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Refereed/Peer-reviewed Aims: To investigate and characterise the pharmacokinetics of febuxostat and the effect of the covariates of renal function and body size descriptors on the pharmacokinetics of the drug. Methods: Blood samples (n = 239) were collected using sparse and rich sampling strategies from healthy (n = 9) and gouty (n = 29) subjects. Febuxostat plasma concentrations were measured by a validated high-performance liquid chromatography method. Population pharmacokinetic analysis was performed using NONMEM. A common variability on bioavailability (FVAR) approach was used to test the effect of fed status on absorption parameters. Covariates were modelled using a power model. Results: The time course of the plasma concentrations of febuxostat is best described by a two-compartment model. In the final model, the population mean for apparent clearance (CL/F), apparent central volume of distribution (Vc/F), apparent peripheral volume of distribution (Vp/F), absorption rate constant (ka) and apparent intercompartmental clearance (Q/F) were 6.91 l h−1, 32.8 l, 19.4 l, 3.6 h−1 and 1.25 l h−1, respectively. The population parmater variability (coefficient of variation) for CL/F, Vc/F and Vp/F were 13.6, 22 and 19.5%, respectively. Food reduced the relative biovailability and ka by 67% and 87%, respectively. Renal function, as assessed by creatinine clearance, was a significant covariate for CL/F while body mass index was a significant covariate for Vc/F. Conclusions: Renal function and body mass index were significant covariates. Further work is warranted to investigate the clinical relevance of these results, notably as renal impairment and obesity are common occurrences in people with gout.

AIMS The aim of this study was to establish the pharmacokinetic profile of serum oestriol (E3 ) concentrations over 24 h following application of vaginal E3 in chronic users (>12 weeks of E3 use). The interindividual and intraindividual differences before and after E3 were examined. METHODS Ten women participated. Vaginal cream was omitted for ≥36 h prior to the study days. Blood sampling was performed for E3 , oestradiol and oestrone concentrations prior to cream application and at 1, 2, 3, 5, 8, 10, 12 and 24 h afterwards. In five women, all samples were repeated on a separate day. RESULTS E3 was absorbed rapidly in most women. Peak serum E3 concentration occurred around 2 h (range 1-5 h). The decline in E3 concentrations was also rapid: falling

The reactions of MnII (O2 CCH3 )2 with NEt3 Me+ CN- and NEt2 Me2 + CN- form (NEt3 Me)2 MnII 5 (CN)12 (1) and (NEt2 Me2 )2 MnII 5 (CN)12 (2), respectively. Structure model-building and Rietveld refinement of high-resolution synchrotron powder diffraction data revealed a cubic [a=24.0093 A (1), 23.8804 A (2)] 3D extended structural motif with adjacent tetrahedral and octahedral MnII sites in a 3:2 ratio. Each tetrahedral MnII site is surrounded by four low-spin octahedral MnII sites, and each octahedral MnII site is surrounded by six high-spin tetrahedral MnII sites; adjacent sites are antiferromagnetically coupled in 3D. Compensation does not occur, and magnetic ordering as a ferrimagnet is observed at Tc =13 K for 2 based on the temperature at which remnant magnetization, Mr (T)→0. The hysteresis has an unusual constricted shape with inflection points around 50 and 1.2 kOe with a 5 K coercivity of 16 Oe and remnant magnetization, Mr , of 2050 emuOe mol-1 . The unusual structure and stoichiometry are attributed to the very ionic nature of the high-spin N-bonded MnII ion, which enables the maximization of the attractive van der Waals interactions through minimization of void space via a reduced ∠ MnNC. This results in an additional example of the Ax MnII y (CN)x+2y (x=0, y=1; x=1, y=3; x=2, y=1; x=2, y=2; x=2, y=3; x=3, y=5; and x=4, y=1) family of compounds possessing an unprecedented stoichiometry and lattice motif that are cation adaptive structured materials.

AIMS: Metformin may have clinical benefits in dialysis patients; however, its safety in this population is unknown. This systematic review evaluated the safety of metformin in dialysis patients. METHODS: MEDLINE, Embase, CENTRAL, PsycINFO and the Cochrane Library were searched for randomised controlled trials and observational studies evaluating metformin use in dialysis patients. Three authors reviewed the studies and extracted data. The primary outcomes were mortality, occurrence of lactic acidosis and myocardial infarction (MI) in patients taking metformin during dialysis treatment for ≥12 months (long term). Risk of bias was assessed using Risk Of Bias In Nonrandomised Studies of Interventions (ROBINS‐1). Overall quality of evidence was assessed using Grading of Recommendations Assessment, Development and Evaluation (GRADE). RESULTS: Fifteen observational studies were eligible; 7 were prospective observational studies and 8 were case reports/case series. No randomised controlled trials were identified. The 7 prospective observational studies (n = 194) reported on cautious metformin use in patients undergoing maintenance dialysis. Only 3 provided long‐term follow‐up data. In 2 long‐term studies of metformin therapy (≤1000 mg/d) in patients undergoing peritoneal dialysis (PD), 1 reported 6 deaths (6/83; 7%) due to major cardiovascular events (3 MI) and the other reported no deaths (0/35). One long‐term study of metformin therapy (250 mg to 500 mg thrice weekly) in patients undergoing haemodialysis reported 4 deaths (4/61; 7%) due to major cardiovascular events (2 MI). These findings provide very low‐quality evidence as they come from small observational studies. CONCLUSION: The evidence regarding the safety of metformin in people undergoing dialysis is inconclusive. Appropriately designed randomised controlled trials are needed to resolve this uncertainty.

