Association of sitting time and breaks in sitting with muscle mass, strength, function, and inflammation in community-dwelling older adults.

The mechanisms through which excessive sitting time impacts health are important to understand. This study found that each hour of sitting per day was not associated with physical function, although associations with poor body composition were observed. Reducing sitting time for improved weight management in older adults needs further exploration. INTRODUCTION: To examine the association of sitting time and breaks in sitting time with muscle mass, strength, function, and inflammation in older Australians. METHODS: Data from the thigh-worn activPAL3™ monitor (7-day continuous wear) was used to derive time spent sitting (hours) and total number of sit-stand transitions per day. Body composition (dual energy X-ray absorptiometry), lower-body muscle strength, function (timed up-and-go [TUG], 4-m gait speed, four square step test, 30-second sit-to-stand), and serum inflammatory markers (interleukin-[IL-6], IL-8, IL-10, tumor necrosis factor-alpha [TNF-α], and adiponectin) were measured. Multiple regression analyses, adjusted for age, sex, ethnicity, education, employment status, marital status, number of prescription medications, smoking status, vitamin D, and stepping time, were used to assess the associations. RESULTS: Data from 123 community-dwelling older adults (aged 65-84 years, 63% female) were used. Total daily sitting time was associated with lower percentage lean mass (ß [95%CI], - 1.70% [- 2.30, - 1.10]) and higher total body fat mass (2.92 kg [1.94, 3.30]). More frequent breaks in sitting time were associated with a 45% reduced risk of having pre-sarcopenia (OR = 0.55; 95% CI 0.34, 0.91; model 1), defined as appendicular lean mass divided by BMI. No significant associations were observed for sitting time or breaks in sitting with measures of muscle strength, function, or inflammation. CONCLUSION: In older community-dwelling adults, greater sitting time was associated with a lower percentage lean mass, while more frequent breaks in sitting time were associated with lower odds of having pre-sarcopenia. This suggests that reducing sedentary time and introducing frequent breaks in sedentary time may be beneficial for improving body composition in healthy older adults.

Gold nanoparticle-based colorimetric biosensors.

Gold nanoparticles (AuNPs) provide excellent platforms for the development of colorimetric biosensors as they can be easily functionalised, displaying different colours depending on their size, shape and state of aggregation. In the last decade, a variety of biosensors have been developed to exploit the extent of colour changes as nano-particles (NPs) either aggregate or disperse, in the presence of analytes. Of critical importance to the design of these methods is that the behaviour of the systems has to be reproducible and predictable. Much has been accomplished in understanding the interactions between a variety of substrates and AuNPs, and how these interactions can be harnessed as colorimetric reporters in biosensors. However, despite these developments, only a few biosensors have been used in practice for the detection of analytes in biological samples. The transition from proof of concept to market biosensors requires extensive long-term reliability and shelf life testing, and modification of protocols and design features to make them safe and easy to use by the population at large. Developments in the next decade will see the adoption of user friendly biosensors for point-of-care and medical diagnosis as innovations are brought to improve the analytical performances and usability of the current designs. This review discusses the mechanisms, strategies, recent advances and perspectives for the use of AuNPs as colorimetric biosensors.

Anaesthetic implications of the changing management of patients with mucopolysaccharidosis.

The mucopolysaccharidoses are a group of inherited metabolic disorders that are renowned for presenting clinical problems, particularly related to cardiac, airway, and skeletal abnormalities, in children during anaesthesia. The changing clinical management of the mucopolysaccharidoses can be described in three phases. An initial phase of accumulation and dissemination of knowledge about the management of this rare disease with a growing recognition that untreated Hurler syndrome and more severe forms of other phenotypes such as Hunter syndrome and Maroteaux-Lamy syndrome were associated with severe complications under anaesthesia. This was followed by a second phase reflecting the beneficial results of new treatments such as haemopoietic stem cell transplantation and enzyme replacement therapy. Early and successful transplantation has dramatically improved long-term outcome and reduced anaesthetic complications in children with Hurler syndrome. Enzyme replacement therapy is available for many forms of mucopolysaccharidosis. If commenced at an early age improvement in many organ systems may be observed with an improved quality of life. However, these current treatment regimens do not appear to improve neurocognitive dysfunction, or cardiac valvular or skeletal abnormalities. We are now entering a third phase where the partial benefits of these treatment regimens are resulting in an increasing number of older patients with partially corrected abnormalities, including difficult airways, presenting for ongoing treatment to a new and potentially unsuspecting group of clinicians. Major airway abnormalities may be encountered and current adult guidelines may need to be adapted. A multidisciplinary team approach involving paediatric and adult anaesthetists is recommended to optimise future management.

