The effect of oral metformin on insulin sensitivity in insulin-resistant ponies

Metformin may be an effective therapeutic option for insulin-resistant (I-R) horses/ponies because, in humans, it reportedly enhances insulin sensitivity (SI) of peripheral tissues without stimulating insulin secretion. To determine the effect of metformin on insulin and glucose dynamics in I-R ponies, six ponies were studied in a cross-over design by Minimal Model analysis of a frequently-sampled intravenous glucose tolerance test (FSIGT). Metformin was administered at 15. mg/kg bodyweight (BW), orally, twice-daily, for 21. days to the metformin-treated group. The control group received a placebo. A FSIGT was conducted before and after treatment. The Minimal Model of glucose and insulin dynamics rendered indices describing SI, glucose effectiveness (Sg), acute insulin response to glucose (AIRg) and the disposition index (DI). The body condition score (BCS), BW and cresty neck score (CNS) were also assessed. There was no significant change in SI, Sg, AIRg, DI, BW, BCS or CNS in response to metformin, or over time in the control group. There were no measurable benefits of metformin on SI, consistent with recent work showing that the bioavailability of metformin in horses is poor, and chronic dosing may not achieve therapeutic blood concentrations. Alternatively, metformin may only be effective in obese ponies losing weight or with hyperglycaemia.

Sensitivity of the NMR density matrix to pulse sequence parameters : a simplified analytic approach

We present a formalism for the analysis of sensitivity of nuclear magnetic resonance pulse sequences to variations of pulse sequence parameters, such as radiofrequency pulses, gradient pulses or evolution delays. The formalism enables the calculation of compact, analytic expressions for the derivatives of the density matrix and the observed signal with respect to the parameters varied. The analysis is based on two constructs computed in the course of modified density-matrix simulations: the error interrogation operators and error commutators. The approach presented is consequently named the Error Commutator Formalism (ECF). It is used to evaluate the sensitivity of the density matrix to parameter variation based on the simulations carried out for the ideal parameters, obviating the need for finite-difference calculations of signal errors. The ECF analysis therefore carries a computational cost comparable to a single density-matrix or product-operator simulation. Its application is illustrated using a number of examples from basic NMR spectroscopy. We show that the strength of the ECF is its ability to provide analytic insights into the propagation of errors through pulse sequences and the behaviour of signal errors under phase cycling. Furthermore, the approach is algorithmic and easily amenable to implementation in the form of a programming code. It is envisaged that it could be incorporated into standard NMR product-operator simulation packages.

The surface-structure sensitivity of dioxygen activation in the anatase-photocatalyzed oxidation reaction

The reaction pathways by which oxygen is incorporated into the substrate in the photocatalytic oxidation of terephthalic acid (TPTA) are vastly different on {001} and {101} facets of an anatase single crystal. This was established by controlling the percentage of {101} and {001} facets, isotopically tracing the origins of the hydroxy group, and studying dioxygen consumption and variance in the concentration of hydroxylation intermediate.

Numerical and experimental studies of cold-formed steel floor systems under standard fire conditions