[TCNE].- (TCNE=tetracyanoethylene) has been isolated as D2h π-[TCNE]22- possessing a long, 2.9 A multicenter 2-electron-4-center (2e- /4c) C-C bond, and as C2 π-[TCNE]22- possessing a longer, 3.04 A multicenter 2e- /6c (4 C+2 N atoms) bond. Temperature-dependent UV/Vis spectroscopic measurements in 2-methyltetrahydrofuran (MeTHF) has led to the determination of the dimerization, 2[TCNE].- ⇌π-[TCNE]22- , equilibrium constants, Keq (T), [[TCNE]22- ]/[[TCNE].- ]2 , enthalpy, ΔH, and entropy, ΔS, of dimerization for [Mepy]2 [TCNE]2 (Mepy=N-methylpyridinium, H3 CNC5 H5+ ) possessing D2h π-[TCNE]22- and [NMe4 ]2 [TCNE]2 possessing C2 π-[TCNE]22- conformations in the solid state; however, both form D2h π-[TCNE]22- in MeTHF solution. Based on ΔH=-3.6±0.1 kcal mol-1 (-15.2 kJ mol-1 ), and ΔS=-11±1 eu (-47 J mol-1 K-1 ) and ΔH=-2.4±0.2 kcal mol-1 (-10.2 kJ mol-1 ), and ΔS=-8±1 eu (-32 J mol-1 K-1 ) in MeTHF for [NMe4 ]2 [TCNE]2 and [Mepy]2 [TCNE]2 , respectively, the calculated Keq (298 K) are 1.6 and 1.3 m-1 , respectively. The observed Keq (145 K) are 3 and 2 orders of magnitude greater for [NMe4 ]2 [TCNE]2 and [Mepy]2 [TCNE]2 , respectively. The Keq (130 K) is 4470, 257, ≈0.8, and ≪0.1 m-1 for [NMe4 ]2 [TCNE]2 , [Mepy]2 [TCNE]2 , [NEt4 ]2 [TCNE]2 , and [N(nBu)4 ]2 [TCNE]2 , respectively, decreasing with increasing cation size. At standard conditions and below ambient temperature the equilibrium favors the dimer for the NMe4+ and Mepy+ cations. From the decreasing enthalpy, NMe4+ >Mepy+ , along with the decrease in dimer formation Keq (T) as NMe4+ >Mepy+ >NEt4+ >N(nBu)4+ , the dimer bond energy decreases with increasing cation size in MeTHF. This is attributed to a decrease in the [A]+ ⋅⋅⋅[TCNE]- attractive interactions with increasing cation size. Solid state UV/Vis spectroscopic determinations of [NMe4 ]2 [TCNE]2 are reported and compared to D2h π-[TCNE]22- conformers. The feasibility and limitations of temperature-dependent electron paramagnetic resonance (EPR) measurements for the determination of Keq (T) are also discussed.

AIMS The aims of the study were to: 1) determine if a plasma oxypurinol concentration-response relationship or an allopurinol dose-response relationship best predicts the dose requirements of allopurinol in the treatment of gout; and 2) to construct a nomogram for calculating the optimum maintenance dose of allopurinol to achieve target serum urate (SU) concentrations. METHODS A nonlinear regression analysis was used to examine the plasma oxypurinol concentration- and allopurinol dose-response relationships with serum urate. In 81 patients (205 samples), creatinine clearance (CLCR ), concomitant diuretic use and SU concentrations before (UP ) and during (UT ) treatment were monitored across a range of allopurinol doses (D, 50-700 mg daily). Plasma concentrations of oxypurinol (C) were measured in 47 patients (98 samples). Models (n = 47 patients) and predictions from each relationship were compared using F-tests, r2 values and paired t-tests. The best model was used to construct a nomogram. RESULTS The final plasma oxypurinol concentration-response relationship (UT = UP - C*(UP - UR )/(ID50 + C), r2 = 0.64) and allopurinol dose-response relationship (UT = UP - D* (UP - UR )/(ID50 + D), r2 = 0.60) did not include CLCR or diuretic use as covariates. There was no difference (P = 0.87) between the predicted SU concentrations derived from the oxypurinol concentration- and allopurinol dose-response relationships. The nomogram constructed using the allopurinol dose-response relationship for all recruited patients (n = 81 patients) required pretreatment SU as the predictor of allopurinol maintenance dose. CONCLUSIONS Plasma oxypurinol concentrations, CLCR and diuretic status are not required to predict the maintenance dose of allopurinol. Using the nomogram, the maintenance dose of allopurinol estimated to reach target concentrations can be predicted from UP .

Non‐thermal plasma activation has been used to enable low‐temperature water‐gas shift over a Au/CeZrO4 catalyst. The activity obtained was comparable with that attained by heating the catalyst to 180 °C providing an opportunity for the hydrogen production to be obtained under conditions where the thermodynamic limitations are minimal. Using in situ diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS), structural changes associated with the gold nanoparticles in the catalyst have been observed which are not found under thermal activation indicating a weakening of the Au−CO bond and a change in the mechanism of deactivation.

Aims To compare the pharmacokinetics of metformin between diabetic Indigenous (Aboriginal and Torres Strait Islander) and non-Indigenous patients. Methods An observational, cross-sectional study was conducted on type 2 diabetic Indigenous and non-Indigenous patients treated with metformin. Blood samples were collected to determine metformin, lactate, creatinine and vitamin B12 concentrations and glycosylated haemoglobin levels. A population model was used to determine the pharmacokinetic parameters. Results The Indigenous patients (median age 55 years) were younger than the non-Indigenous patients (65 years), with a difference of 10 years (95% confidence interval 6–14 years, P < 0.001). The median glycosylated haemoglobin was higher in the Indigenous patients (8.5%) than in the non-Indigenous patients (7.2%), with a difference of 1.4% (0.8–2.2%, P < 0.001). Indigenous patients had a higher creatinine clearance (4.3 l h−1) than the non-Indigenous patients (4.0 l h−1), with a median difference of 0.3 l h−1 (0.07–1.17 l h−1; P < 0.05). The ratio of the apparent clearance of metformin to the creatinine clearance in Indigenous patients (13.1, 10.2–15.2; median, interquartile range) was comparable to that in non-Indigenous patients (12.6, 9.9–14.9). Median lactate concentrations were also similar [1.55 (1.20–1.88) vs. 1.60 (1.35–2.10) mmol l−1] for Indigenous and non-Indigenous patients, respectively. The median vitamin B12 was 306 pmol l−1 (range 105–920 pmol l−1) for the Indigenous patients. Conclusions There were no significant differences in the pharmacokinetics of metformin or plasma concentrations of lactate between Indigenous and non-Indigenous patients with type 2 diabetes mellitus. Further studies are required in Indigenous patients with creatinine clearance