Neutrophil maturation rate determines the effects of dipeptidyl peptidase 1 inhibition on neutrophil serine protease activity.

BACKGROUND AND PURPOSE: Neutrophil serine proteases (NSPs) are activated by dipeptidyl peptidase 1 (DPP1) during neutrophil maturation. The effects of neutrophil turnover rate on NSP activity following DPP1 inhibition was studied in a rat pharmacokinetic/pharmacodynamic model. EXPERIMENTAL APPROACH: Rats were treated with a DPP1 inhibitor twice daily for up to 14 days; NSP activity was measured in onset or recovery studies, and an indirect response model was fitted to the data to estimate the turnover rate of the response. KEY RESULTS: Maximum NSP inhibition was achieved after 8 days of treatment and a reduction of around 75% NSP activity was achieved at 75% in vitro DPP1 inhibition. Both the rate of inhibition and recovery of NSP activity were consistent with a neutrophil turnover rate of between 4-6 days. Using human neutrophil turnover rate, it is predicted that maximum NSP inhibition following DPP1 inhibition takes around 20 days in human. CONCLUSIONS AND IMPLICATIONS: Following inhibition of DPP1 in the rat, the NSP activity was determined by the amount of DPP1 inhibition and the turnover of neutrophils and is thus supportive of the role of neutrophil maturation in the activation of NSPs. Clinical trials to monitor the effect of a DPP1 inhibitor on NSPs should take into account the delay in maximal response on the one hand as well as the potential delay in a return to baseline NSP levels following cessation of treatment.

Evaluating the ORSIM® simulator for assessment of anaesthetists' skills in flexible bronchoscopy: aspects of validity and reliability.

BACKGROUND: Developing expertise in flexible bronchoscopy is limited by inadequate opportunities to train on difficult airways. The new ORSIM bronchoscopy simulator aims to address this by creating virtual patients with difficult airways. This study aims to provide evidence on the validity and reliability of the ORSIM for assessment of subjects on both normal and abnormal airway simulations. METHODS: Novice, trainee, and expert subjects performed seven simulations of varying difficulty and scored the perceived difficulty for each. Time to completion was measured. Three blinded raters independently scored videos of each subject's performance. We measured inter-rater agreement and the difference in raters' scores between subject groups. RESULTS: We recruited 28 study subjects, generating 196 videos for analysis. Expert subjects consistently completed the scenarios faster than novices. Overall performance scores showed significant differences between subject groups (P<0.0001). Inter-rater reliability of scores was >0.8. CONCLUSIONS: Our results provide initial evidence on the validity and reliability of the ORSIM bronchoscopy simulator, supporting its potential value in training and assessment.

Small Steps: Preliminary effectiveness and feasibility of an incremental goal-setting intervention to reduce sitting time in older adults.

OBJECTIVE: This study aimed to evaluate the preliminary effectiveness and feasibility of a theory-informed program to reduce sitting time in older adults. DESIGN: Pre-experimental (pre-post) study. Thirty non-working adult (≥ 60 years) participants attended a one hour face-to-face intervention session and were guided through: a review of their sitting time; normative feedback on sitting time; and setting goals to reduce total sitting time and bouts of prolonged sitting. Participants chose six goals and integrated one per week incrementally for six weeks. Participants received weekly phone calls. OUTCOME MEASURES: Sitting time and bouts of prolonged sitting (≥ 30 min) were measured objectively for seven days (activPAL3c inclinometer) pre- and post-intervention. During these periods, a 24-h time recall instrument was administered by computer-assisted telephone interview. Participants completed a post-intervention project evaluation questionnaire. Paired t tests with sequential Bonferroni corrections and Cohen's d effect sizes were calculated for all outcomes. RESULTS: Twenty-seven participants completed the assessments (71.7 ± 6.5 years). Post-intervention, objectively-measured total sitting time was significantly reduced by 51.5 min per day (p=0.006; d=-0.58) and number of bouts of prolonged sitting by 0.8 per day (p=0.002; d=-0.70). Objectively-measured standing increased by 39 min per day (p=0.006; d=0.58). Participants self-reported spending 96 min less per day sitting (p<0.001; d=-0.77) and 32 min less per day watching television (p=0.005; d=-0.59). Participants were highly satisfied with the program. CONCLUSION: The 'Small Steps' program is a feasible and promising avenue for behavioral modification to reduce sitting time in older adults.