Light gauge cold-formed steel frame (LSF) structures are increasingly used in industrial, commercial and residential buildings because of their non-combustibility, dimensional stability, and ease of installation. A floor-ceiling system is an example of its applications. LSF floor-ceiling systems must be designed to serve as fire compartment boundaries and provide adequate fire resistance. Fire rated floor-ceiling assemblies formed with new materials and construction methodologies have been increasingly used in buildings. However, limited research has been undertaken in the past and hence a thorough understanding of their fire resistance behaviour is not available. Recently a new composite panel in which an external insulation layer is used between two plasterboards has been developed at QUT to provide a higher fire rating to LSF floors under standard fire conditions. But its increased fire rating could not be determined using the currently available design methods. Research on LSF floor systems under fire conditions is relatively recent and the behaviour of floor joists and other components in the systems is not fully understood. The present design methods thus require the use of expensive fire protection materials to protect them from excessive heat increase during a fire. This leads to uneconomical and conservative designs. Fire rating of these floor systems is provided simply by adding more plasterboard sheets to the steel joists and such an approach is totally inefficient. Hence a detailed fire research study was undertaken into the structural and thermal performance of LSF floor systems including those protected by the new composite panel system using full scale fire tests and extensive numerical studies. Experimental study included both the conventional and the new steel floor-ceiling systems under structural and fire loads using a gas furnace designed to deliver heat in accordance with the standard time- temperature curve in AS 1530.4 (SA, 2005). Fire tests included the behavioural and deflection characteristics of LSF floor joists until failure as well as related time-temperature measurements across the section and along the length of all the specimens. Full scale fire tests have shown that the structural and thermal performance of externally insulated LSF floor system was superior than traditional LSF floors with or without cavity insulation. Therefore this research recommends the use of the new composite panel system for cold-formed LSF floor-ceiling systems. The numerical analyses of LSF floor joists were undertaken using the finite element program ABAQUS based on the measured time-temperature profiles obtained from fire tests under both steady state and transient state conditions. Mechanical properties at elevated temperatures were considered based on the equations proposed by Dolamune Kankanamge and Mahendran (2011). Finite element models were calibrated using the full scale test results and used to further provide a detailed understanding of the structural fire behaviour of the LSF floor-ceiling systems. The models also confirmed the superior performance of the new composite panel system. The validated model was then used in a detailed parametric study. Fire tests and the numerical studies showed that plasterboards provided sufficient lateral restraint to LSF floor joists until their failure. Hence only the section moment capacity of LSF floor joists subjected to local buckling effects was considered in this research. To predict the section moment capacity at elevated temperatures, the effective section modulus of joists at ambient temperature is generally considered adequate. However, this research has shown that it leads to considerable over- estimation of the local buckling capacity of joist subject to non-uniform temperature distributions under fire conditions. Therefore new simplified fire design rules were proposed for LSF floor joist to determine the section moment capacity at elevated temperature based on AS/NZS 4600 (SA, 2005), NAS (AISI, 2007) and Eurocode 3 Part 1.3 (ECS, 2006). The accuracy of the proposed fire design rules was verified with finite element analysis results. A spread sheet based design tool was also developed based on these design rules to predict the failure load ratio versus time, moment capacity versus time and temperature for various LSF floor configurations. Idealised time-temperature profiles of LSF floor joists were developed based on fire test measurements. They were used in the detailed parametric study to fully understand the structural and fire behaviour of LSF floor panels. Simple design rules were also proposed to predict both critical average joist temperatures and failure times (fire rating) of LSF floor systems with various floor configurations and structural parameters under any given load ratio. Findings from this research have led to a comprehensive understanding of the structural and fire behaviour of LSF floor systems including those protected by the new composite panel, and simple design methods. These design rules were proposed within the guidelines of the Australian/New Zealand, American and European cold- formed steel structures standard codes of practice. These may also lead to further improvements to fire resistance through suitable modifications to the current composite panel system.

Fire Tests of Cold-formed Steel Wall Systems

Cold-formed steel stud walls are an important component of Light Steel Framing (LSF) building systems used in commercial, industrial and residential buildings. In the conventional LSF stud wall systems, thin-walled steel studs are protected from fire by placing one or two layers of plasterboard on both sides with or without cavity insulation. However, there is very limited data about the structural and thermal performance of these wall systems while past research showed contradicting results about the benefits of cavity insulation. This research proposed a new LSF stud wall system in which a composite panel made of two plasterboards with insulation between them was used to improve the fire rating of walls. Full scale fire tests were conducted using both conventional steel stud walls with and without the use of cavity insulation and the new composite panel system. Eleven full scale load bearing wall specimens were tested to study the thermal and structural performances of the load bearing wall assemblies under standard fire conditions. These tests showed that the use of cavity insulation led to inferior fire performance of walls while also providing good explanations and supporting test data to overcome the incorrect industry assumptions about cavity insulation. Tests demonstrated that the use of external insulation in a composite panel form enhanced the thermal and structural performances of stud walls and increased their fire resistance rating significantly. This paper presents the details of the full scale fire tests of load-bearing wall assemblies lined with plasterboards and different types of insulation under varying load ratios. Test results including the temperature and deflection profiles of walls measured during the fire tests will be presented along with their failure modes and failure times.

Cold and heat waves in the United States

Extreme cold and heat waves, characterised by a number of cold or hot days in succession, place a strain on people’s cardiovascular and respiratory systems. The increase in deaths due to these waves may be greater than that predicted by extreme temperatures alone. We examined cold and heat waves in 99 US cities for 14 years (1987–2000) and investigated how the risk of death depended on the temperature threshold used to define a wave, and a wave’s timing, duration and intensity. We defined cold and heat waves using temperatures above and below cold and heat thresholds for two or more days. We tried five cold thresholds using the first to fifth percentiles of temperature, and five heat thresholds using the ninety-fifth to ninety-ninth percentiles. The extra wave effects were estimated using a two-stage model to ensure that their effects were estimated after removing the general effects of temperature. The increases in deaths associated with cold waves were generally small and not statistically significant, and there was even evidence of a decreased risk during the coldest waves. Heat waves generally increased the risk of death, particularly for the hottest heat threshold. Cold waves of a colder intensity or longer duration were not more dangerous. Cold waves earlier in the cool season were more dangerous, as were heat waves earlier in the warm season. In general there was no increased risk of death during cold waves above the known increased risk associated with cold temperatures. Cold or heat waves earlier in the cool or warm season may be more dangerous because of a build up in the susceptible pool or a lack of preparedness for cold or hot temperatures.