Aims The aim of the study was to identify and quantify factors that control the plasma concentrations of urate during allopurinol treatment and to predict optimal doses of allopurinol. Methods Plasma concentrations of urate and creatinine (112 samples, 46 patients) before and during treatment with various doses of allopurinol (50–600 mg daily) were monitored. Non-linear and multiple linear regression equations were used to examine the relationships between allopurinol dose (D), creatinine clearance (CLcr) and plasma concentrations of urate before (UP) and during treatment with allopurinol (UT). Results Plasma concentrations of urate achieved during allopurinol therapy were dependent on the daily dose of allopurinol and the plasma concentration of urate pre-treatment. The non-linear equation: UT = (1 – D/(ID50 + D)) × (UP – UR) + UR, fitted the data well (r2 = 0.74, P < 0.0001). The parameters and their best fit values were: daily dose of allopurinol reducing the inhibitable plasma urate by 50% (ID50 = 226 mg, 95% CI 167, 303 mg), apparent resistant plasma urate (UR = 0.20 mmol l−1, 95 % CI 0.14, 0.25 mmol l−1). Incorporation of CLcr did not significantly improve the fit (P = 0.09). Conclusions A high baseline plasma urate concentration requires a high dose of allopurinol to reduce plasma urate below recommended concentrations. This dose is dependent on only the pre-treatment plasma urate concentration and is not influenced by CLcr.

Background Current Australian guidelines recommend initiating directed therapy of gentamicin if administration exceeds 48 h. Directed doses of gentamicin require the monitoring of plasma concentrations of gentamicin to determine the 24-h area under the time course of plasma gentamicin concentrations (AUC) and a dosage prediction program, for example TCIWorks or Aladdin. However, doses calculated by such programs have not been compared with an established program. Aim To compare the directed dosage of gentamicin calculated by TCIWorks, Aladdin and an Excel-based program, with an established program, Abbottbase. Methods Peak and trough plasma concentrations after the first and second administered doses of gentamicin were available from three patient groups (n = 20–23) with varying creatinine clearances ( 80 mL/min). The directed dose needed to produce 24-h AUC values of 80 mg.h/L was calculated using each program. Results There was a strong correlation between the directed doses predicted by each of the three programs compared with Abbottbase, following the first administered dose (r2 > 0.97, P < 0.0001). The mean ratio (90% confidence intervals) of these directed doses of the gentamicin were: TCIWorks/Abbottbase 106% (105–107%), Aladdin/Abbottbase 102% (101–103%) and Excel/Abbottbase 108% (106–109%). The correlations and dose ratios were also similar when comparisons were made following the second administered dose. For each of the three renal function groups, all programs yielded similar directed doses. Conclusions The four programs used in the calculation of directed doses of gentamicin yielded similar results. Any would be suitable for use in clinical practice.

AIMS Our aim was to identify and quantify the sources of variability in oxypurinol pharmacokinetics and explore relationships with plasma urate concentrations.

Aim The outcome of surgery for colorectal cancer in each unit in the UK is collated by the National Bowel Cancer Audit Project (NBOCAP). In 2008–2009 our unit had a raw 30-day postoperative mortality close to the national average, but when it was nationally adjusted it appeared to be an outlier. The purpose of this study was to identify reasons for this disparity. Method All records were obtained for patients undergoing surgery for colorectal cancer over the 2 years. Data submitted to NBOCAP to determine adjusted rates were compared with actual data. Results There were major discordances between submitted and actual data for American Society of Anesthesiology grades and timing of surgery. This explained why the unit appeared to be an outlier. Conclusion There is increasing emphasis on outcome of health service delivery, which has important implications. Submission of correct data is essential if objective comparison is to be made on which to base decisions on service delivery among units and within health regions.

AIMS: Allopurinol hypersensitivity (AH) can rarely be manifest as Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) that have high mortality rates. Less serious, but still significant, skin and systemic hypersensitivity reactions form part of the AH spectrum. One hundred per cent of Han Chinese with SJS/TEN due to allopurinol have been found to be at least heterozygous for HLA-B*5801, the carriage rate for this allele in the Han Chinese population being about 15%. The association has been found to be weaker in Caucasians whose HLA-B*5801 carriage rate is less than 6%. We examined the relationship between the different skin hypersensitivity reactions to allopurinol and the HLA-B locus in Australian patients. METHODS: We examined 23 patients referred with AH. RESULTS: Five of six Australian SJS/TEN patients were heterozygous for HLA-B*5801 and four were of South-East Asian origin. Five AH patients without SJS/TEN were all Caucasian and only one of these was positive for HLA-B*5801. Twelve patients with allopurinol-induced maculopapular exanthema were negative for HLA-B*5801, including one South-East Asian. CONCLUSIONS: Cases of AH manifesting as SJS/TENS in Australians are more likely to be in those of Asian heritage. The place of routine testing for HLA-B*5801 prior to commencing allopurinol therapy requires further investigation. However, Han Chinese origin patients commencing allopurinol might be informed of the test and may elect to have it performed as there are alternative hypouricaemic medicines, such as probenecid thereby reducing the risk of a catastrophic reaction to allopurinol.

A new boundary integral operator is introduced for the solution of the soundsoft acoustic scattering problem, i.e., for the exterior problem for the Helmholtz equation with Dirichlet boundary conditions. We prove that this integral operator is coercive in L2(Γ) (where Γ is the surface of the scatterer) for all Lipschitz star-shaped domains. Moreover, the coercivity is uniform in the wavenumber k = ω/c, where ω is the frequency and c is the speed of sound. The new boundary integral operator, which we call the “star-combined” potential operator, is a slight modification of the standard combined potential operator, and is shown to be as easy to implement as the standard one. Additionally, to the authors' knowledge, it is the only second-kind integral operator for which convergence of the Galerkin method in L2(Γ) is proved without smoothness assumptions on Γ except that it is Lipschitz. The coercivity of the star-combined operator implies frequency-explicit error bounds for the Galerkin method for any approximation space. In particular, these error estimates apply to several hybrid asymptoticnumerical methods developed recently that provide robust approximations in the high-frequency case. The proof of coercivity of the star-combined operator critically relies on an identity first introduced by Morawetz and Ludwig in 1968, supplemented further by more recent harmonic analysis techniques for Lipschitz domains. © 2011 Wiley Periodicals, Inc.