Physical activity intensity and type 2 diabetes risk in overweight youth: a randomized trial.

BACKGROUND: The chronic effects of high-intensity endurance training on metabolic health outcomes in overweight adolescents remains poorly understood. OBJECTIVE: To test the hypothesis that high-intensity endurance training (ET) is superior to moderate-intensity ET for improving risk factors for type 2 diabetes in overweight adolescents. DESIGN AND METHODS: In this randomized trial, 106 overweight and obese adolescents (15.2 years; 76% female; 62% Caucasian) were randomly assigned to high-intensity ET (70-85% of heart rate reserve, n=38), moderate-intensity ET (40-55% heart rate reserve; n=32) or control for 6 months (n=36). The primary and secondary outcome measures were insulin sensitivity assessed using a frequently sampled intravenous glucose tolerance test and hepatic triglyceride content with magnetic resonance spectroscopy. Exploratory outcomes were cardiorespiratory fitness, physical activity and MRI and dual x-ray absorptiometry-derived measures of adiposity. RESULTS: The study had 96% retention and attendance was 61±21% and 55±24% in the high- and moderate-intensity ET arms. Intention-to-treat analyses revealed that, at follow-up, insulin sensitivity was not different between high-intensity (-1.0 mU kg(-1) min(-1); 95% confidence interval (CI): -1.6, +1.4 mU kg(-1) min(-1)) and moderate-intensity (+0.26 mU kg(-1) min(-1); 95% CI: -1.3, +1.8 mU kg(-1) min(-1)) ET arms compared with controls (interaction, P=0.97). Similarly, hepatic triglyceride at follow-up was not different in high-intensity (-1.7% fat/water (F/W); 95% CI: -7.0, +3.6% F/W) and moderate-intensity (-0.40% FW; 95% CI: -6.0, +5.3% F/W) ET compared with controls. Both high intensity (+4.4 ml per kg-FFM (fat-free mass) per minute; 95% CI: 1.7, 7.1 ml kg-FFM(-1) min(-1)) and moderate intensity (+4.4 ml kg-FFM(-1) min(-1); 95% CI: 1.6, 7.3 ml kg-FFM(-1) min(-1)) increased cardiorespiratory fitness, relative to controls (interaction P<0.001). CONCLUSIONS: ET improves cardiorespiratory fitness among obese adolescents; however, owing to lack of compliance, the influence of exercise intensity on insulin sensitivity and hepatic triglycerides remains unclear.

Women in Control: Pioneering Diabetes Self-Management Medical Group Visits in the Virtual World.

Background: The current state of diabetes self-management (DSM) education and support for diabetic patients is inadequate, especially for minority women who experience disproportionately high rates of diabetes mellitus (DM) in the US. While DSM education and support enables individuals with diabetes to make positive lifestyle choices and achieve clinical goals, this type of support is difficult to deliver in medical practice settings. Virtual reality can assist DM patients and their clinical teams by providing effective educational tools in an engaging, learner-centered environment that fosters self-efficacy and skill proficiency. Methods: Our prior research demonstrated that virtual worlds are suitable for supporting DSM education. Building upon this success, we are now investigating whether DSM virtual world medical group visits lead to similarly effective health and educational outcomes compared to face-to-face medical group visits. Currently in year one of a five year randomized controlled trial, we aim to compare the effectiveness of a virtual world DSM medical group visit format versus a face-to-face DSM medical group visit format to increase physical activity and improve glucose control (HbA1c) among Black/African American and Hispanic women with uncontrolled DM. We will also conduct a qualitative study of participant engagement with the virtual world platform to characterize learners' interactions with the technology and assess its correlation with DSM behaviors and diabetes control. Discussion: Novel methods to promote diabetes self-management are critically needed, and the use of virtual world technology to conduct medical group visits offers a unique approach to such issue. If successful, our intervention will increase access to culturally-sensitive diabetes care and improve patient engagement in online DSM learning, leading to higher uptake of DSM behaviors and better diabetes control. Importantly, the program can be easily expanded to other chronic disease areas and scaled for widespread use.