Consecutive days of cold water immersion: effects on cycling performance and heart rate variability.

We investigated performance and heart rate (HR) variability (HRV) over consecutive days of cycling with post-exercise cold water immersion (CWI) or passive recovery (PAS). In a crossover design, 11 cyclists completed two separate 3-day training blocks (120 min cycling per day, 66 maximal sprints, 9 min time trialling [TT]), followed by 2 days of recovery-based training. The cyclists recovered from each training session by standing in cold water (10 °C) or at room temperature (27 °C) for 5 min. Mean power for sprints, total TT work and HR were assessed during each session. Resting vagal-HRV (natural logarithm of square-root of mean squared differences of successive R-R intervals; ln rMSSD) was assessed after exercise, after the recovery intervention, during sleep and upon waking. CWI allowed better maintenance of mean sprint power (between-trial difference [90 % confidence limits] +12.4 % [5.9; 18.9]), cadence (+2.0 % [0.6; 3.5]), and mean HR during exercise (+1.6 % [0.0; 3.2]) compared with PAS. ln rMSSD immediately following CWI was higher (+144 % [92; 211]) compared with PAS. There was no difference between the trials in TT performance (-0.2 % [-3.5; 3.0]) or waking ln rMSSD (-1.2 % [-5.9; 3.4]). CWI helps to maintain sprint performance during consecutive days of training, whereas its effects on vagal-HRV vary over time and depend on prior exercise intensity.

Revised reinforcement sensitivity theory : the impact of FFFS and stress on driving

This study investigated the effect of a fear-based personality trait, as conceptualised in Gray’s revised reinforcement sensitivity theory (RST) by the strength of the fight/flight/freeze system (FFFS), on young people’s driving simulator performance under induced psychosocial stress. Seventy-one young drivers completed the Jackson-5 questionnaire of RST traits, followed by a psychosocial stress or relaxation induction procedure (random allocation to groups) and then a city driving simulator task. Some support was found for the hypothesis that higher FFFS sensitivity would result in poorer driving performance under stress, in terms of significantly poorer hazard responses, possibly due to an increased attentional focus on the aversive cues inherent in the stress induction leaving reduced attentional capacity for the driving task. These results suggest that stress may lead to riskier driving behaviour in individuals with fearful RST personality styles.

Visual sensitivity loss in the central thirty degrees of visual field is associated with diabetic peripheral neuropathy

Aims/hypothesis: Impaired central vision has been shown to predict diabetic peripheral neuropathy (DPN). Several studies have demonstrated diffuse retinal neurodegenerative changes in diabetic patients prior to retinopathy development, raising the prospect that non-central vision may also be compromised by primary neural damage. We hypothesise that type 2 diabetic patients with DPN exhibit visual sensitivity loss in a distinctive pattern across the visual field, compared with a control group of type 2 diabetic patients without DPN. Methods: Increment light sensitivity was measured by standard perimetry in the central 30 degree of visual field for two age-matched groups of type 2 diabetic patients, with and without neuropathy (n=40/30). Neuropathy status was assigned using the neuropathy disability score. Mean visual sensitivity values were calculated globally, for each quadrant and for three eccentricities (0-10 degree , 11-20 degree and 21-30 degree ). Data were analysed using a generalised additive mixed model (GAMM). Results: Global and quadrant between-group visual sensitivity mean differences were marginally but consistently lower (by about 1 dB) in the neuropathy cohort compared with controls. Between-group mean differences increased from 0.36 to 1.81 dB with increasing eccentricity. GAMM analysis, after adjustment for age, showed these differences to be significant beyond 15 degree eccentricity and monotonically increasing. Retinopathy levels and disease duration were not significant factors within the model (p=0.90). Conclusions/interpretation: Visual sensitivity reduces disproportionately with increasing eccentricity in type 2 diabetic patients with peripheral neuropathy. This sensitivity reduction within the central 30 degree of visual field may be indicative of more consequential loss in the far periphery.