The condensation products of rhodanine, 3-ethylrhodanine, 3-phenylrhodanine, 3-allylrhodanine and 3-carboxymethylrhodanine with various substituted and unsubstituted pyridine and quinoline aldehydes have been prepared for bacterial and fungicidal evaluation. An earlier series of unsubstituted pyridylmethylene-rhodanines has thus been extended to include products substituted in either or both of the heterocyclic rings. Such substitution may enhance the already known fungicidal character of such rhodanine-aldehyde condensation products. The products obtained by the condensation of the quinoline aldehydes may be considered as substituted in a similar manner as the less accessible dialkylpyridine products and it is possible that these two types of compounds will show a similarity in biological activity. Condensations between the rhodanines and the aldehydes were carried out in acid medium and crystalline coloured condensation products were obtained in good yield.

The condensation products of rhodanine and some of its derivatives with benzaldehyde sulphonic acids have been prepared with a view to obtaining compounds of increased fungicidal properties. The products differ from the majority of previously prepared rhodanine-aldehyde condensation products in that they are appreciably soluble in water. From a fungitoxicological standpoint this increased solubility may well increase the activity of such fungicides as their availability in aqueous media is greatly increased. The condensation products formed relatively insoluble and often crystalline salts with many metallic ions. The precipitation of these salts was briefly considered from the analytical point of view. The condensations between the rhodanines and the benzaldehyde sulphonic acids were carried out in acid media and crystalline coloured products were obtained in good yield.

Zusammenfassung Das Spannungsmuster in der Wand der Herzkammer — bisher im klinischen Bereich stets hypothetisch abgeleitet aus dem intrakavitaren Druck mal einem Geometriefaktor — wird nun in ausreichend eng begrenzter Auflosung der direkten Messung zuganglich. In einer historischen Ubersicht werden die wesentlichen Schritte in fruhen Versuchen zur Messung der lokalen Herzmuskelkraft in ihren methodischen Varianten und deren Aussage dargestellt und kritisch gewertet. In allen Ansatzen ging die Ankopplung des Messystems ans Myokard von einer 2-Punkt-Fixation aus. Damit wurde dem komplizierten Maschenwerk des Myokards in seinem schichtenspezifischen Richtungswechsel Gewalt angetan, so das der Beitrag des lokalen Meswertes zur globalen Leistung des Herzmuskels eigentlich unklar blieb. Ein alternatives Verfahren, das uber die Lateralkompressionskraft eines gebogenen Faserbundels die Maschenspannung im Myokardgitter mist, wird in seiner Entwicklung beschrieben. Uber stiftformige Aufnehmer, die in jeder Lokalisation und Richtung ins Myokard eingefuhrt werden konnen, wird nun in enger Begrenzung jede Schicht der Spannungsmessung zuganglich. Die etwa 1 mm dicken Aufnehmer hinterlassen auch nach chronischer Implantation ein vernachlassigbar kleines Trauma, sind also im Langzeitversuch in ihrer Ankopplung ans Myokard konstant. Als sicheren Hinweis fur die richtungsspezifische Spannungsmessung im Maschengitter kann die hohe Rotationsempfindlichkeit des Mesvorganges gewertet werden. Sie gestattet eine “in situ” topographische Faserverlaufsanalyse in jeder Schichttiefe der Kammerwand. Das Verfahren wurde im Skelettmuskel und im Myokard vergleichend getestet. Danach besteht eine lineare Beziehung zwischen Meswert und Faserspannung zumindest im parallelfaserigen Skelettmuskel. Bei einer systematischen Belastungsstudie im Herzmuskel (Frequenzstimulation, afterload, Katecholamine, Ischamie) andert sich das Kraftsignal jeweils gleichgerichtet zum Ventrikeldruck. Erhebliche quantitative Unterschiede zwischen den Anderungen in der lokalen Kraft und im Ventrikeldruck und in den lokalen Kraften in unterschiedlicher Lokalisation geben die Inhomogenitat des intramuralen Spannungsmusters eindrucksvoll zu erkennen. In seiner letzten methodischen Weiterung als Katheterspitzenkraftaufnehmer zur transvenosen Implantation in alle (einschlieslich septale) Kammerwandabschnitte tritt das Mesverfahren in den Bereich der klinisch moglichen Anwendung. Summary Comparison of classical and metholodological approaches to intramyocardial force distribution patterna The pattern of contractile force in the wall of the heart chambers — formerly in the clinical field always directed hypothetically from intracavity pressure multiplied by a geometric factor — can now be determined by direct measurement over a narrowly defined field. In a historical review the important steps taken in earlier studies on measuring local contractile force are critically reviewed in relation of the measurement system on the myocardium was based on two-point fixation. Thus the complicated meshwork of the myocardium, in its layer-specific direction change ability, left unclear the contribution of the local measurements to the effort of the heart muscle as a whole. An alternative procedure which measured the lateral force of compression of a bundle of muscle fibres enabled the meshwork force to be determined: the development of this technique is described. Pencil-like pick-ups which can be placed in every location and direction within the myocardium can measure pressure in each layer of muscle fibres. The ca. 1 mm. thick pick-ups cause negligible trauma after chronic implantation and so can provide longterm information from the musculature. The high rotation sensitivity of the measurement method allows measurements of direction-specific changes in the fibre network. They allow an in situ topographic fibre course analysis in delph of the heart wall. The technique has been tested in both skeletal and cardiac muscle and the findings compared. There exists a linear relationship between the measurement value and the fibre force, at least in the parallel fibre make-up of skeletal muscle. In a systematic study on heart muscle (frequency stimulation, afterload, catecholamine, ischaemia) the power signal changes in the same direction as ventricular pressure. Considerable quantitative differences between changes in local force and in ventricular pressure and in local pressure in different sites illustrate strikingly the non-homogeneous nature of the intramural force pattern. In its final technical extension in the form of catheter-outlet pick-ups from intravenous implants in all (including septal) heart wall sections it is seen that measurement techniques have a possible use in the clinical field.

