinations was significantly superior to that of ACPA and RF alone (P < 0.0001 and P = 0.015, respectively), but not to that of ACPA_RF combination (P = 0.089) In addition, the CarP_ACPA_RF combination did not improve the diagnostic accuracy of the ACPA_RF combination (AUC mean difference [95% CI] = 0.006 [−0.001 to 0.015], P = 0.10). The number of positive autoantibodies (0, 1, 2, or 3) was not significantly associated with moderate‐severe disease (Disease Activity Score‐28 [DAS‐28] > 3.2) in adjusted multiple regression analysis. Conclusion CarP has good diagnostic accuracy in established RA but not in seronegative RA. The addition of CarP to ACPA and RF alone or in combination does not significantly enhance the diagnostic accuracy of ACPA_RF combination.

Increased concentrations of serum aspartate transaminase (AST) and alanine transaminase (ALT) are common in COVID‐19 patients. However, their capacity to predict mortality, particularly the AST/ALT ratio, commonly referred to as the De Ritis ratio, is unknown. We investigated the association between the De Ritis ratio on admission and in‐hospital mortality in 105 consecutive patients with coronavirus disease of 2019 (COVID‐19) admitted to three COVID‐19 referral centres in Sardinia, Italy. The De Ritis ratio was significantly lower in survivors than nonsurvivors (median: 1.25; IQR: 0.91‐1.64 vs 1.67; IQR: 1.38‐1.97, P = .002) whilst there were no significant between‐group differences in ALT and AST concentrations. In ROC curve analysis, the AUC value of the De Ritis ratio was 0.701 (95% CI 0.603‐0.787, P = .0006) with sensitivity and specificity of 74% and 70%, respectively. Kaplan‐Meier survival curves showed a significant association between the De Ritis ratio and mortality (logrank test P = .014). By contrast, no associations were observed between the ALT and AST concentrations and mortality (logrank test P = .83 and P = .62, respectively). In multivariate Cox regression analysis, the HR in patients with De Ritis ratios ≥1.63 (upper tertile of this parameter) remained significant after adjusting for age, gender, smoking status, cardiovascular disease, intensity of care, diabetes, respiratory diseases, malignancies and kidney disease (HR: 2.46, 95% CI 1.05‐5.73, P = .037). Therefore, the De Ritis ratio on admission was significantly associated with in‐hospital mortality in COVID‐19 patients. Larger studies are required to confirm the capacity of this parameter to independently predict mortality in this group.

Prescribing in heart failure (HF), a common disease state that predominantly affects the older population, is often a challenging task because of the dynamic nature of the condition, requiring frequent monitoring and medication review, the presence of various comorbidities, and the frailty phenotype of many patients. The significant alterations in various organs and tissues occurring in HF, particularly the reduced cardiac output with peripheral hypoperfusion and the structural and functional changes of the gastrointestinal tract, liver and kidney, might affect the pharmacokinetics of several drugs. This review critically appraises the results of published studies investigating the pharmacokinetics of currently marketed cardiovascular and selected non-cardiovascular drugs in HF patients and control groups, identifies gaps in the current knowledge, and suggests avenues for future research in this complex patient population.

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.

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.

Chronic obstructive pulmonary disease (COPD) and asthma are both characterized by heterogeneous chronic airway inflammation and obstruction as well as oxidative stress (OS). However, it is unknown whether OS occurs in early disease and how to best assess its presence. Plasma OS markers (TBARS, PSH, taurine, GSH, ergothioneine and paraoxonase 1 activity) and lung function tests were measured in patients with mild stable asthma (n = 24) and mild stable COPD (n = 29) and in age- and sex-matched controls. Forced expiratory volume in 1 s (FEV1 ) was associated with age both in patients and control groups. By contrast, FEV1 was positively correlated with PSH only in COPD (ρ = 0·49, P = 0·007). In multiple logistic regression analysis, lower PSH was the only OS marker independently associated with increased odds of both asthma (OR = 0·32, 95% CI 0·13-0·78, P = 0·01) and COPD (OR = 0·50, 95% CI 0·26-0·95, P = 0·03). These findings suggest that proteins -SH are a sensitive OS marker in early COPD and asthma.

