Recombinant B-domain-deleted porcine sequence factor VIII (r-pFVIII) for the treatment of bleeding in patients with congenital haemophilia A and inhibitors.

INTRODUCTION: Development of inhibitors to human FVIII (hFVIII) significantly complicates the control of bleeding events in patients with haemophilia A. AIM: This prospective, multicentre, open-label, non-comparative, Phase II study evaluated the haemostatic activity of a recombinant B-domain-deleted porcine FVIII (r-pFVIII), in the treatment of non-life/non-limb-threatening bleeding in individuals with haemophilia A and FVIII inhibitors. METHODS: Acute bleeding episodes in patients with pFVIII inhibitor titres <0.8 BU mL-1 were treated with 50 U kg-1 body weight r-pFVIII. Those with pFVIII inhibitor titres of >0.8 BU mL-1 received an initial calculated r-pFVIII loading dose followed by 50 U kg-1 treatment dose. Treatment continued at 6-hourly intervals until bleeding was determined, controlled or till a maximum of eight doses was reached. RESULTS: All 25 bleeding episodes in nine patients (mean age: 23.7 years; range: 14-34 years) were controlled successfully with eight or fewer injections of r-pFVIII. The median time from bleeding onset to the administration of r-pFVIII was 5.7 h (range: 1.5-20.0 h). Twenty of the bleeding episodes (80%) were controlled with one treatment dose of r-pFVIII (with or without a loading dose, median dose: 200.8 U kg-1 ; range: 50-576 U kg-1 ) regardless of pFVIII level. r-pFVIII was well tolerated and no treatment-emergent serious adverse events were considered by the investigator to be related to r-pFVIII administration. CONCLUSION: The results suggest that FVIII replacement therapy with r-pFVIII could be a viable alternative to bypassing agents for the treatment of bleeding episodes in individuals with haemophilia A and FVIII inhibitors.

Square dielectric THz waveguides.

A holey cladding dielectric waveguide with square cross section is designed, simulated, fabricated and characterized. The TOPAS waveguide is designed to be single mode across the broad frequency range of 180 GHz to 360 GHz as shown by finite-difference time domain simulation and to robustly support simultaneous TE and TM mode propagation. The square fiber geometry is realized by pulling through a heat distribution made square by appropriate furnace design. The transmitted mode profile is imaged using a vector network analyzer with a pinhole at the receiver module. Good agreement between the measured mode distribution and the calculated mode distribution is demonstrated.

Managing land application of coal seam water: A field study of land amendment irrigation using saline-sodic and alkaline water on a Red Vertisol.

Coal seam (CS) gas operations coproduce water with gas from confined CS aquifers. This CS water represents a potential agricultural resource if the water is able to be chemically amended to comply with management guidelines. Stoichiometric quantities of sulphur and gypsum amendments can be used to neutralise the alkalinity and reduce the sodicity of CS water respectively. These amendments can either be mixed in-line at a water treatment plant or applied directly to land prior to the application of CS water (a practice termed land amendment irrigation - LAI). This study compared the efficacy of LAI with in-line chemical amendment of CS water and irrigation with non-saline, non-sodic and non-alkaline (good quality) water under field conditions in southern Queensland. Soil chemical properties, soluble Ca, Mg, K, Na, electrical conductivity (EC), pH, chloride and alkalinity, as well as saturated hydraulic conductivity were measured to determine the impact of the irrigation treatments on soil chemical and physical conditions. Irrigation of lucerne pasture using solid-set sprinklers applied a total of 6.7 ML/ha of each treatment irrigation water to the experimental plots over a 10-month period. Alkalinity was neutralised using LAI, with no increase in soil alkalinity observed. Soil sodicity did not exceed threshold electrolyte concentration values under either CS water irrigation treatment. Soil chemical and physical properties were comparable for both LAI and in-line chemical amendment of CS water. Soil saturated hydraulic conductivity was maintained under all irrigation treatments. Results showed that the constrained capacity of the irrigation system was unable to meet crop evapotranspiration demand. This resulted in accumulation of salt within the root-zone under the CS water treatments compared to the good quality water treatment. LAI successfully chemically amended Bowen Basin CS water facilitating its beneficial use for agricultural irrigation.

International study of objectively measured physical activity and sedentary time with body mass index and obesity: IPEN adult study.