Two-level overlapping Schwarz methods for elliptic partial differential equations combine local solves on overlapping domains with a global solve of a coarse approximation of the original problem. To obtain robust methods for equations with highly varying coefficients, it is important to carefully choose the coarse approximation. Recent theoretical results by the authors have shown that bases for such robust coarse spaces should be constructed such that the energy of the basis functions is minimized. We give a simple derivation of a method that finds such a minimum energy basis using one local solve per coarse space basis function and one global solve to enforce a partition of unity constraint. Although this global solve may seem prohibitively expensive, we demonstrate that a one-level overlapping Schwarz method is an effective and scalable preconditioner and we show that such a preconditioner can be implemented efficiently using the Sherman-Morrison-Woodbury formula. The result is an elegant, scalable, algebraic method for constructing a robust coarse space given only the supports of the coarse space basis functions. Numerical experiments on a simple two-dimensional model problem with a variety of binary and multiscale coefficients confirm this. Numerical experiments also show that, when used in a two-level preconditioner, the energy-minimizing coarse space gives better results than other coarse space constructions, such as the multiscale finite element approach. Copyright (C) 2009 John Wiley & Sons, Ltd.

Background Standardised neuropsychological and cognitive measures present some limitations in their applicability and generalisability to individuals with intellectual disability (ID). Alternative approaches to defining the cognitive signatures of various forms of ID are needed to advance our understanding of the profiles of strengths and weaknesses as well as the affected brain areas. Aim To evaluate the utility and feasibility of six non-verbal comparative neuropsychological (CN) tasks administered in a modified version of the Wisconsin General Test Apparatus (WGTA) to confirm and extend our knowledge of unique cognitive signatures of Fragile X syndrome (FXS) and Down syndrome (DS). Method A test battery of CN tasks adapted from the animal literature was administered in a modified WGTA. Tasks were selected that have established or emerging brain–behaviour relationships in the domains of visual-perceptual, visual-spatial, working memory and inhibition. Results Despite the fact that these tasks revealed cognitive signatures for the two ID groups, only some hypotheses were supported. Results suggest that whereas individuals with DS were relatively impaired on visual-perceptual and visual-spatial reversal learning tasks they showed strengths in egocentric spatial learning and object discrimination tasks. Individuals with FXS were relatively impaired on object discrimination learning and reversal tasks, which was attributable to side preferences. In contrast, these same individuals exhibited strengths in egocentric spatial learning and reversal tasks as well as on an object recognition memory task. Both ID groups demonstrated relatively poor performance for a visual-spatial working memory task. Conclusion Performance on the modified WGTA tasks differentiated cognitive signatures between two of the most common forms of ID. Results are discussed in the context of the literature on the cognitive and neurobiological features of FXS and DS.

1 Hoverfly data, obtained from 20 species during 1991–2007 from a single garden in Peterborough, England, were analysed to test for temporal trends in timing of first and last appearance, flight-period length and maximum number. 2 During this period of climate warming, first appearance in spring has become significantly earlier for three species and flight period longer for a different set of three species. 3 Key correlates of first appearance date and flight-period length were winter temperature, which increased over the study period, and spring temperature which showed a non-significant warming trend. Wetter summers also marginally lengthened the flight period. In addition, there were significant year effects, suggestive of population responses to changing climate independent of prevailing temperature. 4 However, there was little evidence that last appearances in autumn have become later, and maximum numbers have not increased. 5 These trends match those reported from other, better-studied taxa.

Background While clozapine is an effective treatment for refractory schizophrenia, its use is limited by haematological side effects. Treatment options that allow continued prescription of clozapine by tackling these side effects will greatly aid patients for whom this medication is all too often their only hope of recovery. Method In this case report, we describe what we believe are two ‘firsts’ in the clozapine literature: the use of granulocyte-colony stimulating factor on a prophylactic basis in an intellectually disabled patient receiving clozapine for refractory schizophrenia. Result Treatment with granulocyte-colony stimulating factor prevented discontinuation of clozapine, enabling our intellectually disabled patient’s recovery from a schizophrenic illness.

In this article, we describe a new class of domain decomposition preconditioners suitable for solving elliptic PDEs in highly fractured or heterogeneous media, such as arise in groundwater flow or oil recovery applications. Our methods employ novel coarsening operators, which are adapted to the heterogeneity of the media. In contrast to standard methods (based on piecewise polynomial coarsening), the new methods can achieve robustness with respect to coefficient discontinuities even when these are not resolved by a coarse mesh. This situation arises often in practical flow computation, in both the deterministic and (Monte-Carlo simulated) stochastic cases. An example of a suitable coarsener is provided by multiscale finite elements. In this article, we explore the linear algebraic aspects of the multiscale algorithm, showing that it involves a blend of both classical overlapping Schwarz methods and nonoverlapping Schur methods. We also extend the algorithm and the theory from its additive variant to obtain new hybrid and deflation variants. Finally, we give extensive numerical experiments on a range of heterogeneous media problems illustrating the properties of the methods. © 2007 Wiley Periodicals, Inc. Numer Methods Partial Differential Eq 23: 859-878, 2007

A BUSINESS MODEL CAN BE USED IN A TECHNICAL ENVIRONMENT TO ACHIEVE HIGH-LEVEL CUSTOMER SERVICE AND COMMUNITY SUPPORT.

Metformin therapy is limited in patients with chronic kidney disease (CKD) due to the potential risk of lactic acidosis. This open-label observational study investigated metformin and lactate concentrations in patients with CKD (n = 22; creatinine clearances 15–40 ml/min) and in two dialysed patients. Patients were prescribed a range of metformin doses (250–2000 mg daily) and metformin concentrations were compared with data from healthy subjects (scaled to 1500 mg twice daily). A subset of patients (n = 7) was controlled on low doses of metformin (250 or 500 mg daily). No correlation between metformin and lactate concentrations was observed. Three patients had high lactate concentrations (>2.7 mmol/l) and two had high metformin concentrations (3–5 mg/l), but none had any symptoms of lactic acidosis. Reducing metformin dosage and monitoring metformin concentrations will allow the safe use of metformin in CKD, provided that renal function is stable.