Use of angiotensin system inhibitors (ASIs; angiotensin receptor blockers or angiotensin-converting enzyme inhibitors) has been reported to be associated with improved survival in metastatic renal cell carcinoma (mRCC), particularly when used with vascular endothelial growth factor-targeted therapies. This study was a secondary pooled analysis of two Phase III randomized controlled trials (RCTs) of patients with mRCC: NCT00334282 comparing pazopanib to placebo and NCT00720941 comparing pazopanib to sunitinib. ASI users were defined as patients using an ASI at baseline. Association with overall survival (OS; primary outcome) and progression-free survival (PFS) was evaluated using Cox proportional hazards regression. The association was adjusted in multivariable analysis for baseline systolic blood pressure (SBP), use of other antihypertensive drugs and prognostic factors comprising the Heng risk criteria for mRCC. Of 1,545 patients pooled from the two RCTs, 649 (42%) were using one or more antihypertensive drugs at baseline, 385 (59%) of which were using an ASI. In the multivariable analysis of patients using pazopanib or sunitinib, no significant association was observed between baseline ASI use and OS (hazard ratio [HR] 0.97 [95% confidence interval (CI) 0.80-1.18], p = 0.80) or PFS (HR 0.88 [95% CI 0.73-1.06], p = 0.17). Exploratory subgroup analysis of NCT00720941 highlighted that the effect of baseline ASI use on OS may differ between patients treated with sunitinib and pazopanib. In conclusion, use of ASIs at baseline was not a significant independent prognostic factor for improved survival in a pooled analysis of mRCC patients treated with pazopanib or sunitinib.

Aim The aim was to investigate associations between drugs with anticholinergic effects (DACEs) and cognitive impairment, falls and all-cause mortality in older adults. Methods A literature search using CINAHL, Cochrane Library, Embase and PubMed databases was conducted for randomized controlled trials, prospective and retrospective cohort and case-control studies examining the use of DACEs in subjects ≥65 years with outcomes on falls, cognitive impairment and all-cause mortality. Retrieved articles were published on or before June 2013. Anticholinergic exposure was investigated using drug class, DACE scoring systems (anticholinergic cognitive burden scale, ACB; anticholinergic drug scale, ADS; anticholinergic risk scale, ARS; anticholinergic component of the drug burden index, DBIAC) or assessment of individual DACEs. Meta-analyses were performed to pool the results from individual studies. Results Eighteen studies fulfilled the inclusion criteria (total 124 286 participants). Exposure to DACEs as a class was associated with increased odds of cognitive impairment (OR 1.45, 95% CI 1.16, 1.73). Olanzapine and trazodone were associated with increased odds and risk of falls (OR 2.16, 95% CI 1.05, 4.44; RR 1.79, 95% CI 1.60, 1.97, respectively), but amitriptyline, paroxetine and risperidone were not (RR 1.73, 95% CI 0.81, 2.65; RR 1.80, 95% CI 0.81, 2.79; RR 1.39, 95% CI 0.59, 3.26, respectively). A unit increase in the ACB scale was associated with a doubling in odds of all-cause mortality (OR 2.06, 95% CI 1.82, 2.33) but there were no associations with the DBIAC (OR 0.88, 95% CI 0.55, 1.42) or the ARS (OR 3.56, 95% CI 0.29, 43.27). Conclusions Certain individual DACEs or increased overall DACE exposure may increase the risks of cognitive impairment, falls and all-cause mortality in older adults. Language: en

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

A small library of guanidino-lactams were synthesized in four steps and good overall yields by following the routes: preparation of guanylating agents, synthesis of protected guanidino-acids, cyclization to fully protected guanidino-lactams, and deprotection to the target compounds. The guanidino-lactams were assayed as antimicrobials on E. coli showing no significant antibiotic activity.

BACKGROUND We conducted a meta-analysis to review the available evidence regarding the associations between peripheral blood neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) and the presence of rheumatoid arthritis (RA). METHODS PubMed, Web of Science and Scopus, from inception to January 2018, were searched for studies reporting on NLR and PLR in RA in comparison with healthy subjects. Standardized mean difference (SMD) was calculated with a confidence interval (CI) of 95%. RESULTS Thirteen NLR studies (1550 RA patients and 1128 healthy controls) and 8 PLR studies (380 RA patients and 305 healthy controls) were included in the meta-analysis. NLR and PLR were significantly higher in patients with RA when compared to controls (SMD = 0.79, 95% CI 0.55-1.03; P

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

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.