BACKGROUND: Physical activity (PA) has been consistently implicated in the etiology of obesity, whereas recent evidence on the importance of sedentary time remains inconsistent. Understanding of dose-response associations of PA and sedentary time with overweight and obesity in adults can be improved with large-scale studies using objective measures of PA and sedentary time. The purpose of this study was to examine the strength, direction and shape of dose-response associations of accelerometer-based PA and sedentary time with body mass index (BMI) and weight status in 10 countries, and the moderating effects of study site and gender. METHODS: Data from the International Physical activity and the Environment Network (IPEN) Adult study were used. IPEN Adult is an observational multi-country cross-sectional study, and 12 sites in 10 countries are included. Participants wore an accelerometer for seven consecutive days, completed a socio-demographic questionnaire and reported height and weight. In total, 5712 adults (18-65 years) were included in the analyses. Generalized additive mixed models, conducted in R, were used to estimate the strength and shape of the associations. RESULTS: A curvilinear relationship of accelerometer-based moderate-to-vigorous PA and total counts per minute with BMI and the probability of being overweight/obese was identified. The associations were negative, but weakened at higher levels of moderate-to-vigorous PA (>50 min per day) and higher counts per minute. No associations between sedentary time and weight outcomes were found. Complex site- and gender-specific findings were revealed for BMI, but not for weight status. CONCLUSIONS: On the basis of these results, the current Institute of Medicine recommendation of 60 min per day of moderate-to-vigorous PA to prevent weight gain in normal-weight adults was supported. No relationship between sedentary time and the weight outcomes was present, calling for further examination. If moderator findings are confirmed, the relationship between PA and BMI may be country- and gender-dependent, which could have important implications for country-specific health guidelines.

Electrochemical and physicochemical properties of small phosphonium cation ionic liquid electrolytes with high lithium salt content.

Electrolytes of a room temperature ionic liquid (RTIL), trimethyl(isobutyl)phosphonium (P111i4) bis(fluorosulfonyl)imide (FSI) with a wide range of lithium bis(fluorosulfonyl)imide (LiFSI) salt concentrations (up to 3.8 mol kg(-1) of salt in the RTIL) were characterised using a combination of techniques including viscosity, conductivity, differential scanning calorimetry (DSC), electrochemical impedance spectroscopy (EIS), nuclear magnetic resonance (NMR) and cyclic voltammetry (CV). We show that the FSI-based electrolyte containing a high salt concentration (e.g. 1 : 1 salt to IL molar ratio, equivalent to 3.2 mol kg(-1) of LiFSI) displays unusual transport behavior with respect to lithium ion mobility and promising electrochemical behavior, despite an increase in viscosity. These electrolytes could compete with the more traditionally studied nitrogen-based ionic liquids (ILs) in lithium battery applications.

Ionic liquids and ultrasound in combination: synergies and challenges.

Ionic liquids, as reaction media, and sonochemistry are two recently developing fields of chemistry that present some similarities. Firstly, they constitute separately unconventional approaches to reaction chemistry that, in many cases, generate improvements in yield, rate and selectivity compared to classical chemistry, or even change the mechanisms or products expected. In addition, both are often associated with green chemistry concepts as a result of their properties and their possible eco-friendly uses. A recent trend has been to combine these two technologies in a range of different applications and the results demonstrate very significant and occasionally surprising synergetic effects. Here we critically review the advantages and limitations of the ionic liquid/ultrasound combination in different applications in chemistry, to understand how, and in which respects, it could become an essential tool of sustainable chemistry in the future. Many practical and theoretical aspects associated with this combination of techniques are not understood or resolved and we discus where fundamental studies might further advance this field.

Effects of acute glucocorticoid blockade on metabolic dysfunction in patients with Type 2 diabetes with and without fatty liver.

To investigate the potential of therapies which reduce glucocorticoid action in patients with Type 2 diabetes we performed a randomized, double-blinded, placebo-controlled crossover study of acute glucocorticoid blockade, using the glucocorticoid receptor antagonist RU38486 (mifepristone) and cortisol biosynthesis inhibitor (metyrapone), in 14 men with Type 2 diabetes. Stable isotope dilution methodologies were used to measure the rates of appearance of glucose, glycerol, and free fatty acids (FFAs), including during a low-dose (10 mU·m⁻² ·min⁻¹) hyperinsulinemic clamp, and subgroup analysis was conducted in patients with high or low liver fat content measured by magnetic resonance spectroscopy (n = 7/group). Glucocorticoid blockade lowered fasting glucose and insulin levels and improved insulin sensitivity of FFA and glycerol turnover and hepatic glucose production. Among this population with Type 2 diabetes high liver fat was associated with hyperinsulinemia, higher fasting glucose levels, peripheral and hepatic insulin resistance, and impaired suppression of FFA oxidation and FFA and glycerol turnover during hyperinsulinemia. Glucocorticoid blockade had similar effects in those with and without high liver fat. Longer term treatments targeting glucocorticoid action may be useful in Type 2 diabetes with and without fatty liver.