Extensor motoneurone properties are altered immediately before and during fictive locomotion in the adult decerebrate rat.

This study examined motoneurone properties during fictive locomotion in the adult rat for the first time. Fictive locomotion was induced via electrical stimulation of the mesencephalic locomotor region in decerebrate adult rats under neuromuscular blockade to compare basic and rhythmic motoneurone properties in antidromically identified extensor motoneurones during: (1) quiescence, before and after fictive locomotion; (2) the 'tonic' period immediately preceding locomotor-like activity, whereby the amplitude of peripheral flexor (peroneal) and extensor (tibial) nerves are increased but alternation has not yet occurred; and (3) locomotor-like episodes. Locomotion was identified by alternating flexor-extensor nerve activity, where the motoneurone either produced membrane oscillations consistent with a locomotor drive potential (LDP) or did not display membrane oscillation during alternating nerve activity. Cells producing LDPs were referred to as such, while those that did not were referred to as 'idle' motoneurones. LDP and idle motoneurones during locomotion had hyperpolarized spike threshold (Vth ; LDP: 3.8 mV; idle: 5.8 mV), decreased rheobase and an increased discharge rate (LDP: 64%; idle: 41%) during triangular ramp current injection even though the frequency-current slope was reduced by 70% and 55%, respectively. Modulation began in the tonic period immediately preceding locomotion, with a hyperpolarized Vth and reduced rheobase. Spike frequency adaptation did not occur in spiking LDPs or firing generated from sinusoidal current injection, but occurred during a sustained current pulse during locomotion. Input conductance showed no change. Results suggest motoneurone modulation occurs across the pool and is not restricted to motoneurones engaged in locomotion.

Adaptations of motoneuron properties to chronic compensatory muscle overload.

The aim of the study was to determine whether chronic muscle overload has measurable effect on electrophysiological properties of motoneurons (MNs), and whether duration of this overload influences intensity of adaptations. The compensatory overload was induced in the rat medial gastrocnemius (MG) by bilateral tenotomy of its synergists (lateral gastrocnemius, soleus, and plantaris); as a result, only the MG was able to evoke the foot plantar flexion. To assure regular activation of the MG muscle, rats were placed in wheel-equipped cages and subjected to a low-level treadmill exercise. The intracellular recordings from MG motoneurons were made after 5 or 12 wk of the overload, and in a control group of intact rats. Some of the passive and threshold membrane properties as well as rhythmic firing properties were considerably modified in fast-type MNs, while remaining unaltered in slow-type MNs. The significant changes included a shortening of the spike duration and the spike rise time, an increase of the afterhyperpolarization amplitude, an increase of the input resistance, a decrease of the rheobase, and a decrease of the minimum current necessary to evoke steady-state firing. The data suggest higher excitability of fast-type MNs innervating the overloaded muscle, and a shift towards electrophysiological properties of slow-type MNs. All of the adaptations could be observed after 5 wk of the compensatory overload with no further changes occurring after 12 wk. This indicates that the response to an increased level of chronic activation of MNs is relatively quick and stable.

Physical activity and sedentary behaviour: applying lessons to chronic obstructive pulmonary disease.

In health and disease, the benefits of regular participation in moderate to vigorous intensity physical activity are well documented. However, individuals with chronic conditions, such as those with chronic obstructive pulmonary disease (COPD), typically do very little activity at a moderate or vigorous intensity. Much of their day is instead spent in sedentary behaviour, such as sitting or reclining, which requires very little energy expenditure. This high level of time spent in sedentary behaviour can have serious health consequences, including increased risk of diabetes, cardiovascular disease and premature mortality. There is emerging evidence to suggest that participation in light intensity physical activities (e.g. standing or slow walking) may have benefits for cardio-metabolic health. Given the low aerobic capacity of individuals with moderate to severe COPD, increasing light intensity activity (through reducing sedentary time) may be a feasible additional strategy to improve health in this population, alongside traditional recommendations to increase the time spent in moderate to vigorous intensity physical activity. This review provides an overview of physical activity and sedentary behaviour, with a particular emphasis on these behaviours for people with COPD. It provides suggestions for the measurement of these behaviours within the clinical setting, as well as for interventions that may be effective at increasing physical activity and reducing sedentary behaviour in this population.