* Therapeutic drug monitoring of serum digoxin concentrations (SDC) is considered useful in enhancing the therapeutic benefits of digoxin and minimizing the incidence of adverse drug reactions. * The quality of requests for SDC has been reported to be generally unsatisfactory. However, studies have focused on few information parameters. * A better knowledge of these issues might be useful to target appropriate areas of weakness within heathcare systems.* The poor quality of the information in SDC requests involves a wide range of codes from the contact details of the requester to the time interval between the last dose of digoxin and blood sampling. * Misuse of the therapeutic drug monitoring service is common across different specialties and healthcare settings.To assess the quality of the information provided with serum digoxin concentration (SDC) requests received by a therapeutic drug monitoring service in a regional health service.We conducted a retrospective audit of a consecutive series of 685 SDC requests during a 7-month period. Information regarding (i) contact details, (ii) reasons for request, (iii) dose, (iv) route of administration, (v) concurrent therapy, (vi) treatment duration and (vii) time interval between the last dose and sampling was reviewed and coded as appropriate or inappropriate/missing. Data were analysed according to the origin of request, i.e. from different specialties/wards (emergency department and critical care, cardiology and coronary care unit, medicine and aged care, surgery, and general/private practice) and healthcare settings (teaching hospital, geriatric hospital and general/private practice).The quality of SDC requests was generally poor across different specialties and healthcare settings. The information provided for the coded parameters was appropriate only in 19.1% (i), 6.4% (ii), 54.7% (iii), 45.8% (iv), 12.8% (v), 32.9% (vi) and 47.1% (vii) of cases. No SDC request was complete in all the information codes. SDC requests from general/private practice lacked more often details regarding the dose (information provided in 46.7% of requests, P = 0.007 vs. other specialties; P = 0.02 vs. other settings) and the route of administration (20.0%, P0.001 vs. other specialties and vs. other settings). SDC requests from the emergency department and critical care unit lacked more often details regarding the treatment duration (22.6%, P0.001 vs. other specialties) and the time interval between the last dose and blood sampling (40.1%, P = 0.01 vs. other specialties).The quality of the information in SDC requests is poor across different specialties and healthcare settings. Educational strategies to ensure the appropriate use of this service are urgently needed.

Background: The tilt table test (TTT) is a useful diagnostic tool in people with unexplained syncope, dizziness, and falls. However, preexisting comorbidities and medications affecting hemodynamic response might affect TTT outcome (i.e. presence or absence of vasomotor syncope). We studied the influence of these compounding factors on TTT outcome. Methods: One hundred and sixty-four elderly patients with a mean (±SD) age of 80.0 ± 6.1 years (M:F 104:60) underwent TTT. Heart rate and blood pressure were recorded continuously using a noninvasive device (Task Force Monitor™, CNS systems, Graz, Austria). Predictors of TTT outcome in a backward regression analysis included age, gender, comorbidities (chronic heart failure, hypertension, diabetes, and cerebrovascular disease), and drugs (β-blockers, angiotensin-converting enzyme inhibitors, calcium channel blockers, diuretics, digoxin, opioids, antidepressants, and nonsteroidal antiinflammatory agents). Results: TTT was positive in 30 patients (18.3%). None of the above factors were a significant predictor of TTT outcome. The use of calcium channel blockers predicted a drop in systolic blood pressure after 2 minutes of TTT (P = 0.048, R2= 0.018). However, this was not associated with significant changes in heart rate and did not influence TTT outcome. Conclusion: The TTT outcome was not influenced by comorbidities or medications. TTT is a reliable diagnostic tool in a population characterized by significant comorbidities and polypharmacy.

Beta-adrenoceptor blockers and thrombolytic agents are of established value in the pharmacological management of heart failure and ST-elevation myocardial infarction, respectively. However, there is uncertainty as to whether these therapeutic strategies can be safely and effectively adopted in elderly patients with comorbidities, particularly in old-old individuals. This review focuses on these trials and the age-related efficacy and safety of these drugs.

Advancing age is characterized by impairment in the function of the many regulatory processes that provide functional integration between cells and organs. Therefore, there may be a failure to maintain homeostasis under conditions of physiological stress. The reduced homeostatic ability affects different regulatory systems in different subjects, thus explaining at least partly the increased interindividual variability occurring as people get older. Important pharmacokinetic and pharmacodynamic changes occur with advancing age. Pharmacokinetic changes include a reduction in renal and hepatic clearance and an increase in volume of distribution of lipid soluble drugs (hence prolongation of elimination half-life) whereas pharmacodynamic changes involve altered (usually increased) sensitivity to several classes of drugs such as anticoagulants, cardiovascular and psychotropic drugs. This review focuses on the main age-related physiological changes affecting different organ systems and their implications for pharmacokinetics and pharmacodynamics of drugs.

