Controlling Near-Surface Ni Composition in Octahedral PtNi(Mo) Nanoparticles by Mo Doping for a Highly Active Oxygen Reduction Reaction Catalyst.

We report and study the translation of exceptionally high catalytic oxygen electroreduction activities of molybdenum-doped octahedrally shaped PtNi(Mo) nanoparticles from conventional thin-film rotating disk electrode screenings (3.43 ± 0.35 A mgPt-1 at 0.9 VRHE) to membrane electrode assembly (MEA)-based single fuel cell tests with sustained Pt mass activities of 0.45 A mgPt-1 at 0.9 Vcell, one of the highest ever reported performances for advanced shaped Pt alloys in real devices. Scanning transmission electron microscopy with energy dispersive X-ray analysis (STEM-EDX) reveals that Mo preferentially occupies the Pt-rich edges and vertices of the element-anisotropic octahedral PtNi particles. Furthermore, by combining in situ wide-angle X-ray spectroscopy, X-ray fluorescence, and STEM-EDX elemental mapping with electrochemical measurements, we finally succeeded to realize high Ni retention in activated PtNiMo nanoparticles even after prolonged potential-cycling stability tests. Stability losses at the anodic potential limits were mainly attributed to the loss of the octahedral particle shape. Extending the anodic potential limits of the tests to the Pt oxidation region induced detectable Ni losses and structural changes. Our study shows on an atomic level how Mo adatoms on the surface impact the Ni surface composition, which, in turn, gives rise to the exceptionally high experimental catalytic ORR reactivity and calls for strategies on how to preserve this particular surface composition to arrive at performance stabilities comparable with state-of-the-art spherical dealloyed Pt core-shell catalysts.

Direct observations of dynamic PtCo interactions in fuel cell catalyst precursors at the atomic level using E(S)TEM.

Reduction reactions in practical bimetallic platinum-cobalt electrode catalyst precursors containing platinum, cobalt and cobalt oxides in hydrogen at 200, 450 and 700 °C for 6 h have been studied in situ using an aberration corrected environmental (scanning) transmission electron microscope (AC E(S)TEM). Little difference was observed in reduction at 200 °C but during and after reduction at 450 °C, small nanoparticles less than 3 nm in diameter with tetragonal PtCo structures were observed and limited Pt3 Co ordering could be seen on the surfaces of larger nanoparticles. During and after reduction at 700 °C, fully ordered Pt3 Co and PtCo nanoparticles larger than 4 nm were produced and the average nanoparticle size almost trebled relative to the fresh precursor. After reduction at 450 and 700 °C, most nanoparticles were disordered platinum/cobalt alloys with fcc structure. After reduction at 700 °C many of the smallest nanoparticles disappeared suggesting Ostwald ripening had occurred. Mechanisms concerning the thermal transformation of mixed cobalt and platinum species are discussed, offering new insights into the creation of bimetallic platinum-cobalt nanoparticles in fuel cell catalysts.

Mesoscale simulations of confined Nafion thin films.

The morphology and transport properties of thin films of the ionomer Nafion, with thicknesses on the order of the bulk cluster size, have been investigated as a model system to explain the anomalous behaviour of catalyst/electrode-polymer interfaces in membrane electrode assemblies. We have employed dissipative particle dynamics (DPD) to investigate the interaction of water and fluorocarbon chains, with carbon and quartz as confining materials, for a wide range of operational water contents and film thicknesses. We found confinement-induced clustering of water perpendicular to the thin film. Hydrophobic carbon forms a water depletion zone near the film interface, whereas hydrophilic quartz results in a zone with excess water. There are, on average, oscillating water-rich and fluorocarbon-rich regions, in agreement with experimental results from neutron reflectometry. Water diffusivity shows increasing directional anisotropy of up to 30% with decreasing film thickness, depending on the hydrophilicity of the confining material. A percolation analysis revealed significant differences in water clustering and connectivity with the confining material. These findings indicate the fundamentally different nature of ionomer thin films, compared to membranes, and suggest explanations for increased ionic resistances observed in the catalyst layer.