Bioenergetics for the growth of Staphylococcus lentus in biocompatible choline salts.

Choline-based biocompatible salts were used as "nutrients" for the growth of Staphylococcus lentus bacteria. Increase in the growth rate of bacteria was observed, compared to conventional carbon sources. In the case of the ionic liquid, choline lactate, the increase was pronounced. Bacterial growth was correlated with power-time curve in an investigation monitored online by reaction calorimetry. From the power-time curve, three phases of the growth can be distinctly seen. Heat yield coefficients estimated for the growth of S. lentus were found to match well with those reported hitherto. A comparative study of heat yields (catabolic) between glucose and choline lactate revealed significant information; the heat yield due to choline lactate (Y (Q/S)) consumption and oxygen (Y (Q/O)) were 23.4 kJ/g and 435 kJ/mol and whereas that for glucose with oxygen were 9.6 kJ/g and 427 kJ/mol, respectively, showing clearly the preferential affinity of choline lactate by the bacteria rather than glucose. This study also established that the use of ionic liquids as nutrients can be monitored using bioreaction calorimetry.

Inter-unit variability in two ParvoMedics TrueOne 2400 automated metabolic gas analysis systems.

Knowing the inter-unit variability, especially the technological error, is important when using many physiological measurement systems, yet no such inter-unit analysis has been undertaken on duplicate automated gas analysis systems. This study investigated the inter-unit performance of two identical ParvoMedics TrueOne 2400 automated gas analysis systems during a range of submaximal steady-state exercises performed on an electromagnetic cycle ergometer. Fifteen adult males were tested on two separate days a rest, 30, 60, 90, and 120 Watts with the duplicate gas analysis units arranged (1) collaterally (2 min of steady-state expired gas was alternately passed through each system), and (2) simultaneously (identical steady-state expired gas was passed simultaneously through both systems). Total within-subject variation (biological + technological) was determined from the collateral tests, but the unique inter-unit variability (technological error between identical systems) was shown by the simultaneous tests. Absolute percentage errors (APE), coefficient of variations (CV), effect sizes and Bland-Altman analyses were undertaken on the metabolic data, including expired ventilation (V (E)), oxygen consumption (VO(2)) and carbon dioxide production (VCO(2)). The few statistically significant differences detected between the two duplicate systems were determined to have small or trivial effect sizes, and their magnitudes to be of little physiological importance. The total within-subject variations for VO(2), VCO(2) and V (E) each equated to a mean CV and mean APE value of ~4 and ~6 %, whilst the respective inter-unit technological errors equated to ~1.5 and ~2.1 %. The two ParvoMedics TrueOne 2400 systems demonstrated excellent inter-unit agreement.

Effects of built environment on walking among Hong Kong older adults.

1. Reliable and valid interviewer-administered questionnaires were developed to investigate associations of perceived neighbourhood attributes of Hong Kong older adults with their walking for transportation and recreation. 2. Access to and availability of different types of services and destinations, provision of facilities for resting/sitting in the neighbourhood, and easy access to/from residential buildings may help maintain an active lifestyle by facilitating walking for transport in the neighbourhood. 3. Access to services, indoor places for walking, environmental aesthetics, low traffic, and absence of physical barriers may promote recreational walking..

Pharmacokinetics and safety of OBI-1, a recombinant B domain-deleted porcine factor VIII, in subjects with haemophilia A.