Activity-guided fractionation of a chloroform-soluble extract of Lonchocarpus aff. fluvialis stem bark using a human epidermoid (KB) tumour cell line as a monitor afforded five rotenoids, one pterocarpan, one chalcone, three flavanones, one flavone and one triterpenoid. All of the compounds isolated proved to be of previously known structure. Among them, the rotenoids (-)-sumatrol and (+/-)-villosinol, the dibenzoylmethane derivative (+)-3,4-methylenedioxy-2'-methoxy-[2",3":4',3']-furanodibenzoylmethane, and the flavanones (-)-isoglabrachromene and (-)-candidone have been shown to exhibit significant cytotoxic activity against human cancer cells for the first time. This is the first report of the chemical constituents of this species, and the profile of compounds obtained was in accordance with the established chemosystematic patterns of species in the tribe Tephrosieae (Leguminosae, Papilionoideae).

A destructive cycle of oxidative stress and mitochondrial dysfunction is proposed in neurodegenerative disease. Lipid peroxidation, one outcome of oxidative challenge, can lead to the formation of 4-hydroxy-2(E)-nonenal (HNE), a lipophilic alkenal that forms stable adducts on mitochondrial proteins. In this study, we characterized the effects of HNE on brain mitochondrial respiration. We used whole rat brain mitochondria and concentrations of HNE comparable to those measured in patients with Alzheimer's disease. Our results showed that HNE inhibited respiration at multiple sites. Complex I-linked and complex II-linked state 3 respirations were inhibited by HNE with IC50 values of approximately 200 microM HNE. Respiration was apparently diminished owing to the inhibition of complex III activity. In addition, complex II activity was reduced slightly. The lipophilicity and adduction characteristics of HNE were responsible for the effects of HNE on respiration. The inhibition of respiration was not prevented by N-acetylcysteine or aminoguanidine. Studies using mitochondria isolated from porcine cerebral cortex also demonstrated an inhibition of complex I- and complex II-linked respiration. Thus, in neurodegenerative disease, oxidative stress may impair mitochondrial respiration through the production of HNE.

The mechanisms that underlie dopaminergic neurodegeneration in Parkinson's disease (PD) are not known but have been proposed to involve oxidation of dopamine and related catechols. In other organ systems, cytotoxicity from catechol oxidation is profoundly influenced by mercapturate metabolism. Here we have tested the hypothesis that catechol thioethers produced in the mercapturic acid pathway may act as dopaminergic neurotoxins. A rat mesencephalic/neuroblastoma hybrid (MES) cell line was exposed to dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), or eight different catechol thioethers for up to 24 h, and the extent of apoptosis was quantified by a microculture kinetic assay. Apoptosis also was confirmed morphologically with Giemsa-stained cultures and by demonstration of internucleosomal DNA fragmentation. The results showed that dopamine at 5-50 microM produced concentration-dependent increases in the percentage of apoptotic MES cells. At 25 and 50 microM dopamine, the maximal proportions of apoptotic cells were detected at approximately 19 (20.7 +/- 2.0%) and 14 h (30.3 +/- 3.5%), respectively. None of the catechol thioethers (up to 5 microM) alone induced significant apoptosis in MES cells. However, when MES cells were incubated with dopamine (25 microM) and catechol thioethers (5 microM) to mimic pathological conditions, 5-S-N-acetylcysteinyldopamine, 5-S-homocysteinyldopamine, and 5-S-homocysteinyl-DOPAC significantly increased the percentage of apoptotic cells compared with dopamine alone. These results suggest that mercapturate metabolism of endogenous catechols may yield products that facilitate dopaminergic neurodegeneration.

Aims To examine the pharmacokinetics of ciprofloxacin and fleroxacin in plasma and sputum of patients with an acute exacerbation of chronic bronchitis or bronchiectasis following the first dose and again during the third day of treatment. Methods Twelve patients, aged >35 years, with acute infective exacerbation of bronchitis or bronchiectasis were allocated randomly to treatment with either fleroxacin 400 mg daily or ciprofloxacin 500 mg twice daily in an open, parallel group design. Plasma and sputum were collected during the first and third days of treatment. The time course of concentrations in sputum was modelled assuming that it acted as a negligibly small compartment of distribution. Results The mean sputum to plasma ratios of both ciprofloxacin and fleroxacin were approximately 1 on both days 1 and 3. Peak concentrations of ciprofloxacin in sputum were achieved 1.6 (95% CI on mean difference 0.8–2.3) and 1.2 (0.4–1.9) h later than in plasma on day 1 and day 3, respectively (mean difference±95% confidence interval). For fleroxacin, the corresponding delay in time to peak concentrations was less marked and not significant. Fleroxacin accumulated in plasma (accumulation index 1.52±0.07) and sputum (accumulation index 1.79±0.39) from day 1 to day 3. Accumulation did not occur for ciprofloxacin because the dose interval (12 h) was considerable longer than its half life (3–4 h). Conclusions The sputum to plasma ratio of ciprofloxacin and fleroxacin is approximately 1. The time to peak concentrations of ciprofloxacin in sputum is slightly delayed compared with plasma. Fleroxacin accumulates over time in both plasma and sputum consistent with its longer half-life.

Betulinic acid is a naturally occurring pentacyclic triterpenoid. Betulinic acid has recently been selected by the National Cancer Institute for addition into the RAID (Rapid Access to Intervention in Development) programme. The agent exhibits potential anti-tumour activity and functions in this regard via apoptosis. The objective of the present study was to determine the pharmacokinetics of betulinic acid in CD-1 mice. Serum samples were obtained at designed times after a single 250 or 500 mg/kg intraperitoneal (IP) dose of betulinic acid. Tissue samples (skin, heart, liver, spleen, kidney, lung, brain, colon, caecum, ovary, uterus, thymus, lymph node, bladder, perirenal fat, mammary gland and small intestine) were collected after betulinic acid administration (500 mg/kg). Betulinic acid was extracted with methylene chloride and quantitatively analysed by HPLC/MS. Oleanolic acid and madecassic acid were used as internal standards. Pharmacokinetic parameters were calculated using the WinNonlin pharmacokinetic software package. A two-compartment, first-order model was selected for pharmacokinetic modelling. The results showed that after IP 250 and 500 mg/kg betulinic acid, the serum concentrations reached peaks at 0.15 and 0.23 h, respectively. The 250 and 500 mg/kg above betulinic acid IP doses were found to have elimination half-lives of 11.5 and 11.8 h and total clearances of 13.6 and 13.5 L/kg/h, respectively. The pharmacokinetic parameters observed for IP betulinic acid 500 mg/kg in the skin of mice were as follows: k(a) (h(-1)) 0.257, k(10) (h(-1)) 0.234, t(1/2(alpha)) (h) 2.63, t(1/2(beta)) (h) 20.2, V (L/kg) 0.61, AUC (microg/h/mL) 3504, T(max) (h) 3.90 and C(max) (microg/mL) 300.9. The distribution of betulinic acid in tissues at 24 h post-IP administration in a descending order was as follows: perirenal fat, ovary, spleen, mammary gland, uterus, bladder, lymph node, liver, small intestine, caecum, lung, thymus, colon, kidney, skin, heart and brain.