Transcriptional changes in rat α-motoneurons resulting from increased physical activity.

Electrophysiological properties of lumbar α-motoneurons change after chronic increases and decreases in hindlimb neuromuscular activity. Although modeling of these changes suggests that motoneurons probably alter gene expression in these situations, there is no evidence that this is the case. In this study, we measured the content of several mRNAs in lumbar motoneurons, harvested using laser capture microdissection, from rats previously subjected to normal cage activity, voluntary wheel exercise for 16weeks, and forced treadmill training for 7days and 16weeks. As a result of the prolonged daily treadmill training, but not the voluntary wheel training, significant increases occurred in muscle peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC-1α) mRNA, and in muscle PGC-1α and cytochrome oxidase proteins, in soleus and plantaris muscles. Significant changes in mRNA contents (decreases) were evident for the receptors 5-hydroxytryptamine (serotonin) receptor 1A (5HT1a), GABA A receptor, subunit alpha 2 (GABAAα2), and for the potassium conductance calcium-activated channel protein (SK2) in the motoneurons from 16-week-trained rats, and for glutamate receptor, metabotropic 1 (mGluR1) in the voluntary wheel-trained rats. Motoneurons from 16-week treadmill-trained rats also did not demonstrate the decreases in several mRNAs that were evident after 7days of treadmill exercise, suggesting an adaptation of motoneurons to acute stress. The mRNA changes following prolonged daily treadmill training are consistent with a reduction in inhibitory influences onto motoneurons, and a transition toward motoneurons that innervate slower contracting muscle fibers. These results demonstrate that the previously reported physiological changes in motoneurons with altered activity are accompanied by changes in gene expression.

Characteristics of AZD9708, a novel, selective ß2-adrenoceptor agonist with rapid onset and long duration of action.

Here we describe the pre-clinical pharmacological profile of AZD9708, a novel long-acting ß(2)-adrenoceptor agonist that has potential as a once-daily therapy for asthma and chronic obstructive pulmonary disease (COPD). AZD9708 is a potent and selective agonist at the human ß(2)-adrenoceptor, with selectivity over human ß(1)- and ß(3)-adrenoceptors of >500 and >24 fold, respectively. AZD9708 relaxes carbachol-induced contraction of human bronchial rings with a time to 90% of maximal relaxation of 13-20 min, similar to that seen with formoterol and quicker than salmeterol. In anesthetized guinea pigs, AZD9708 provides significant protection against histamine-induced airway constriction at 24 h after intratracheal and nebulized doses. This is longer than with intratracheal salmeterol, which is bronchoprotective for approximately 8 h, and formoterol, which is bronchoprotective for 8 and 12 h following nebulized and intratracheal dosing, respectively. AZD9708 also shows the potential for a greater therapeutic margin than widely used ß(2)-adrenoceptor agonists such as formoterol. At a defined efficacy dose that provides 80% bronchoprotection (ED(80)), formoterol leads to a decrease in blood potassium levels in guinea pigs, whilst AZD9708 is not associated with significant reductions in potassium levels at doses up to 7 times the ED(80). [(14)C]AZD9708 is associated with extensive protein binding in both human (mean 1.0% free) and rat (mean 2.6% free) plasma. This pharmacological profile indicates the potential of AZD9708 to become an important addition to the range of bronchodilators available for the treatment of patients with obstructive airways disease.

Plasticity of rat motoneuron rhythmic firing properties with varying levels of afferent and descending inputs.