OBI-1 is a recombinant B-domain deleted porcine factor VIII (FVIII). FVIII treatment in those with haemophilia A may be complicated by the development of anti-FVIII antibodies (inhibitors) leading to a failure to respond to treatment with human FVIII. To compare the pharmacokinetics and safety of a single dose of OBI-1 with Hyate:C in subjects with haemophilia A and inhibitors, subjects were randomized to receive either Hyate:C followed by placebo or placebo followed by OBI-1 in a double-blind fashion. FVIII levels were assayed using both a one-stage coagulation assay (OSCA) and chromogenic assay. Pharmacokinetic parameters for FVIII were calculated for 6/9 subjects randomized; in three subjects baseline anti-porcine FVIII inhibitors led to a lack of measurable FVIII activity. Mean C(max) appeared higher for OBI-1 (OSCA: 176.00 U dL(-1), standard deviation ± 88.00; chromogenic: 151.00 ± 31.51 U dL(-1)) than Hyate:C (OSCA: 82.3 ± 19.22 U dL(-1); chromogenic: 52.67 ± 13.8 U dL(-1)). Mean AUC also appeared higher for OBI-1 (OSCA: 2082.87 ± 1323.43 U h(-1) dL(-1) ; chromogenic: 1817.28 ± 625.14 U h(-1) dL(-1)) than Hyate:C (OSCA: 1177.8 ± 469.49 U h(-1) dL(-1); chromogenic: 707.61 ± 420.05 U h(-1) dL(-1)). Two infusion-related events occurred: one with Hyate:C, one with placebo. Four of five subjects without anti-porcine FVIII inhibitors at baseline remained porcine FVIII inhibitor negative 29 days after infusion. A single dose of OBI-1 appears to have higher bioavailability than Hyate:C in subjects with haemophilia A without measurable anti-porcine FVIII inhibitors, and is well tolerated. These results should be confirmed in a larger phase 2/3 study.

Validity, reliability and stability of the portable Cortex Metamax 3B gas analysis system.

This study investigated the performance of the portable Cortex Metamax 3B (MM3B) automated gas analysis system during both simulated and human exercise using adolescents. Repeated measures using a Gas Exchange System Validator (GESV) across a range of simulated metabolic rates, showed the MM3B to be adequately reliable (both percentage errors, and percentage technical error of measurements <2%) for measuring expired ventilation (V (E)), oxygen consumption (VO(2)), and carbon dioxide production (VCO(2)). Over a 3 h period, the MM3B was shown to be acceptably stable in measuring gas fractions, as well as V (E), VO(2), and VCO(2) generated by the GESV, especially at moderate and high metabolic rates (drifts <2% and of minor physiological significance). Using eight healthy adolescents during rest, moderate, and vigorous cycle ergometry, the validity of the MM3B was tested against the primary criterion Douglas bag method (DBM) and a secondary criterion machine known to be accurate, the Jaeger Oxycon Pro system. No significant errors in V (E) were noted, yet the MM3B significantly overestimated both VO(2) and VCO(2) by approximately 10-17% at moderate and vigorous exercise as compared to the DBM and at all exercise levels compared to the Oxycon Pro. No significant differences were seen in any metabolic variable between the two criterion systems (DBM and Oxycon Pro). It is concluded the MM3B produces acceptably stable and reliable results, but is not adequately valid during moderate and vigorous exercise without some further correction of VO(2) and VCO(2).

The effect of coordinating and non-coordinating additives on the transport properties in ionic liquid electrolytes for lithium batteries.

In the present study we expand our analysis of using two contrasting organic solvent additives (toluene and THF) in an ionic liquid (IL)/Li NTf(2) electrolyte. Multinuclear Pulsed-Field Gradient (PFG) NMR, spin-lattice (T(1)) relaxation times and conductivity measurements over a wide temperature range are discussed in terms of transport properties and structuring of the liquid. The conductivity of both additive samples is enhanced the most at low temperatures, with THF slightly more effective than toluene. Both the anion and lithium self-diffusivity are enhanced in the same order by the additives (THF > toluene) while that of the pyrrolidinium cation is marginally enhanced. (1)H spin-lattice relaxation times indicate a reasonable degree of structuring and anisotropic motion within all of the samples and both (19)F and (7)Li highlight the effectiveness of THF at influencing the lithium coordination within these systems.

Exercise and diet in weight management: updating what works.

The world is facing major problems associated with the rapid increase in levels of overweight and obesity. Solving this problem via appropriate modifications to exercise habits and/or diet appears easy, but in practice it is inordinately difficult and only a small percentage manage to maintain their weight loss over the long term. However, a number of strategies can be used to increase the chances of success. Medical doctors, dieticians and other allied health professionals are potentially well placed to provide guidance to those at risk of overweight/obesity. This review is aimed at supporting major initiatives targeting an increase in community physical activity to help reduce the prevalence of overweight/obesity, such as the "Change4Life" campaign in the UK (http://www.nhs.uk/change4life) and the "Exercise is Medicine" campaign in the USA (http://www.exerciseismedicine.org). By providing a concise summary of the evidence-based research that can be easily understood by a wide range of health professionals, this review hopes to provide a useful document that can be used to enhance preventive counselling by promoting appropriate changes in lifestyle that will ultimately increase levels of physical activity, as well as reduce levels of overweight/obesity and other associated chronic hypokinetic conditions.