Feasibility of a multi-modal exercise program on cognition in older adults with Type 2 diabetes - a pilot randomised controlled trial.

BACKGROUND: Type 2 Diabetes (T2D) is associated with increased risk of dementia. We aimed to determine the feasibility of a randomised controlled trial (RCT) examining the efficacy of exercise on cognition and brain structure in people with T2D. METHODS: A 6-month pilot parallel RCT of a progressive aerobic- and resistance-training program versus a gentle movement control group in people with T2D aged 50-75 years (n = 50) at the University of Tasmania, Australia. Assessors were blinded to group allocation. Brain volume (total, white matter, hippocampus), cortical thickness and white matter microstructure (fractional anisotrophy and mean diffusivity) were measured using magnetic resonance imaging, and cognition using a battery of neuropsychological tests. Study design was assessed by any changes (during the pilot or recommended) to the protocol, recruitment by numbers screened and time to enrol 50 participants; randomisation by similarity of characteristics in groups at baseline, adherence by exercise class attendance; safety by number and description of adverse events and retention by numbers withdrawn. RESULTS: The mean age of participants was 66.2 (SD 4.9) years and 48% were women. There were no changes to the design during the study. A total of 114 people were screened for eligibility, with 50 participants with T2D enrolled over 8 months. Forty-seven participants (94%) completed the study (23 of 24 controls; 24 of 26 in the intervention group). Baseline characteristics were reasonably balanced between groups. Exercise class attendance was 79% for the intervention and 75% for the control group. There were 6 serious adverse events assessed as not or unlikely to be due to the intervention. Effect sizes for each outcome variable are provided. CONCLUSION: This study supports the feasibility of a large scale RCT to test the benefits of multi-modal exercise to prevent cognitive decline in people with T2D. Design changes to the future trial are provided. TRIAL REGISTRATION: ANZCTR 12614000222640 ; Registered 3/3/2014; First participant enrolled 26/6/2014, study screening commenced 1/9/2014; Australian and New Zealand Clinical Trial Registry.

Osteoarthritis bone marrow lesions at the knee and large artery characteristics.

OBJECTIVE: There is evidence to suggest vascular involvement in the initiation and progression of osteoarthritis (OA). The relationship between large artery characteristics and pathogenesis of OA has not been investigated and was the aim of this study. DESIGN: Large artery characteristics (i.e., aortic stiffness, brachial and central blood pressure (BP) variables) and bone marrow lesions (BMLs; measured by magnetic resonance imaging as a surrogate index of OA) were recorded in 208 participants (aged 63 ± 7 years; mean ± SD) with symptomatic knee OA. Relationships between large artery characteristics and BML were assessed by multiple regression adjusting for age, sex and body mass index. RESULTS: There was a high prevalence of BML presence in the study population (70%), but no significant difference between participants with and without BML for all large artery and BP variables (P > 0.05 all). Furthermore, there were no significant relationships between BML size and aortic stiffness (r = -0.033, P = 0.71), central pulse pressure (r = 0.028, P = 0.74), augmentation index (r = 0.125, P = 0.14), brachial pulse pressure (r = 0.005, P = 0.95) or brachial systolic BP (r = -0.066, P = 0.44). When participants were stratified according to high or low aortic stiffness, there was no significant difference between groups regarding the proportion of those with a BML (64% vs. 70% respectively; P = 0.69). CONCLUSIONS: Variables indicative of large artery characteristics are not significantly correlated with BML size or presence in people with symptomatic knee OA. Thus, large artery characteristics may not have a causative influence in the development of OA, but this needs to be confirmed in prospective studies.

Building HIA approaches into strategies for green space use: an example from Plymouth's (UK) Stepping Stones to Nature project.