Hindlimb motoneuron excitability was compared among exercise-trained (E), sedentary (S), and spinal cord transected (T) Sprague-Dawley rats by examining the slope of the frequency-current (F/I) relationship with standard intracellular recording techniques in rats anesthetized with ketamine-xylazine. The T group included spinal transected and spinal isolated rats; the E animals were either spontaneously active (exercise wheel) or treadmill trained; and rats in the S group were housed in pairs. An analysis of motoneuron initial [1st interspike interval (ISI)], early (mean of 1st three ISIs), and steady-state (mean of last 3 ISIs) discharge rate slopes resulting from increasing and decreasing 500-ms injected square-wave depolarizing current pulses was used to describe rhythmic motoneuron properties. The steepest slope occurred in the S group (55.3 ± 22.2 Hz/nA), followed by the T group (35.5 ± 15.3 Hz/nA), while the flattest slope was found in the E group (25.4 ± 10.9 Hz/nA). The steepest steady-state slope occurred in the S group but was found to be similar between the T and E groups. Furthermore, a spike-frequency adaptation (SFA) index revealed a slower adaptation in motoneurons of the E animals only (∼40% lower). Finally, evidence for a secondary range of firing existed more frequently in the T group (41%) compared with the S (12%) and E (31%) groups. The lower F/I slope and lower SFA index of motoneurons for E rats may be a result of an increase in Na(+) conductance at the initial segment. The results show that motoneuronal rhythmic firing behavior is plastic, depending on the volume of daily activation and on intact descending pathways.

Lifestyle intervention on diet and exercise reduced excessive gestational weight gain in pregnant women under a randomised controlled trial.

OBJECTIVE: To examine the effect of an exercise and dietary intervention during pregnancy on excessive gestational weight gain (EGWG), dietary habit and physical activity in pregnant women. DESIGN: Randomised controlled trial. SETTING: Community-based study. POPULATION: Nondiabetic urban-living pregnant women (<26 weeks of gestation). METHODS: Participants in the intervention group were provided with community-based group exercise sessions, instructed home exercise and dietary counselling between 20 and 36 weeks of gestation. Participants in both groups received physical activity and food intake surveys at enrolment and 2 months after the enrolment. MAIN OUTCOME MEASURES: Prevalence of EGWG and measures of physical activity and food intakes between the two groups. RESULTS: A total of 190 pregnant women, 88 in the control group and 102 in the intervention group, completed the study. Decreased daily intakes of calorie, fat, saturated fat and cholesterol were detected in participants in the intervention group at 2 months after enrolment compared with the control group (P<0.01). Participants in the intervention group had higher physical activity 2 months after enrolment compared with the control group (P<0.01). The lifestyle intervention during pregnancy reduced the prevalence of EGWG in the intervention group compared with the control group (P<0.01) according to the guidelines of the Institute of Medicine. CONCLUSION: The findings suggest that lifestyle intervention during pregnancy increased physical activity, improved dietary habits and reduced EGWG in urban-living pregnant women.

Rheumatoid arthritis patients with active disease and no history of cardiac pathology have higher brain natriuretic peptide (BNP) levels than patients with inactive disease or healthy control subjects.

BACKGROUND: Rheumatoid arthritis (RA) is associated with increased incidence cardiac failure. It is yet unclear how much the increased incidence is secondary to ischaemic damage, or whether inflammatory cytokines might have a direct effect on the myocardium. OBJECTIVES: To establish if patients with active rheumatoid arthritis but no history of cardiac disease have higher serum levels of brain natriuretic peptide (BNP), than patients with less active RA, or disease-free controls. METHODS: 90 patients with RA and 31 healthy control subjects were recruited. Each was screened to exclude previous history of cardiac disease. RA disease activity was measured using the DAS28 assessment, and other demographic, physical and laboratory tests performed. Serum BNP levels were measured in all subjects. RESULTS: There was no difference in the age, percentage females or BMI between the RA and control subjects. Median BNP in the RA patients was 80.0 pg/ml (IQR 38.0-132.0) compared with 48.5 (26.0-86.0) in the control subjects (p=0.017). There was a significant correlation between DAS28 and serum BNP in the RA group, r=0.37, p<0.01. RA patients were divided into three groups according to DAS28 scores. Patients with very active disease (DAS28>5.1) had significantly higher BNP levels than patients with moderately active disease (3.2

Dual bronchodilatory and pulmonary anti-inflammatory activity of RO5024118, a novel agonist at vasoactive intestinal peptide VPAC2 receptors.

