Inhibition of myeloperoxidase- and neutrophil-mediated oxidant production by tetraethyl and tetramethyl nitroxides

The powerful oxidant HOCl (hypochlorous acid and its corresponding anion, −OCl) generated by the myeloperoxidase (MPO)–H2O2–Cl− system of activated leukocytes is strongly associated with multiple human inflammatory diseases; consequently there is considerable interest in inhibition of this enzyme. Nitroxides are established antioxidants of low toxicity that can attenuate oxidation in animal models, with this ascribed to superoxide dismutase or radical-scavenging activities. We have shown (M.D. Rees et al., Biochem. J. 421, 79–86, 2009) that nitroxides, including 4-amino-TEMPO (4-amino-2,2,6,6-tetramethylpiperidin-1-yloxyl radical), are potent inhibitors of HOCl formation by isolated MPO and activated neutrophils, with IC50 values of ~1 and ~6 µM respectively. The utility of tetramethyl-substituted nitroxides is, however, limited by their rapid reduction by biological reductants. The corresponding tetraethyl-substituted nitroxides have, however, been reported to be less susceptible to reduction. In this study we show that the tetraethyl species were reduced less rapidly than the tetramethyl species by both human plasma (89–99% decreased rate of reduction) and activated human neutrophils (62–75% decreased rate). The tetraethyl-substituted nitroxides retained their ability to inhibit HOCl production by MPO and activated neutrophils with IC50 values in the low-micromolar range; in some cases inhibition was enhanced compared to tetramethyl substitution. Nitroxides with rigid structures (fused oxaspiro rings) were, however, inactive. Overall, these data indicate that tetraethyl-substituted nitroxides are potent inhibitors of oxidant formation by MPO, with longer plasma and cellular half-lives compared to the tetramethyl species, potentially allowing lower doses to be employed.

Determinants of the citation rate of medical research publications from a developing country

Background The number of citations received by an article is considered as an objective marker judging the importance and the quality of the research work. The present study aims to study the determinants of citations for research articles published by Sri Lankan authors. Methods Papers were selectively retrieved from the SciVerse Scopus® (Elsevier Properties S.A, USA) database for 10 years from 1st January 1997 to 31st December 2006, of which 50% were selected for inclusion by simple random sampling. The primary outcome measure was citation rate (defined as the number of citations during the 2 subsequent years after publication). Citation data was collected using the SciVerse Scopus® Citation Analyzer and self citations were excluded. A linear regression analysis was performed with ‘number of citations’ as the continuous dependent variable and other independent variables. Result The number of publications has steadily increased during the period of study. Over three quarter of papers were published in international journals. More than half of publications were research studies (55.3%), and most of the research studies were descriptive cross-sectional studies (27.1%). The mean number of citations within 2 years of publication was 1.7 and 52.1% of papers were not cited within the first two years of publication. The mean number of citations for collaborative studies (2.74) was significantly higher than that of non-collaborative studies (0.66). The mean number of citations did not significantly change depending on whether the publication had a positive result (2.08) or not (2.92) and was also not influenced by the presence (2.30) or absence (1.99) of the main study conclusion in the title of the article. In the linear regression model, the journal rank, number of authors, conducting the study abroad, being a research study or systematic review/meta-analysis and having regional and/or international collaboration all significantly increased the number of citations. Conclusion The journal rank, number of authors, conducting the study abroad, being a research study or systematic review/meta-analysis and having regional and/or international collaboration all significantly increased the number of citations. However, the presence of a positive result in the study did not influence the citation rate.

Physical mechanisms underlying the strain-rate-dependent mechanical behavior of kangaroo shoulder cartilage

Due to anatomical and biomechanical similarities to human shoulder, kangaroo was chosen as a model to study shoulder cartilage. Comprehensive enzymatic degradation and indentation tests were applied on kangaroo shoulder cartilage to study mechanisms underlying its strain-rate-dependent mechanical behavior. We report that superficial collagen plays a more significant role than proteoglycans in facilitating strain-rate-dependent behavior of kangaroo shoulder cartilage. By comparing the mechanical properties of degraded and normal cartilages it was noted that proteoglycan and collagen degradation significantly compromised strain-rate-dependent mechanical behavior of the cartilage. Superficial collagen contributed equally to the tissue behavior at all strain-rates. This is different to studies reported on knee cartilage and confirms the importance of superficial collagen on shoulder cartilage mechanical behavior. A porohyperelastic numerical model also indicated that collagen disruption would lead to faster damage of the shoulder cartilage than when proteoglycans are depleted.