The health and well-being benefits of access to green space are well documented. Research suggests positive findings regardless of social group, however barriers exist that limit access to green space, including proximity, geography and differing social conditions. Current public health policy aims to broaden the range of environmental public health interventions through effective partnership working, providing opportunities to work across agencies to promote the use of green space. Health Impact Assessment (HIA) is a combination of methods and procedures to assess the potential health and well-being impacts of policies, developments and projects. It provides a means by which negative impacts can be mitigated and positive impacts can be enhanced, and has potential application for assessing green space use. This paper describes the application of a HIA approach to a multi-agency project (Stepping Stones to Nature--SS2N) in the UK designed to improve local green spaces and facilitate green space use in areas classified as having high levels of deprivation. The findings suggest that the SS2N project had the potential to provide significant positive benefits in the areas of physical activity, mental and social well-being. Specific findings for one locality identified a range of actions that could be taken to enhance benefits, and mitigate negative factors such as anti-social behaviour. The HIA approach proved to be a valuable process through which impacts of a community development/public health project could be enhanced and negative impacts prevented at an early stage; it illustrates how a HIA approach could enhance multi-agency working to promote health and well-being in communities.

Arterial stiffness, central blood pressure and body size in health and disease.

BACKGROUND: Body size is associated with increased brachial systolic blood pressure (SBP) and aortic stiffness. The aims of this study were to determine the relationships between central SBP and body size (determined by body mass index (BMI), waist circumference and waist/hip ratio) in health and disease. We also sought to determine if aortic stiffness was correlated with body size, independent of BP. METHODS: BMI, brachial BP and estimated central SBP (by SphygmoCor and radial P2) were recorded in controls (n=228), patients with diabetes (n=211), coronary artery disease (n=184) and end-stage kidney disease (n=68). Additional measures of waist circumference and arterial stiffness (aortic and brachial pulse wave velocity (PWV)) were recorded in a subgroup of 75 controls (aged 51 ± 12 years) who were carefully screened for factors affecting vascular function. RESULTS: BMI was associated with brachial (r=0.30; P<0.001) and central SBP (r=0.29; P<0.001) in the 228 controls, but not the patient populations (r<0.13; P>0.15 for all comparisons). In the control subgroup, waist circumference was also significantly correlated with brachial SBP (r=0.29; P=0.01), but not central SBP (r=0.22; P=0.07). Independent predictors of aortic PWV in the control subgroup were brachial SBP (ß=0.43; P<0.001), age (ß=0.37; P<0.001), waist circumference (ß=0.39; P=0.02) and female sex (ß=-0.24; P=0.03), but not BMI. CONCLUSION: In health, there are parallel increases in central and brachial SBP as BMI increases, but these relationships are not observed in the presence of chronic disease. Moreover, BP is a stronger correlate of arterial stiffness than body size.

Role of human tissue kallikrein in gastrointestinal stromal tumour invasion.

BACKGROUND: Human tissue kallikrein (hK1) generates vasodilator kinins from kininogen and promotes angiogenesis by kinin-dependent and kinin-independent mechanisms. Here, we investigate the expression and functional relevance of hK1 in human gastrointestinal stromal tumour (GIST). METHODS: Vascularisation and hK1 expression of GIST samples were assessed by immunohistochemistry. In two GIST cell lines, hK1 expression was assessed by PCR, and hK1 protein levels and activity were measured by ELISA and an amidolytic assay, respectively. The effect of hK1 silencing, inhibition or overexpression on GIST cell proliferation, migration and paracrine induction of angiogenesis was studied. Finally, local and systemic levels of hK1 were assessed in mice injected with GIST cells. RESULTS: Human tissue kallikrein was detected in 19 out of 22 human GIST samples. Moreover, GIST cells express and secrete active hK1. Titration of hK1 demonstrated its involvement in GIST invasive behaviour, but not proliferation. Furthermore, hK1 released by GIST cells promoted endothelial cell migration and network formation through kinin-dependent mechanisms. Gastrointestinal stromal tumour implantation in nude mice resulted in local and systemic hK1 expression proportional to tumour dimension. CONCLUSIONS: Human tissue kallikrein is produced and released by GIST and participates in tumour invasion. Further studies are needed to validate hK1 as a diagnostic biomarker and therapeutic target in GIST.