The hazards of prescribing many drugs, including side-effects, drug interactions, and difficulties of compliance, have long been recognized as particular problems when prescribing for elderly people. The need for appropriate and rational prescribing for elderly patients has been prioritized in the National Service Framework for Older People. This review addresses the research evidence on epidemiology of prescribing in elderly patients, methods of measuring the quality, and the role of the prescriber and the multidisciplinary team in the day-to-day optimization of drug therapy.

Stroke and dementia represent a major health burden for elderly subjects as they are associated with significant morbidity and mortality. The rates of stroke and dementia are progressively increasing due to the ageing population in most westernized countries. Therefore, both these conditions represent a major therapeutic target. However, the therapeutic options available for the management of stroke and dementia remain largely unsatisfactory, the main reason being the difficulty in transferring the results obtained in animal and in vitro studies to the clinical setting. This review focuses on the recent advances in pathophysiology and treatment of these conditions and future directions for research. Moreover, the technique of functional magnetic resonance imaging is discussed in detail as a tool to assess the effects of therapeutic agents on the central nervous system and monitor the progression of diseases. Finally, an overview of the issue of drug delivery into the central nervous system is presented.

The ageing process is associated with important changes in the responses of the cardiovascular system to pharmacological stimuli. They are not limited to the arterial system, involved in the modulation of cardiac afterload and vascular resistance, but they also involve the low-resistance capacitance venous system and the heart. The main changes include loss of large artery compliance, dysfunction of some of the systems modulating resistance vessel tone, increased activity of the sympathetic nervous system, and reduced haemodynamic responses to inotropic agents. This review focuses on the effects of ageing on arterial and venous reactivity to drugs and hormones, the autonomic nervous system, and the cardiovascular responses to inotropic agents. Some of the age-related changes might be at least partially reversible. This may have important therapeutic implications.

OBJECTIVES: To elucidate the pathophysiological mechanism of the vasodepressor form (VD) of carotid sinus syndrome (CSS) by maneuvers designed to induce generalized sympathetic activation after baroreceptor unloading (lower body negative pressure, LBNP) or direct peripheral adrenoreceptor stimulation via local administration of norepinephrine (NA). DESIGN: Subjects were identified with VD of CSS through diagnostic testing. SETTING: Research laboratory. PARTICIPANTS: Eleven young controls (YC) (mean age ± standard error of mean = 22.8 ± 0.7), eight elderly controls (EC) (72.6 ± 0.6), and eight elderly patients with VD (78.7 ± 1.7). MEASUREMENTS: Forearm arterial blood flow (FABF) was measured in the left and right arms by venous occlusion plethysmography. Measurements were performed during baseline conditions, LBNP (−20 mmHg), and intra-arterial NA infusion in the left brachial artery at three progressively increasing rates (60, 120, and 240 pmol/min). RESULTS: During LBNP, FABF significantly decreased in YC (baseline 3.61 ± 0.30 vs −20 mmHg 2.96 ± 0.24 mL/100 g/min, P = .030) and EC (4.05 ± 0.74 vs 3.69 ± 0.65 mL/100 g/min, P = .033) but increased in elderly patients with VD (3.65 ± 0.60 vs 4.54 ± 0.80 mL/100 g/min, P = .020). During NA infusion, a significant forearm vasoconstriction occurred in YC (FABF left:right ratio 1.00 ± 0.05 at baseline; 0.81 ± 0.08 at 60 pmol/min, P = .034; 0.81 ± 0.05 at 120 pmol/min, P < .001; 0.72 ± 0.04 at 240 pmol/min, P < .001), whereas no significant FABF changes were observed in EC (1.04 ± 0.06; 0.96 ± 0.07, P = .655; 0.89 ± 0.10, P = .401; 0.94 ± 0.10, P = .590) or elderly patients with VD (1.04 ± 0.06; 1.16 ±0 .10, P = .117; 1.04 ± 0.08, P = .602; 1.11 ± 0.10, P = .305). CONCLUSION: VD of CSS is associated with a paradoxical vasodilatation during LBNP and an impairment of peripheral α-adrenergic responsiveness, which may be age-related.