Investigation of the mechanical behavior of kangaroo humeral head cartilage tissue by a porohyperelastic model based on the strain-rate-dependent permeability

Solid–interstitial fluid interaction, which depends on tissue permeability, is significant to the strain-rate-dependent mechanical behavior of humeral head (shoulder) cartilage. Due to anatomical and biomechanical similarities to that of the human shoulder, kangaroos present a suitable animal model. Therefore, indentation experiments were conducted on kangaroo shoulder cartilage tissues from low (10−4/s) to moderately high (10−2/s) strain-rates. A porohyperelastic model was developed based on the experimental characterization; and a permeability function that takes into account the effect of strain-rate on permeability (strain-rate-dependent permeability) was introduced into the model to investigate the effect of rate-dependent fluid flow on tissue response. The prediction of the model with the strain-rate-dependent permeability was compared with those of the models using constant permeability and strain-dependent permeability. Compared to the model with constant permeability, the models with strain-dependent and strain-rate-dependent permeability were able to better capture the experimental variation at all strain-rates (p<0.05). Significant differences were not identified between models with strain-dependent and strain-rate-dependent permeability at strain-rate of 5×10−3/s (p=0.179). However, at strain-rate of 10−2/s, the model with strain-rate-dependent permeability was significantly better at capturing the experimental results (p<0.005). The findings thus revealed the significance of rate-dependent fluid flow on tissue behavior at large strain-rates, which provides insights into the mechanical deformation mechanisms of cartilage tissues.

Using smartphones for cycling safety: A survey of riders preferences and interest in new technologies

Cyclists are among the most vulnerable road users. Many recent interventions have aimed at improving their safety on the road, such as the minimum overtaking distance rule introduced in Queensland in 2014. Smartphones offer excellent opportunities for technical intervention for road safety at a limited cost. Indeed, they have a lot of available processing power and many embedded sensors that allow analysing a rider's (or driver's) motion, behaviour, and environment; this is especially relevant for cyclists, as they do not have the space or power allowance that can be found in most motor vehicles. The aim of the study presented in this paper is to assess cyclists’ support for a range of new smartphone-based safety technologies. The preliminary results for an online survey with cyclists recruited from Bicycle Queensland and Triathlon Queensland, with N=191, are presented. A number of innovative safety systems such as automatic logging of incidents without injuries, reporting of dangerous area via a website/app, automatic notification of emergency services in case of crash or fall, and advanced navigation apps were assessed. A significant part of the survey is dedicated to GoSafeCycle, a cooperative collision prevention app based on motion tracking and Wi-Fi communications developed at CARRS-Q. Results show a marked preference toward automatic detection and notification of emergencies (62-70% positive assessment) and GoSafeCycle (61.7% positive assessment), as well as reporting apps (59.1% positive assessment). Such findings are important in the context of current promotion of active transports and highlight the need for further development of system supported by the general public.

Risedronate in adults with osteogenesis imperfecta type I: Increased bone mineral density and decreased bone turnover, but high fracture rate persists

Summary Bisphosphonates can increase bone mineral density (BMD) in children with osteogenesis imperfecta (OI). In this study of adults with OI type I, risedronate increased BMD at lumbar spine (but not total hip) and decreased bone turnover. However, the fracture rate in these patients remained high. Introduction Intravenous bisphosphonates given to children with OI can increase BMD and reduce fracture incidence. Oral and/or intravenous bisphosphonates may have similar effects in adults with OI. We completed an observational study of the effect of risedronate in adults with OI type I. Methods Thirty-two adults (mean age, 39 years) with OI type I were treated with risedronate (total dose, 35 mg weekly) for 24 months. Primary outcome measures were BMD changes at lumbar spine (LS) and total hip (TH). Secondary outcome measures were fracture incidence, bone pain, and change in bone turnover markers (serum procollagen type I aminopropeptide (P1NP) and bone ALP). A meta-analysis of published studies of oral bisphosphonates in adults and children with OI was performed. Results Twenty-seven participants (ten males and seventeen females) completed the study. BMD increased at LS by 3.9% (0.815 vs. 0.846 g/cm 2, p=0.007; mean Z-score, -1.93 vs. -1.58, p=0.002), with no significant change at TH. P1NP fell by 37% (p=0.00041), with no significant change in bone ALP (p=0.15). Bone pain did not change significantly (p=0.6). Fracture incidence remained high, with 25 clinical fractures and 10 major fractures in fourteen participants (0.18 major fractures per person per year), with historical data of 0.12 fractures per person per year. The meta-analysis did not demonstrate a significant difference in fracture incidence in patients with OI treated with oral bisphosphonates. Conclusions Risedronate in adults with OI type I results in modest but significant increases in BMD at LS, and decreased bone turnover. However, this may be insufficient to make a clinically significant difference to fracture incidence.