Antibody-drug conjugates for previously treated aggressive lymphomas: focus on polatuzumab vedotin.

INTRODUCTION: Antibody-drug conjugates (ADCs) are immunoconjugates and comprise a monoclonal antibody that is chemically attached to a cytotoxic drug (or payload) via a stable chemical linker. Since the approval of the first ADC in 2000, there are now nine different approved agents and over 100 ADCs in the drug-development pipeline. AREAS COVERED: This review briefly describes the ADCs approved for treatment of lymphoma and their distinguishing factors in terms of target, linker and payload. The clinical implications of the use of ADCs are also considered. Here, we focus on polatuzumab vedotin, an ADC targeted to CD79b, which is approved for the treatment of patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) who have received at least one (EU approval) or two (US approval) prior therapies and are not eligible for bone marrow transplantation. The characteristics of polatuzumab vedotin are discussed and clinical data are presented. The future of polatuzumab vedotin clinical development, and ADCs in general, are also considered. EXPERT OPINION: ADCs represent a significant advance in the treatment of lymphoma. Polatuzumab vedotin has shown clinical efficacy and a tolerable safety profile in both first-line and R/R DLBCL; future studies are planned to further investigate this ADC.

An observational cohort study of 3 units versus 5 units slow intravenous bolus oxytocin in women undergoing elective caesarean delivery.

This study sought to compare postpartum blood loss and maternal outcomes after 3IU and 5IU oxytocin at elective caesarean delivery. In a prospective observational study, 73 women undergoing elective caesarean delivery under spinal anaesthetic received a slow I.V. injection of either 3IU (n = 35) or 5IU (n = 38) oxytocin after delivery. The main outcome was gravimetrically measured 24-hour postpartum blood loss with a non-inferiority margin of 300 mL. Uterine tone, phenylephrine dose, emesis and hypotension after oxytocin administration were secondary outcomes. Gravimetric postpartum blood loss was lower in the 3IU group (-58.8 mL [95% CI: -212.1, 94.3]) after adjusting for BMI, pre-delivery vasopressor dose, parity, and risk of uterine atony, with the upper confidence limit below the 300 mL margin in support of non-inferiority. Patients receiving 3IU had a higher (non-significant) rate of having post-delivery phenylephrine to treat hypotension (RR = 1.59 [95% CI: 0.97, 2.63]), but of those treated, the 3IU group required significantly less (-427 mcg [95% CI: -740, -114]). The 3IU group had a lower prevalence of vomiting compared to those receiving 5IU (6% versus 24%; P = 0.047). Administration of 3IU oxytocin was non-inferior compared to standard 5IU with respect to blood loss in women undergoing elective caesarean delivery.

Brachial-to-radial systolic blood pressure amplification in patients with type 2 diabetes mellitus.