BACKGROUND AND PURPOSE: Vasoactive intestinal peptide is expressed in the respiratory tract and induces its effects via its receptors, VPAC(1) and VPAC(2). RO5024118 is a selective VPAC(2) receptor agonist derived via chemical modification of an earlier VPAC(2) agonist, RO0251553. In the present studies, we characterized the pharmacological activity of RO5024118. EXPERIMENTAL APPROACH: Stability of RO5024118 to human neutrophil elastase was assessed. Bronchodilatory activity of RO5024118 was investigated in guinea pig and human isolated airway smooth muscle preparations and in a guinea pig bronchoconstriction model. Pulmonary anti-inflammatory activity of RO5024118 was investigated in a lipopolysaccharide mouse model and in a porcine pancreatic elastase (PPE) rat model. KEY RESULTS: RO5024118 demonstrated increased stability to neutrophil elastase compared with RO0251553. In human and guinea pig isolated airway preparations, RO5024118 induced bronchodilatory effects comparable with RO0251553 and the long-acting ß-agonist salmeterol and was significantly more potent than native vasoactive intestinal peptide and the short-acting ß-agonist salbutamol. In 5-HT-induced bronchoconstriction in guinea pigs, RO5024118 exhibited inhibitory activity with similar efficacy as, and longer duration than, RO0251553. In a lipopolysaccharide-mouse model, RO5024118 inhibited neutrophil and CD8(+) cells and myeloperoxidase levels. In rats, intratracheal instillation of PPE induced airway neutrophilia that was resistant to dexamethasone. Pretreatment with RO5024118 significantly inhibited PPE-induced neutrophil accumulation. CONCLUSIONS AND IMPLICATIONS: These results demonstrate that RO5024118 induces dual bronchodilatory and pulmonary anti-inflammatory activity and may be beneficial in treating airway obstructive and inflammatory diseases. LINKED ARTICLES: This article is part of a themed section on Analytical Receptor Pharmacology in Drug Discovery. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2010.161.issue-6.

Use of complementary and alternative therapies in children.

The use of complementary and alternative therapies in children has recently shown explosive growth, despite little scientific evidence of benefit, a need for better regulatory oversight, and continuing gaps in the knowledge and attitudes of pediatric health professionals.

Recent developments in selenium research.

Some of the main biochemical features of selenium have emerged only in the last five years, although it has been known to be an essential element for nearly 40 years. The investigations into selenoproteome gene expression and a better understanding of the selenocysteine synthetic pathway have undoubtedly provided the evidence that underpins the biochemical roles of the element. To date, 25 selenium-containing proteins have been identified in humans but the functions of a number of these have yet to be elucidated. The roles of the selenium-containing enyzmes (glutathione peroxidases, thioredoxin reductases and iodothyronine deiodinases) are well established, the first two being linked with antioxidant activity, and the latter involved with thyroid hormone metabolism. Recently, the interaction between sulphur, in the same periodic group and therefore chemically similar, and selenium has been investigated in a bid to understand the role of both elements in disease. There is renewed interest in the anticancer properties of selenium-containing compounds as evidence of their effectiveness in animal models has been demonstrated. Herein, selenium metabolism, gene expression, interaction with sulphur, and role in cancer are reviewed.

Effects of exercise training on alpha-motoneurons.

Evidence is presented that one locus of adaptation in the "neural adaptations to training" is at the level of the alpha-motoneurons. With increased voluntary activity, these neurons show evidence of dendrite restructuring, increased protein synthesis, increased axon transport of proteins, enhanced neuromuscular transmission dynamics, and changes in electrophysiological properties. The latter include hyperpolarization of the resting membrane potential and voltage threshold, increased rate of action potential development, and increased amplitude of the afterhyperpolarization following the action potential. Many of these changes demonstrate intensity-related adaptations and are in the opposite direction under conditions in which chronic activity is reduced. A five-compartment model of rat motoneurons that innervate fast and slow muscle fibers (termed "fast" and "slow" motoneurons in this paper), including 10 active ion conductances, was used to attempt to reproduce exercise training-induced adaptations in electrophysiological properties. The results suggest that adaptations in alpha-motoneurons with exercise training may involve alterations in ion conductances, which may, in turn, include changes in the gene expression of the ion channel subunits, which underlie these conductances. Interestingly, the acute neuromodulatory effects of monoamines on motoneuron properties, which would be a factor during acute exercise as these monoaminergic systems are activated, appear to be in the opposite direction to changes measured in endurance-trained motoneurons that are at rest. It may be that regular increases in motoneuronal excitability during exercise via these monoaminergic systems in fact render the motoneurons less excitable when at rest. More research is required to establish the relationships between exercise training, resting and exercise motoneuron excitability, ion channel modulation, and the effects of neuromodulators.