Ni-Mn-Ga thin films produced by pulsed laser deposition

Polycrystalline Ni-Mn-Ga thin films have been deposited by the pulsed laser deposition (PLD) technique, using slices of a Ni-Mn-Ga single crystal as targets and onto Si (100) substrates at temperatures ranging from 673 K up to 973 K. Off-stoichiometry thin films were deposited at a base pressure of 1×10-6-Torr or in a 5 mTorr Ar atmosphere. Samples deposited in vacuum and temperatures above 823 K are magnetic at room temperature and show the austenitic {220} reflection in their x-ray diffraction patterns. The temperature dependences of both electrical resistance and magnetic susceptibility suggest that these samples exhibit a structural martensitic transition at around 260 K. The magnetoresistance ratio at low temperature can be as high as 1.3%, suggesting the existence of a granular structure in the films

Quantitative x-ray photoelectron spectroscopy study of Al/AlOx bilayers

An x-ray photoelectron spectroscopy (XPS) analysis of Nb/Al wedge bilayers, oxidized by both plasma and natural oxidation, is reported. The main goal is to show that the oxidation state¿i.e., O:(oxidize)Al ratio¿, structure and thickness of the surface oxide layer, as well as the thickness of the metallic Al leftover, as functions of the oxidation procedure, can be quantitatively evaluated from the XPS spectra. This is relevant to the detailed characterization of the insulating barriers in (magnetic) tunnel junctions

3-Hydroxybutyrate coinfused with noradrenaline decreases resulting plasma levels of noradrenaline in Wistar rats

Pentobarbital-anaesthetized male Wistar rats were infused with 6microgkg-1min-1 of noradrenaline. The infusion was supplemented with 8.5 mgkg-1min-1 of D-3-hydroxybutyrate (3-OHB) for 15 min in order to determine its effect on the adrenergic response of the rat. Plasma levels of noradrenaline rose to a plateau of approximately 50 nmoll-1 with infusion. In the group infused with noradrenaline alone, noradrenaline levels were maintained for 1h. Supplementation with 3-OHB induced a decrease in plasma noradrenaline level that was inversely correlated with 3-OHB level. Aortic and interscapular brown adipose tissue temperatures increased with noradrenaline infusion, but the rise was arrested by 3-OHB; replacing 3-OHB with glucose had no effect. Infusion of saline, glucose or 3-OHB in the absence of noradrenaline did not induce a rise in temperature in either tissue. Blood 3-OHB concentration increased to 1.2 mmoll-1 during 3-OHB infusion, decreasing rapidly at the end of infusion. Blood glucose levels increased with noradrenaline infusion; the presence of high 3-OHB levels decreased glucose concentration. The effects observed were transient and dependent on 3-OHB concentration; these effects may help explain most of the other effects of noradrenaline described here. The role of 3-OHB as a regulator of adrenergic responses seems to be part of a complex fail-safe mechanism which prevents wasting.

Clear detection of ADIPOQ locus as the major gene for plasma adiponectin: results of genome-wide association analyses including 4659 European individuals.

OBJECTIVE: Plasma adiponectin is strongly associated with various components of metabolic syndrome, type 2 diabetes and cardiovascular outcomes. Concentrations are highly heritable and differ between men and women. We therefore aimed to investigate the genetics of plasma adiponectin in men and women. METHODS: We combined genome-wide association scans of three population-based studies including 4659 persons. For the replication stage in 13795 subjects, we selected the 20 top signals of the combined analysis, as well as the 10 top signals with p-values less than 1.0 x 10(-4) for each the men- and the women-specific analyses. We further selected 73 SNPs that were consistently associated with metabolic syndrome parameters in previous genome-wide association studies to check for their association with plasma adiponectin. RESULTS: The ADIPOQ locus showed genome-wide significant p-values in the combined (p=4.3 x 10(-24)) as well as in both women- and men-specific analyses (p=8.7 x 10(-17) and p=2.5 x 10(-11), respectively). None of the other 39 top signal SNPs showed evidence for association in the replication analysis. None of 73 SNPs from metabolic syndrome loci exhibited association with plasma adiponectin (p>0.01). CONCLUSIONS: We demonstrated the ADIPOQ gene as the only major gene for plasma adiponectin, which explains 6.7% of the phenotypic variance. We further found that neither this gene nor any of the metabolic syndrome loci explained the sex differences observed for plasma adiponectin. Larger studies are needed to identify more moderate genetic determinants of plasma adiponectin.