Brachial-to-radial-systolic blood pressure amplification (Bra-Rad-SBPAmp) can affect central SBP estimated by radial tonometry. Patients with type 2 diabetes mellitus (T2DM) have vascular irregularities that may alter Bra-Rad-SBPAmp. By comparing T2DM with non-diabetic controls, we aimed to determine the (1) magnitude of Bra-Rad-SBPAmp; (2) haemodynamic factors related to Bra-Rad-SBPAmp; and (3) effect of Bra-Rad-SBPAmp on estimated central SBP. Twenty T2DM (64±8 years) and 20 non-diabetic controls (60±8 years; 50% male both) underwent simultaneous cuff deflation and two-dimensional ultrasound imaging of the brachial and radial arteries. The first Korotkoff sound (denoting SBP) was identified from the first inflection point of Doppler flow during cuff deflation. Bra-Rad-SBPAmp was calculated by radial minus brachial SBP. Upper limb and systemic haemodynamics were recorded by tonometry and ultrasound. Radial SBP was higher than brachial SBP for T2DM (136±19 vs 127±17 mm Hg; P<0.001) and non-diabetic controls (135±12 vs 121±11 mm Hg; P<0.001), but Bra-Rad-SBPAmp was significantly lower in T2DM (9±8 vs 14±7 mm Hg; P=0.042). The product of brachial mean flow velocity × brachial diameter was inversely and independently correlated with Bra-Rad-SBPAmp in T2DM (ß=-0.033 95% confidence interval -0.063 to -0.004, P=0.030). When radial waveforms were calibrated using radial, compared with brachial SBP, central SBP was significantly higher in both groups (T2DM, 116±13 vs 125±15 mm Hg; and controls, 112±10 vs 124±11 mm Hg; P<0.001 both) and there was a significant increase in the number of participants classified with 'central hypertension' (SBP⩾130 mm Hg; P=0.004). Compared with non-diabetic controls, Bra-Rad-SBPAmp is significantly lower in T2DM. Regardless of disease status, radial SBP is higher than brachial SBP and this results in underestimation of central SBP using brachial-BP-calibrated radial tonometry.

Exercise blood pressure: clinical relevance and correct measurement.

Blood pressure (BP) is a mandatory safety measure during graded intensity clinical exercise stress testing. While it is generally accepted that exercise hypotension is a poor prognostic sign linked to severe cardiac dysfunction, recent meta-analysis data also implicate excessive rises in submaximal exercise BP with adverse cardiovascular events and mortality, irrespective of resting BP. Although more data is needed to derive submaximal normative BP thresholds, the association of a hypertensive response to exercise with increased cardiovascular risk may be due to underlying hypertension that has gone unnoticed by conventional resting BP screening methods. Delayed BP decline during recovery is also associated with adverse clinical outcomes. Thus, above and beyond being used as a routine safety measure during stress testing, exercise (and recovery) BP may be useful for identifying high-risk individuals and also as an aid to optimise care through appropriate follow-up after exercise stress testing. Accordingly, careful attention should be paid to correct measurement of exercise stress test BP (before, during and after exercise) using a standardised approach with trained operators and validated BP monitoring equipment (manual or automated). Recommendations for exercise BP measurement based on consolidated international guidelines and expert consensus are presented in this review.

BJP is linking its articles to the IUPHAR/BPS Guide to PHARMACOLOGY.

LINKED EDITORIALS: This Editorial is part of a series. To view the other Editorials in this series, visit: http://onlinelibrary.wiley.com/doi/10.1111/bph.12956/abstract; http://onlinelibrary.wiley.com/doi/10.1111/bph.12954/abstract; http://onlinelibrary.wiley.com/doi/10.1111/bph.12955/abstract and http://onlinelibrary.wiley.com/doi/10.1111/bph.12856/abstract. VIDEO: To view the video on the IUPHAR/BPS Guide to PHARMACOLOGY, visit: https://www.youtube.com/watch?v=Qhy3q33VtRI.

Pharmacokinetics and effect on blood pressure of doxazosin in normal subjects and patients with renal failure.

The antihypertensive efficacy and pharmacokinetics of a single 1 mg oral dose of doxazosin were investigated in five healthy male volunteers, six patients with renal failure not on hemodialysis, and four patients with end-stage renal failure studied between two hemodialyses. The dialyzability of doxazosin was studied in five patients. The maximum fall in blood pressure of both volunteers and patients occurred between 4 and 8 hours. In four of five volunteers the blood pressure had returned to baseline within 10 to 12 hours, whereas in the patients with renal failure it took as long as 72 hours. Maximum plasma concentrations were reached in 2.6 to 3.6 hours. The mean AUC did not differ significantly between the groups. The mean (SE) elimination t1/2 was 12.6 hours (3.3) in the volunteers and 13.3 hours (1.8) in the patients with renal insufficiency (not significant). Doxazosin was not appreciably dialyzable.