Comparison of measured sleeping metabolic rate and predicted basal metabolic rate during the first year of life : evidence of a bias changing with increasing metabolic rate

Objective: To compare measurements of sleeping metabolic rate (SMR) in infancy with predicted basal metabolic rate (BMR) estimated by the equations of Schofield. Methods: Some 104 serial measurements of SMR by indirect calorimetry were performed in 43 healthy infants at 1.5, 3, 6, 9 and 12 months of age. Predicted BMR was calculated using the weight only (BMR-wo) and weight and height (BMR-wh) equations of Schofield for 0-3-y-olds. Measured SMR values were compared with both predictive values by means of the Bland-Altman statistical test. Results: The mean measured SMR was 1.48 MJ/day. The mean predicted BMR values were 1.66 and 1.47 MJ/day for the weight only and weight and height equations, respectively. The Bland-Altman analysis showed that BMR-wo equation on average overestimated SMR by 0.18 MJ/day (11%) and the BMR-wh equation underestimated SMR by 0.01 MJ/day (1%). However the 95% limits of agreement were wide: -0.64 to + 0.28 MJ/day (28%) for the former equation and -0.39 to + 0.41 MJ/day (27%) for the latter equation. Moreover there was a significant correlation between the mean of the measured and predicted metabolic rate and the difference between them. Conclusions: The wide variation seen in the difference between measured and predicted metabolic rate and the bias probably with age indicates there is a need to measure actual metabolic rate for individual clinical care in this age group.

Design-driven digital futures: The role of design-led innovation in the creation of online connected communities for new mobility solutions

Online communities have fundamentally changed how humans connected and are now so common they are fundamental to the human experience. As the Internet developed for Web 1.0 to Web 2.0, the functionality of these communities has far exceeded initial expectations. These communities have shifted from simply places to share information to ways to access products and services that bridge the online and offline worlds. This shift has led to the disruption of many industries with the transportation industry being one such sector. Both private transport providers and public transport systems face competition from online communities who are able to link services providers and customers more effectively and innovatively. These types of communities fall under what has been popularised as collaborative consumption or the sharing economy. The aim of this study is to explore the role of Design-led Innovation in the creation of digital futures, specifically online connected communities for successful new mobility solutions. To explore this proposition multiple data collection methods are proposed;Content Analysis, ii) A Comparative Qualitative Study consisting of Qualitative Interviews and Focus Groups / Design Workshops and iii) An Action Research Cycle of Embedded Practice. The multidisciplinary nature of this study grounds this research in a novel position contributing to new knowledge in both the field of design, and also a deeper understanding of the larger fast-growing online community phenomena.

MRI-based strain and strain rate analysis of left ventricle: A modified hierarchical transformation model

Background Different from other indicators of cardiac function, such as ejection fraction and transmitral early diastolic velocity, myocardial strain is promising to capture subtle alterations that result from early diseases of the myocardium. In order to extract the left ventricle (LV) myocardial strain and strain rate from cardiac cine-MRI, a modified hierarchical transformation model was proposed. Methods A hierarchical transformation model including the global and local LV deformations was employed to analyze the strain and strain rate of the left ventricle by cine-MRI image registration. The endocardial and epicardial contour information was introduced to enhance the registration accuracy by combining the original hierarchical algorithm with an Iterative Closest Points using Invariant Features algorithm. The hierarchical model was validated by a normal volunteer first and then applied to two clinical cases (i.e., the normal volunteer and a diabetic patient) to evaluate their respective function. Results Based on the two clinical cases, by comparing the displacement fields of two selected landmarks in the normal volunteer, the proposed method showed a better performance than the original or unmodified model. Meanwhile, the comparison of the radial strain between the volunteer and patient demonstrated their apparent functional difference. Conclusions The present method could be used to estimate the LV myocardial strain and strain rate during a cardiac cycle and thus to quantify the analysis of the LV motion function.