Influence of ion structure on thermal runaway behaviour of aprotic and protic ionic liquids.

Accelerated rate calorimetric studies have been employed to study the exothermic and thermal runaway behaviour of some aprotic and protic ionic liquids based on several families of ions including the bis(flurorsulfonyl)imide anion ([FSI]-); it was found that the protic salts are safer than aprotic salts of the [FSI]- anion.

Cardiovascular drugs as antidiabetic agents: evidence for the prevention of type 2 diabetes.

Given the long-term health consequences and increasing incidence of type 2 diabetes, there is great interest to potentially prevent or delay its onset. Primary prevention studies have demonstrated that intensive exercise and weight reduction, and to a lesser extent certain antidiabetic agents, can reduce new onset diabetes in at-risk individuals. Results from post hoc analyses and secondary end-point outcomes of large randomized controlled trials of cardiovascular drugs suggest that these may also have beneficial effects, reducing the incidence of new onset diabetes in addition to their proven cardiovascular benefits. Multiple meta-analyses confirm that drugs primarily acting on the renin-angiotensin system (RAS) reduce the incidence of diabetes in the populations studied, perhaps via improved insulin sensitivity and/or effects on pancreatic beta cells. However, results from the recent Diabetes REduction Approaches with Medication study specifically failed to show a significant reduction in the incidence of diabetes with ramipril in individuals with abnormal glucose tolerance at baseline. There is only limited evidence that statins improve glucose tolerance, and although beta-blockers tend to have detrimental effects on glucose tolerance, newer agents with vasodilatory properties may confer benefits. With current guidelines, the use of cardiovascular drugs modifying the RAS will increase in at-risk individuals, but at present, they cannot be recommended to prevent diabetes.

2-Methylthioadenosine[beta-32P]diphosphate. An agonist and radioligand for the receptor that inhibits the accumulation of cyclic AMP in intact blood platelets.

2-Methylthio-ADP and its radioactive analogue [beta-32P]2-methylthio-ADP were synthesized and used to investigate platelet receptors for ADP. 2-Methylthio-ADP induced platelet aggregation and shape change, and inhibited cyclic AMP accumulation in platelets exposed to prostaglandin E1. Compared with ADP, 2-methylthio-ADP was 3-5 times as active as an aggregating agent and 150-200 times as active as an inhibitor of cyclic AMP accumulation. Binding of [beta-32P]2-methylthio-ADP to platelets was measured after centrifuging them through silicone oil to separate platelets from their suspension medium. Binding was reversible, saturable, and specific, with between 400 and 1,200 sites/cell in different platelet preparations. There was no evidence for a second class of binding sites with different affinity. The second order association rate constant was approximately 3.5 X 10(6) M-1 S-1, and the first order dissociation rate was 0.024 s-1, both measured at 23 degrees C. The dissociation equilibrium constant (approximately 15 nM) was about three times higher than the concentration giving half-maximal inhibition of prostaglandin E1-stimulated cyclic AMP accumulation in platelet-rich plasma. Binding was inhibited by ADP (Ki = 3.5 microM), ATP (7 microM), 2-azido-ADP (0.12 microM), inosine diphosphate (IDP, 150 microM), guanosine diphosphate (GDP, 350 microM), and AMP (800 microM). Binding of 2-methylthio-ADP was also blocked by the non-cell-penetrating thiol reagent, p-mercuribenzene sulphonate, a reagent that blocks the inhibition of adenylate cyclase by ADP, but which does not block the ability of ADP to induce aggregation or platelet shape change. The amount of 2-methylthio-ADP bound at saturation was independent of pH in the range 6-8, but the affinity was reduced at pH 6 compared with pH 6.5-8.0. The dissociation constant was not temperature dependent in the range 32 degrees -40 degrees C, whereas the rate of dissociation of 2-methylthio-ADP from platelets after the addition of an excess of ADP approximately doubled over this range. The activation energy for dissociation was approximately 15 kcal/mol. Our results support the conclusion that platelets have a receptor for ADP, which inhibits cyclic AMP accumulation, and which has a sulphydryl group in the binding pocket.