Phenobarbital in the acute management of febrile convulsions.

Blood levels of phenobarbital were determined after a single oral or intramuscular (IM) dose in children in the hospital after febrile convulsions. At a dose of 15 mg/kg, both the oral and IM routes gave therapeutic blood levels within 90 minutes. Absorption from the IM route before 90 minutes was inconsistent and would be unlikely to arrest an established convulsion within a critical time period. For use as a drug to prevent convulsions, oral phenobarbital at 15 mg/kg deserves further study.

Doxepin plasma concentrations in clinical practice. Could there be a pharmacokinetic explanation for low concentrations?

During therapeutic use of doxepin, we have often observed unexpectedly low doxepin plasma concentrations in patients on moderate dosages, e.g. 100 to 200mg daily. While non-compliance seemed the most likely explanation, we present the data for 6 patients in whom we considered non-compliance unlikely. The data can be explained by hypothesizing that in some patients, there is not a linear dosage-plasma concentration relationship and that on a steady dosage, plasma concentrations are not always maintained. If these phenomena can be more carefully documented they may assume clinical importance; indeed for 2 of the patients studied the falling plasma concentrations on a steady dosage were associated with a recurrence of depression.

Tinidazole pharmacokinetics in severe renal failure.

The single-dose pharmacokinetics of intravenously and orally administered tinidazole were studied in normal subjects and patients with severe chronic renal failure. The clearance of tinidazole was also measured in patients on regular haemodialysis. After intravenous administration the mean elimination half-life of tinidazole was 17.1 +/- 2.3 (SD) hours in the normal subjects and 16.9 +/- 4.9 hours in patients with renal failure; the mean apparent volumes of distribution were 0.80 +/- 0.09 L/kg and 0.69 +/- 0.09 L/kg, respectively. Following oral administration the mean elimination half-life was 15.6 +/- 1.6 hours in the normal subjects and 18.4 +/- 3.5 hours in patients with renal failure; there were no statistically significant differences in these pharmacokinetic parameters. There was no accumulation of the major metabolite (hydroxymethyl tinidazole) in normal subjects or in patients with renal failure. Tinidazole clearance during haemodialysis was 71 +/- 7.7 ml/min. In the presence of renal failure no modification of tinidazole dosage would appear to be necessary. Tinidazole should be administered in full dosage following haemodialysis.

Cardiovascular implications of exposure to traffic air pollution during exercise.

Regular aerobic exercise is recommended by physicians to improve health and longevity. However, individuals exercising in urban regions are often in contact with air pollution, which includes particles and gases associated with respiratory disease and cancer. We describe the recent evidence on the cardiovascular effects of air pollution, and the implications of exercising in polluted environments, with a view to informing clinicians and other health professionals. There is now strong evidence that fine and ultra fine particulate matter present in air pollution increases cardiovascular morbidity and mortality. The main mechanisms of disease appear to be related to an increase in the pathogenic processes associated with atherosclerosis. People exercising in environments pervaded by air contaminants are probably at increased risk, due to an exercise-induced amplification in respiratory uptake, lung deposition and toxicity of inhaled pollutants. We make evidence-based recommendations for minimizing exposure to air-borne toxins while exercising, and suggest that this advice be passed on to patients where appropriate.

Circadian pharmacokinetics of methotrexate.

Six patients with intermediate- and high-grade non-Hodgkin's lymphoma were treated with 400 mg/m2 i.v. methotrexate (MTX) at 0600 and 1800 hours. Despite evidence of circadian rhythms in renal function, the pharmacokinetics of total and free serum MTX showed no significant difference between these two times. The marked two-fold circadian variation in MTX pharmacokinetics previously reported in rats was not observed in these patients.