Corneal sensitivity is related to established measures of diabetic peripheral neuropathy

Purpose:  The objective was to investigate the association between corneal sensitivity and established measures of diabetic peripheral neuropathy (DPN). Methods:  Corneal sensitivity was measured in 93 individuals with diabetes, 146 diabetic individuals without neuropathy and 61 control individuals without diabetes or neuropathy using a non-contact corneal aesthesiometer at the baseline visit of a five-year longitudinal natural history study of DPN. The correlation between corneal sensitivity and established measures of neuropathy was estimated and multi-dimensional scaling was used to represent similarities and dissimilarities between variables. Results:  The corneal sensitivity threshold was significantly correlated with a majority of established measures of DPN. Correlation coefficients ranged from -0.32 to 0.26. Using multi-dimensional scaling, non-contact corneal aesthesiometry was closer to the neuropathy disability score, diabetic neuropathy symptom score and Neuropad and most dissimilar to electrophysiological parameters and quantitative sensory testing. Conclusion:  Corneal sensitivity, although not strongly related, is associated with other functional measures of DPN and might provide a useful adjunct in identifying functional loss of small nerve fibre integrity.

Sensitivity to the MEK inhibitor E6201 in melanoma cells is associated with mutant BRAF and wildtype PTEN status

BACKGROUND: Melanoma is the most lethal form of skin cancer, but recent advances in molecularly targeted agents against the Ras/Raf/MAPK pathway demonstrate promise as effective therapies. Despite these advances, resistance remains an issue, as illustrated recently by the clinical experience with vemurafenib. Such acquired resistance appears to be the result of parallel pathway activation, such as PI3K, to overcome single-agent inhibition. In this report, we describe the cytotoxicity and anti-tumour activity of the novel MEK inhibitor, E6201, in a broad panel of melanoma cell lines (n = 31) of known mutational profile in vitro and in vivo. We further test the effectiveness of combining E6201 with an inhibitor of PI3K (LY294002) in overcoming resistance in these cell lines. RESULTS: The majority of melanoma cell lines were either sensitive (IC50 < 500 nM, 24/31) or hypersensitive (IC50 < 100 nM, 18/31) to E6201. This sensitivity correlated with wildtype PTEN and mutant BRAF status, whereas mutant RAS and PI3K pathway activation were associated with resistance. Although MEK inhibitors predominantly exert a cytostatic effect, E6201 elicited a potent cytocidal effect on most of the sensitive lines studied, as evidenced by Annexin positivity and cell death ELISA. Conversely, E6201 did not induce cell death in the two resistant melanoma cell lines tested. E6201 inhibited xenograft tumour growth in all four melanoma cell lines studied to varying degrees, but a more pronounced anti-tumour effect was observed for cell lines that previously demonstrated a cytocidal response in vitro. In vitro combination studies of E6201 and LY294002 showed synergism in all six melanoma cell lines tested, as defined by a mean combination index < 1. CONCLUSIONS: Our data demonstrate that E6201 elicits a predominantly cytocidal effect in vitro and in vivo in melanoma cells of diverse mutational background. Resistance to E6201 was associated with disruption of PTEN and activation of downstream PI3K signalling. In keeping with these data we demonstrate that co-inhibition of MAPK and PI3K is effective in overcoming resistance inherent in melanoma.

Muscle, skin and core temperature after −110°C cold air and 8°C water treatment

The aim of this investigation was to elucidate the reductions in muscle, skin and core temperature following exposure to −110°C whole body cryotherapy (WBC), and compare these to 8°C cold water immersion (CWI). Twenty active male subjects were randomly assigned to a 4-min exposure of WBC or CWI. A minimum of 7 days later subjects were exposed to the other treatment. Muscle temperature in the right vastus lateralis (n = 10); thigh skin (average, maximum and minimum) and rectal temperature (n = 10) were recorded before and 60 min after treatment. The greatest reduction (P<0.05) in muscle (mean ± SD; 1 cm: WBC, 1.6±1.2°C; CWI, 2.0±1.0°C; 2 cm: WBC, 1.2±0.7°C; CWI, 1.7±0.9°C; 3 cm: WBC, 1.6±0.6°C; CWI, 1.7±0.5°C) and rectal temperature (WBC, 0.3±0.2°C; CWI, 0.4±0.2°C) were observed 60 min after treatment. The largest reductions in average (WBC, 12.1±1.0°C; CWI, 8.4±0.7°C), minimum (WBC, 13.2±1.4°C; CWI, 8.7±0.7°C) and maximum (WBC, 8.8±2.0°C; CWI, 7.2±1.9°C) skin temperature occurred immediately after both CWI and WBC (P<0.05). Skin temperature was significantly lower (P<0.05) immediately after WBC compared to CWI. The present study demonstrates that a single WBC exposure decreases muscle and core temperature to a similar level of those experienced after CWI. Although both treatments significantly reduced skin temperature, WBC elicited a greater decrease compared to CWI. These data may provide information to clinicians and researchers attempting to optimise WBC and CWI protocols in a clinical or sporting setting.