Determination of meropenem in plasma and filtrate-dialysate from patients under continuous veno-venous haemodiafiltration by SPE-LC.

Meropenem, a carbapenem antibiotic displaying a broad spectrum of antibacterial activity, is administered in Medical Intensive Care Unit to critically ill patients undergoing continuous veno-venous haemodiafiltration (CVVHDF). However, there are limited data available to substantial rational dosing decisions in this condition. In an attempt to refine our knowledge and propose a rationally designed dosage regimen, we have developed a HPLC method to determine meropenem after solid-phase extraction (SPE) of plasma and dialysate fluids obtained from patients under CVVHDF. The assay comprises the simultaneous measurement of meropenem's open-ring metabolite UK-1a, whose fate has never been studied in CVVHDF patients. The clean-up procedure involved a SPE on C18 cartridge. Matrix components were eliminated with phosphate buffer pH 7.4 followed by 15:85 MeOH-phosphate buffer pH 7.4. Meropenem and UK-1a were subsequently desorbed with MeOH. The eluates were evaporated under nitrogen at room temperature (RT) and reconstituted in phosphate buffer pH 7.4. Separation was performed at RT on a Nucleosil 100-5 microm C18 AB cartridge column (125 x 4 mm I.D.) equipped with a guard column (8 x 4 mm I.D.) with UV-DAD detection set at 208 nm. The mobile phase was 1 ml min(-1), using a step-wise gradient elution program: %MeOH/0.005 M tetrabutylammonium chloride pH 7.4; 10/90-50/50 in 27 min. Over the range of 5-100 microg ml(-1), the regression coefficient of the calibration curves (plasma and dialysate) were >0.998. The absolute extraction recoveries of meropenem and UK-1a in plasma and filtrate-dialysate were stable and ranged from 88-93 to 72-77% for meropenem, and from 95-104 to 75-82% for UK-1a. In plasma and filtrate-dialysate, respectively, the mean intra-assay precision was 4.1 and 2.6% for meropenem and 4.2 and 3.7% for UK-1a. The inter-assay variability was 2.8 and 3.6% for meropenem and 2.3 and 2.8% for UK-1a. The accuracy was satisfactory for both meropenem and UK-1a with deviation never exceeding 9.0% of the nominal concentrations. The stability of meropenem, studied in biological samples left at RT and at +4 degrees C, was satisfactory with < 5% degradation after 1.5 h in blood but reached 22% in filtrate-dialysate samples stored at RT for 8 h, precluding accurate measurements of meropenem excreted unchanged in the filtrate-dialysate left at RT during the CVVHDF procedure. The method reported here enables accurate measurements of meropenem in critically ill patients under CVVHDF, making dosage individualisation possible in such patients. The levels of the metabolite UK-1a encountered in this population of patients were higher than those observed in healthy volunteers but was similar to those observed in patients with renal impairment under hemodialysis.

Determination of trimipramine and its demethylated and hydroxylated metabolites in plasma by gas chromatography-mass spectrometry.