Slow gastric emptying and intolerance to nasogastric feeds occurs in up to 40–50% of critically ill patients [1, 2]. Not only does this result in inadequate nutritional support, but it is also a major risk factor for gastro-oesophageal reflux and aspiration, with potential adverse affects on both morbidity and mortality [2, 3]. The currently available therapeutic options for managing delayed gastric emptying and feed intolerance in critically ill patients are: total parenteral nutrient therapy, prokinetic therapy and postpyloric feeding [4, 5]. Of these, treatment with prokinetic agents is efficacious and frequently used as the first-line therapy to avoid the septic complications associated with total parenteral nutrient therapy and the technical demand of postpyloric feeding [4, 5]. Low-dose erythromycin (1–3 mg kg−1), a motilin agonist, is a widely used prokinetic agent in critically ill patients. However, erythromycin has recently been reported to effect human haemodynamics adversely, with a fall in systolic blood pressure (SBP) of 10 ± 9 mmHg 1.5–2.5 h after an oral dose of 300 mg [6]. The mechanism responsible for the hypotension following erythromycin remains unclear. In animals, infusion of motilin was found to induce endothelial-dependent vasodilation and a transient reduction in blood pressure (BP) [7]. As erythromycin leads to an increase in plasma motilin concentrations in humans, it is conceivable that the hypotension associated the drug is related to the endothelium-mediated vasodilation exerted by motilin [8]. Although erythromycin is frequently used in critically ill patients, its haemodynamic effects in this group are unknown. A reduction of 10 mmHg in SBP after erythromycin may not be important in healthy subjects but may be clinically relevant in patients with potential cardiovascular compromise such as the critically ill [6]. This study therefore aimed to examine the acute effects of a single intravenous prokinetic dose of erythromycin on BP) and heart rate (HR) in critically ill patients, who were intolerant to nasogastric feeds and were not on inotropic supportive therapy. Nineteen mechanically ventilated, critically ill patients (age 52 ± 18 years, M:F 10 : 9, Acute Physiology and Chronic Health Evaluation II score 21 ± 6, length of Intensive Care Unit stay 10 ± 9 days) were randomized to either erythromycin (i.v. 200 mg) or placebo (i.v. normal saline) in a cross-over study, 12 h apart. Intolerance to intragastric feeding was defined as vomiting or regurgitation during feeding, or a 6-hourly gastric aspirate > 250 ml [9]. The cut-off gastric aspirate > 250 ml used in this study is a previously published clinical marker of feed intolerance [9, 10]. The majority of patients were sedated with morphine and midazolam and only two patients received propofol alone. Five patients received nasogastric antihypertensive medications (ACE inhibitors n = 3, β-blockers n = 1 and calcium channel blockers n = 1). Continuous lying BP (systolic, diastolic and mean) and HR were measured via an arterial line at 15-min intervals for 60 min before and 180 min after the administration of prokinetic therapy by using an automatic device (TRAM-RAC 4A; General Electric, Milwaukee, WI, USA). A reduction in SBP of >10% from baseline was defined as a clinically significant change. The study was approved by the Local Research Ethics Committee. Each subject gave written informed consent prior to the study. The effects of erythromycin on BP and HR were analysed using a linear mixed effects model fitted to the data. In this model, group status (erythromycin or placebo) and time were treated as fixed effects, while subject was treated as a random effect. Data are expressed as mean ± SD, except in Figure 1, where the error bars represent 95% confidence intervals. A P-value

Non-selective nonsteroidal anti-inflammatory drugs (NSAIDs) have long been known to cause gastrointestinal and renal toxicity. More recently, adverse cardiovascular effects have been associated with the selective COX-2 inhibitors. However, current studies that show an increased cardiovascular risk with non-selective NSAIDs raise the question of the exclusive contribution of COX-2 to this type of toxicity. Aldosterone, a key cardiovascular hormone, can induce deleterious effects, such as myocardial fibrosis and vascular stiffening. Non-selective NSAIDs inhibit the metabolism of aldosterone in vitro by human renal tissue, predicating an increased plasma aldosterone concentration in vivo. The question remains whether inhibition of aldosterone metabolism by non-selective NSAIDs is a casual or causal factor in NSAID-induced cardiovascular toxicity.