In vivo velocity vector imaging and time-resolved strain rate measurements in the wall of blood vessels using MRI

In this paper, we present a new approach for velocity vector imaging and time-resolved measurements of strain rates in the wall of human arteries using MRI and we prove its feasibility on two examples: in vitro on a phantom and in vivo on the carotid artery of a human subject. Results point out the promising potential of this approach for investigating the mechanics of arterial tissues in vivo.

Rapid assessment of genotype-by-environment interactions and heritability for growth rate in aquaculture species using in vitro fertilisation and DNA tagging

Commercial environments may receive only a fraction of expected genetic gains for growth rate as predicted from the selection environment This fraction is the result of undesirable genotype-by-environment interactions (G x E) and measured by the genetic correlation (r(g)) of growth between environments. Rapid estimates of genetic correlation achieved in one generation are notoriously difficult to estimate with precision. A new design is proposed where genetic correlations can be estimated by utilising artificial mating from cryopreserved semen and unfertilised eggs stripped from a single female. We compare a traditional phenotype analysis of growth to a threshold model where only the largest fish are genotyped for sire identification. The threshold model was robust to differences in family mortality differing up to 30%. The design is unique as it negates potential re-ranking of families caused by an interaction between common maternal environmental effects and growing environment. The design is suitable for rapid assessment of G x E over one generation with a true 0.70 genetic correlation yielding standard errors as low as 0.07. Different design scenarios were tested for bias and accuracy with a range of heritability values, number of half-sib families created, number of progeny within each full-sib family, number of fish genotyped, number of fish stocked, differing family survival rates and at various simulated genetic correlation levels

Bayesian designs with frequentist and Bayesian error rate considerations

So far, most Phase II trials have been designed and analysed under a frequentist framework. Under this framework, a trial is designed so that the overall Type I and Type II errors of the trial are controlled at some desired levels. Recently, a number of articles have advocated the use of Bavesian designs in practice. Under a Bayesian framework, a trial is designed so that the trial stops when the posterior probability of treatment is within certain prespecified thresholds. In this article, we argue that trials under a Bayesian framework can also be designed to control frequentist error rates. We introduce a Bayesian version of Simon's well-known two-stage design to achieve this goal. We also consider two other errors, which are called Bayesian errors in this article because of their similarities to posterior probabilities. We show that our method can also control these Bayesian-type errors. We compare our method with other recent Bayesian designs in a numerical study and discuss implications of different designs on error rates. An example of a clinical trial for patients with nasopharyngeal carcinoma is used to illustrate differences of the different designs.

Modelling growth rate of Penaeus monodon Fabricius in intensively managed ponds: effects of temperature, pond age and stocking density

Records of shrimp growth and water quality made during 12 crops from each of 48 ponds, over a period of 6.5 years, were provided by a Queensland, Australia, commercial shrimp farm, These data were analysed with a new growth model derived from the Gompertz model. The results indicate that water temperature, mortality and pond age significantly affect growth rates. After 180 days, shrimp reach 34 g at constant 30 degrees C, but only 15 g after the same amount of time at 20 degrees C. Mortality, through thinning the density of shrimp in the ponds, increased the growth rate, but the effect is small. With continual production, growth rates at first remained steady, then appeared to decrease for the sixth and seventh crop, after which they have increased steadily with each crop. It appears that conservative pond management, together with a gradual improvement in husbandry techniques, particularly feed management, brought about this change. This has encouraging implications for the long-term sustainability of the farming methods used. The growth model can be used to predict productivity, and hence, profitability, of new aquaculture locations or new production strategies.