Background: Although Cytomegalovirus (CMV) retinitis is now a common intraocular infection, current therapy is only virostatic so ongoing treatment is required. Etoposide was found to be virocidal for CMV in laboratory experiments and it might prove to be beneficial clinically. We investigated the toxicity and intraocular concentration of etoposide (VP16) and its new analogue etoposide-phosphate (VP16P) following intravitreal injections in rabbit eyes. Methods: First a sequential dose–response was assessed with flash electroretinogram for both eyes of light- and dark-adapted rabbits (n = 7; one rabbit for each dose) over a range of light intensities before and after intravitreal injection of VP16 or VP16P to one eye; the other eye was injected with normal saline as a control. A multidose study was then performed on four rabbits. A non-toxic dose of VP16P (50 or 75 g) was injected into the vitreous of one eye on four occasions 1 week apart. A photopic electroretinogram was performed before the first injection and 6 weeks after the last injection. All the eyes from the electroretinogram studies were fixed in formalin, placed in paraffin, then stained with haematoxylin and eosin and examined under a light microscope. To determine the time-course of the intraocular concentrations of VP16P a sequential pharmacokinetic study was performed using a further 12 rabbits. Each rabbit was injected with 50 g VP16P to one eye and 75 g VP16P to the other eye. Three of these rabbits were killed at 1, 3, 6 and 9 h after injection. Samples of vitreous were assayed for both VP16 and VP16P using HPLC. An in vitro dose–response assay was performed using third-passage bovine retinal pigment epithelial (RPE) cells cultured in Dulbecco’s modified Eagles medium with fetal calf serum. The effect of a log–dose increment of VP16P on the RPE cell proliferation was assessed using tritiated thymidine incorporation. Results: The electroretinogram studies suggested that VP16 was toxic even with the 10 g dose. For VP16P a toxic effect was noted following injection of a single dose greater than 100 g. Multiple injections of 50 or 75 g VP16P did not produce a toxic response. Histological examination demonstrated significant abnormality only with the 500 g dose of VP16 or VP16P. VP16P was rapidly metabolized to VP16 in the eye, producing concentrations of 2.0 g/mL or more for up to 9 h following a 75-μg dose. This suggests that the electroretinogram findings following VP16 injections were confounded by a toxic effect of the ethanol solvent (which is absent from the VP16P preparation). VP16P was quite potent, the ID50 was about 0.1 g/mL for bovine RPE cells in the in vitro assay. Discussion: These results indicate that multiple 75-g VP16P intravitreal injections were not toxic to the rabbit eye and provide a therapeutic intraocular concentration for up to 9 h after the injection.

The effect on the rot-proofiing activity towards cotton of condensation products of Rhodanine and some of its N-substituted derivatives with pyridine aldehydes is investigated.

Six healthy lactating mothers who gave birth to preterm infants at a median post conceptional age of 29.5 (range 26-30) weeks were given 2.5 mg phylloquinone (vitamin K1) orally daily for 2 weeks beginning at a median postconceptional age of 31.5 (range 28-32) weeks. Phylloquinone was measured in the breastmilk daily for 14 d. Trough plasma phylloquinone concentrations were also determined on four occasions. Phylloquinone levels in the breastmilk increased from a baseline of 3 +/- 2.3 ng ml(-1) to 22.6 +/- 16.3 ng ml(-1) (mean +/- SD) after the first dose (p < 0.05); a gradual increase was noted until phylloquinone levels reached a plateau of 64.2 +/- 31.4 ng ml(-1) after the sixth daily dose.

The taste of six psychotropic drugs (amitriptyline HCl, clomipramine HCl, desipramine HCl, imipramine HCl, doxepin HCl, and trifluoperazine HCl) can be detected at concentrations of 0.1 mM or less in both young and elderly individuals. At concentrations 4 times higher than the detection thresholds, these drugs have bitter as well as other unpleasant taste properties. Oral exposure to these drugs not only induces a taste from the drug itself but also alters taste perception of other compounds such as NaCl and sucrose. These results indicate that both hypogeusia and dysgeusia may be induced by psychotropic medications.

Purpose: As a quality improvement measure, we undertook this work to incorporate usability testing into the implementation procedures for new electronic documents and forms used by four affiliated radiation therapy centers. Methods: A human factors specialist provided training in usability testing for a team of medical physicists, radiation therapists, and radiation oncologists from four radiotherapy centers. A usability testing plan was then developed that included controlled scenarios and standardized forms for qualitative and quantitative feedback from participants, including patients. Usability tests were performed by end users using the same hardware and viewing conditions that are found in the clinical environment. A pilot test of a form used during radiotherapy CT simulation was performed in a single department; feedback informed adaptive improvements to the electronic form, hardware requirements, resource accessibility and the usability testing plan. Following refinements to the testing plan, usability testing was performed at three affiliated cancer centers with different vault layouts and hardware. Results: Feedback from the testing resulted in the detection of 6 critical errors (omissions and inability to complete task without assistance), 6 non-critical errors (recoverable), and multiple suggestions for improvement. Usability problems with room layout were detected at one center and problems with hardware were detected at one center. Upon amalgamation and summary of the results, three key recommendations were presented to the document's authors for incorporation into the electronic form. Documented inefficiencies and patient safety concerns related to the room layout and hardware were presented to administration along with a request for funding to purchase upgraded hardware and accessories to allow a more efficient workflow within the simulator vault. Conclusion: By including usability testing as part of the process when introducing any new document or procedure into clinical use, associated risks can be identified and mitigated before patient care and clinical workflow are impacted.