Open Access article Resistance exercise training is known to be effective in increasing muscle mass in older people. Acute measurement of protein metabolism data has indicated that the magnitude of response may differ between sexes. We compared adaptive responses in muscle mass and function to 18 weeks resistance exercise training in a cohort of older (>65 years) men and women. Resistance exercise training improved knee extensor maximal torque, 4 m walk time, time to complete five chair rises, muscle anatomical cross‐sectional area (ACSA) and muscle quality with no effect on muscle fat/water ratio or plasma glucose, insulin, triacylglycerol, IL‐6, and TNF‐α. Differences between sexes were observed for knee extensor maximal torque and muscle quality with greater increases observed in men versus women (P < 0.05). Maximal torque increased by 15.8 ± 10.6% in women and 41.7 ± 25.5% in men, whereas muscle quality increased by 8.8 ± 17.5% in women and by 33.7 ± 25.6% in men. In conclusion, this study has demonstrated a difference in the magnitude of adaptation, of some of the outcome measures employed, in response to 18 weeks of resistance exercise training between men and women. The mechanisms underlying this observation remain to be established.

Purpose Studies on the risk of stroke in users of non-steroidal anti-inflammatory drugs (NSAIDs) have provided conflicting results. We studied the association between the use of non-selective ns-NSAIDs, selective COX-2 inhibitors, or either of these NSAIDs, and the incidence of stroke-related hospitalization in elderly subjects. Methods We conducted a retrospective nested case-control study on Australian veterans using nationwide hospital admission and pharmacy dispensing data. Conditional logistic regression analysis was used to estimate both crude and adjusted odds ratios (OR) and 95% confidence intervals (CI) for the risk of events for three different measures of prescription supply exposure over the last 2 years; (1) whether supplied at least once; (2) supply frequency: supplied more than twice within the last 30 days, once or twice within the last 30 days, or once or more within 30 days to 2 years; and (3) total supplies. Results There was a trend toward a reduced risk of ischemic stroke with any NSAID (OR 0.95, 95%CI 0.89–1.00) if supplied at least once within the last 2 years and a mildly reduced risk in those supplied any NSAID once or twice within the last 30 days (OR 0.89, 95%CI 0.81–0.98). Use of either ns-NSAIDs or selective COX-2 inhibitors were not associated with a significant change in risk. Conclusions The use of any NSAIDs is not associated with an increase in the risk of ischemic stroke in Australian veterans. Copyright © 2010 John Wiley & Sons, Ltd.

Patient education increases compliance and reduces toxicity or lack of effect during warfarin treatment [1–4]. A proportion of patients start warfarin treatment while in hospital. The need for adequate patient education before discharge is essential to ensure treatment efficacy and minimize toxicity. Although studies have shown that drug information provided to hospitalized patients is inadequate there are no specific data regarding warfarin treatment before discharge [5, 6]. This issue is clinically relevant because acute care patients are being discharged earlier than even before and with increasingly complicated medication regimens [7]. The guidelines for use of the National In-patient Medication Chart, introduced in Australia in 2005, state that all hospitalized patients commenced on warfarin should receive counselling and be given an information booklet. The prescribing doctor or pharmacist must fill a warfarin education record (WER), located next to the warfarin ordering section in the medication chart, as a record that these risk mitigation activities have been completed [8]. We audited the provision of patient education and written drug information to those patients commenced on warfarin during hospitalization at Flinders Medical Centre, a public teaching hospital within a regional health service, between June 2006 and December 2006. The following parameters were extracted from the central patient database: patient hospital number, date of admission, and hospital location for the specified time period. In order to determine which of these patients were treated with warfarin investigation results were reviewed to identify which patients had successive coagulation studies performed on at least 2 consecutive days during admission. Medical records for each of these patients were then reviewed to determine whether the patient had been started on warfarin during admission. In order to assess the distribution of a warfarin information booklet concurrent with initiation of warfarin treatment during admission the following parameters were gathered: age, gender, reason for warfarin use, and completion of the WER box in the drug chart. This information was entered into a database for analysis. The primary outcome was WER completion. No ethics committee approval was sought as this was a retrospective audit. Data are presented as means (SD) or frequencies. Comparisons between groups were performed by Student's t-test or Fischer exact test. A binary logistic regression was performed to identify the factors independently associated with WER completion (SPSS for Windows 14.0, Chicago, IL, USA). A P value