The role of comfort in child restraint use practices

Suboptimal restraint use, particularly the incorrect use of restraints, is a significant and widespread problem among child vehicle occupants, and increases the risk of injury. Previous research has identified comfort as a potential factor influencing suboptimal restraint use. Both the real comfort experienced by the child and the parent’s perception of the child’s comfort are reported to influence the optimal use of restraints. Problems with real comfort may lead the child to misuse the restraint in their attempt to achieve better comfort whilst parent-perceived discomfort has been reported as a driver for premature graduation and inappropriate restraint choice. However, this work has largely been qualitative. There has been no research that objectively studies either the association between real and parent-perceived comfort, or any association between comfort and suboptimal restraint use. One barrier to such studies is the absence of validated tools for quantifying real comfort in children. We aimed to develop methods to examine both real and parent-perceived comfort and examine their effects on suboptimal restraint use. We conducted online parent surveys (n=470) to explore what drives parental perceptions of their child’s comfort in restraint systems (study 1) and used data from field observation studies (n=497) to examine parent-perceived comfort and its relationship with observed restraint use (study 2). We developed methods to measure comfort in children in a laboratory setting (n=14) using video analysis to estimate a Discomfort Avoidance Behaviour (DAB) score, pressure mapping and adapted survey tools to differentiate between comfortable and induced discomfort conditions (study 3). The DAB rate was then used to compare an integrated booster with an add-on booster (study 4) Preliminary analysis of our recent online survey of Australian parents (study 1) indicates that 23% of parents report comfort as a consideration when making a decision to change restraints. Logistic regression modelling of data collected during the field observation study (study 2) revealed that parent-perceived discomfort was not significantly associated with premature graduation. Contrary to expectation, children of parents who reported that their child was comfortable were almost twice as likely to have been incorrectly restrained (p<0.01, 95% CI 1.24 - 2.77).In the laboratory study (study 3) we found our adapted survey tools did not provide a reliable measurement of real comfort among children. However our DAB score was able to differentiate between comfortable and induced discomfort conditions and correlated well with pressure mapping. Preliminary results from the laboratory comparison study (study 4) indicate a positive correlation between DAB rate and use errors. In experiments conducted to date, we have seen a significantly higher DAB rate in the integrated booster compared to the add-on booster (p < 0.01). However, this needs to be confirmed in a naturalistic setting and in further experiments that take length of time under observation into account. Our results suggest that while some parents report concern about their child’s comfort, parent-reported comfort levels were not associated with restraint choice. If comfort is important for optimal restraint use, it is likely to be the real comfort of the child rather than that reported by the parent. The method we have developed for studying real comfort can be used in naturalistic studies involving child occupants to further understand this relationship. This work will be of interest to vehicle and child restraint manufacturers interested in improving restraint design for young occupants as well as researchers and other stakeholders interested in reducing the incidence of restraint misuse among children.

Specialisation versus special interest: The Australian podiatry experience

Background Ensuring efficient and effective delivery of health care to an ageing population has been a major driver for a review of the health workforce in Australia. As part of this process a National Registration and Accreditation Scheme (NRAS) has evolved with one goal being to improve workforce flexibility within a nationally consistent model of governance. In addition to increased flexibility, there have been discussions about maintaining standards and the role of specialisation. This study aims to explore the association between practitioners’ self-perceptions about their special interest in musculoskeletal, diabetes related and podopaediatric foot care and the actual podiatry services they deliver in Australia. Methods A cross sectional on-line survey was administered on behalf of the Australasian Podiatry Council and its’ state based member associations. Self-reported data were collected over a 3-week interval and captured information about the practitioners by gender, years of clinical experience, area of work by state, work setting, and location. For those participants that identified with an area of special interest or specialty, further questions were asked regarding support for the area of special interest through education, and activities performed in treating patients in the week prior to survey completion. Queensland University of Technology Human Research Ethics approval was sought and confirmed exemption from review. Results 218 podiatrists participated in the survey. Participants were predominately female and worked in private practices. The largest area of personal interest by the podiatrists was related to the field of musculoskeletal podiatry (n = 65), followed closely by diabetes foot care (n = 61), and a third area identified was in the management of podopaediatric conditions (n = 26). Conclusions Health workforce reform in Australia is in part being managed by the federal government with a goal to meet the health care needs of Australians into the future. The recognition of a specialty registration of podiatric surgery and endorsement for scheduled medicines was established with this workforce reform in mind. Addition of new subspecialties may be indicated based on professional development, to maintain high standards and meet community expectations.