1. A sensitive, stereospecific assay using gas chromatography-mass spectrometry (GC/MS) was established to measure the concentrations of the enantiomers of ibuprofen in small volumes (50 microliters) of blister fluid. 2. The concentrations of the enantiomers in blister fluid, assessed in eight patients, were similar to those in synovial fluid, both fluids behaving as peripheral compartments with respect to plasma. 3. The mean rate constants of transfer of R-ibuprofen into (0.14 +/- 0.06 h-1) and out of (0.20 +/- 0.04 h-1) blister fluid were not significantly different from those for synovial fluid (0.19 +/- 0.12 h-1, 0.34 +/- 0.11 h-1, respectively). Similarly, the mean rate constants of transfer of S-ibuprofen into (0.22 +/- 0.07 h-1) and out of (0.27 +/- 0.08 h-1) blister fluid were not significantly different from those for synovial fluid (0.29 +/- 0.10, 0.36 +/- 0.11 h-1). However, the correlations were poor between the transfer constants for each of the enantiomers between plasma, and both blister and synovial fluid (P > 0.2). 4. The complex rate constant of transfer of S-ibuprofen into blister fluid (0.22 +/- 0.07 h-1) was greater than that of R-ibuprofen (0.14 +/- 0.07 h-1), which may be explained by the lesser protein binding of the S-enantiomer.(ABSTRACT TRUNCATED AT 250 WORDS)

Summary Fifty-seven healthy female patients who underwent gynaecological laparoscopic surgery received either desflurane or propofol for induction and maintenance of anaesthesia. Inhalational induction was generally well tolerated, and consciousness was lost in approximately 2 min (mean end-tidal concentrations of desflurane were 8.3% with 60% nitrous oxide, and 7.1% with oxygen). Recovery of consciousness and orientation were more rapid in patients in whom anaesthesia was maintained with desflurane than with propofol, but there were no differences in psychomotor function test scores at 30 min. The data suggest that desflurane provides controllable anaesthesia and rapid recovery of consciousness after laparoscopic surgery.

A series of 2-benzyl-4-sulfonyl-4H-isoquinoline-1,3-diones was prepared. Members of this series are potent and selective inhibitors of cyclooxygenase-2 (COX-2) in both microsomal and cellular assays. Two representatives demonstrated activity in the carrageenan-induced paw edema model in rats upon oral administration.

Aiphanol (1), a novel stilbenolignan, along with isorhapontigenin (2), piceatannol (3), and luteolin, were isolated by bioassay-guided fractionation from the seeds of Aiphanes aculeata Willd. (Arecaceae). The structure of compound 1 was elucidated by spectroscopic methods. Compound 1 is based on an unprecedented stilbenolignan skeleton in which a stilbene moiety is linked with a phenylpropane unit through a dioxane bridge. Compounds 1 and 2 exhibited significant inhibitory activities against cyclooxygenases-1 and -2.

This report describes some aspects of beta,beta'-iminodipropionitrile (IDPN) neuropathy in rats as observed by ultrastructural methods and X-ray diffraction. Light microscopy shows gross swelling of the axons in proximal lumbar spinal roots 8 days after intraperitoneal injection of IDPN. Mean axon cross-sectional area and mean axon perimeter increased to 280% and 160% of their control values, respectively. At the same time, myelin membrane packing was not visibly disturbed. In addition, X-ray diffraction patterns, recorded under physiological conditions, demonstrate that the myelin lipid bilayer thickness and widths of the aqueous spaces between bilayers did not change. Related observations are made on posterior tibial nerve (PNS myelin) and ventral spinal cord (CNS myelin). The various observations together are interpreted in terms of a fluid myelin membrane. It is proposed that the myelin membrane flows during axon swelling even though normal membrane-membrane contacts are maintained within the sheath. Membrane flow and slippage between membranes are explained in terms of a molecular model of the myelin multilayer.

(R)-2-Arylpropionates are often inverted to the pharmacologically active S-enantiomers in vivo, although there is significant interspecies variability in inversion. In order to provide a basis for determining the biochemical consequences of this unique process using rats as a model, it was important to establish the pharmacokinetic disposition of the enantiomers of ibuprofen, a drug well inverted in man and flurbiprofen, a drug apparently poorly inverted in man. Rats were dosed i.v. with a single dose of (R)-or (S)-ibuprofen (20 mg/kg), (R,S)-ibuprofen (40 mg/kg), (R)- or (S)-flurbiprofen (10 mg/kg), or (R,S)-flurbiprofen (20 mg/kg). Each treatment group consisted of six animals. Serial blood samples were withdrawn over a period of 6 h for ibuprofen and 10 h for flurbiprofen. These drugs were assayed in plasma by a stereospecific HPLC assay. The pharmacokinetics of the ibuprofen and flurbiprofen enantiomers were evaluated using a two-compartment open model with conversion of the R- to S-enantiomers in the central compartment. There was 50 ± 4% inversion of (R)-ibuprofen, a figure similar to that observed in man and (R)-ibuprofen had a higher clearance (12.6 ± 1.3 ml/min/kg) than (S)-ibuprofen (7.7 ± 0.7 ml/min/kg; P < 0.01). The clearance of (R)- flurbiprofen after racemate (2.3 ± 0.1 ml/min/kg) was higher than its clearance when administered alone (1.7 ± 0.2 ml/min/kg; P < 0.01), indicating a pharmacokinetic interaction between the enantiomers (most probably at plasma protein binding sites). A corresponding difference was not observed for ibuprofen. There was a small amount of inversion of (R)-flurbiprofen as determined by area analysis (4.5 ± 1.6%). However, this calculation may be in some error because of the interaction between the enantiomers. These data demonstrate quantitative similarities in the inversion of ibuprofen and flurbiprofen in rats and man, a useful basis for comparing the effects of these two drugs on fatty acid metabolism.