A gas chromatographic-mass spectrometric (GC-MS) method has been developed, for the determination of trimipramine (TRI), desmethyltrimipramine (DTRI), didesmethyltrimipramine (DDTRI), 2-hydroxytrimipramine (2-OH-TRI) and 2-hydroxydesmethyltrimipramine (2-OH-DTRI). The method includes two derivatization steps with trifluoroacetic acid anhydride and N-methyl-N-(tert.-butyldimethyl silyl)trifluoroacetamide and the use of an SE-54 capillary silica column. The limits of quantitation were found to be 2 ng/ml for DTRI and 4 ng/ml for all other substances. Besides, methods have been optimized for the hydrolysis of the glucuronic acid conjugated metabolites. This specific detection method is useful, as polymedication is a usual practice in clinical situations, and its sensitivity allows its use for single-dose pharmacokinetic studies.

Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma.

Concentrations of liver enzymes in plasma are widely used as indicators of liver disease. We carried out a genome-wide association study in 61,089 individuals, identifying 42 loci associated with concentrations of liver enzymes in plasma, of which 32 are new associations (P = 10(-8) to P = 10(-190)). We used functional genomic approaches including metabonomic profiling and gene expression analyses to identify probable candidate genes at these regions. We identified 69 candidate genes, including genes involved in biliary transport (ATP8B1 and ABCB11), glucose, carbohydrate and lipid metabolism (FADS1, FADS2, GCKR, JMJD1C, HNF1A, MLXIPL, PNPLA3, PPP1R3B, SLC2A2 and TRIB1), glycoprotein biosynthesis and cell surface glycobiology (ABO, ASGR1, FUT2, GPLD1 and ST3GAL4), inflammation and immunity (CD276, CDH6, GCKR, HNF1A, HPR, ITGA1, RORA and STAT4) and glutathione metabolism (GSTT1, GSTT2 and GGT), as well as several genes of uncertain or unknown function (including ABHD12, EFHD1, EFNA1, EPHA2, MICAL3 and ZNF827). Our results provide new insight into genetic mechanisms and pathways influencing markers of liver function.

Antibacterial burst-release from minimal Ag-containing plasma polymer coatings.

Biomaterials releasing silver (Ag) are of interest because of their ability to inhibit pathogenic bacteria including antibiotic-resistant strains. In order to investigate the potential of nanometre-thick Ag polymer (Ag/amino-hydrocarbon) nanocomposite plasma coatings, we studied a comprehensive range of factors such as the plasma deposition process and Ag cation release as well as the antibacterial and cytocompatible properties. The nanocomposite coatings released most bound Ag within the first day of immersion in water yielding an antibacterial burst. The release kinetics correlated with the inhibitory effects on the pathogens Pseudomonas aeruginosa or Staphylococcus aureus and on animal cells that were in contact with these coatings. We identified a unique range of Ag content that provided an effective antibacterial peak release, followed by cytocompatible conditions soon thereafter. The control of the in situ growth conditions for Ag nanoparticles in the polymer matrix offers the possibility to produce customized coatings that initially release sufficient quantities of Ag ions to produce a strong adjacent antibacterial effect, and at the same time exhibit a rapidly decaying Ag content to provide surface cytocompatibility within hours/days. This approach seems to be favourable with respect to implant surfaces and possible Ag-resistance/tolerance built-up.

Prediction of free imatinib concentrations based on total plasma concentrations in patients with gastrointestinal stromal tumours.

AIM: Total imatinib concentrations are currently measured for the therapeutic drug monitoring of imatinib, whereas only free drug equilibrates with cells for pharmacological action. Due to technical and cost limitations, routine measurement of free concentrations is generally not performed. In this study, free and total imatinib concentrations were measured to establish a model allowing the confident prediction of imatinib free concentrations based on total concentrations and plasma proteins measurements. METHODS: One hundred and fifty total and free plasma concentrations of imatinib were measured in 49 patients with gastrointestinal stromal tumours. A population pharmacokinetic model was built up to characterize mean total and free concentrations with inter-patient and intrapatient variability, while taking into account α1 -acid glycoprotein (AGP) and human serum albumin (HSA) concentrations, in addition to other demographic and environmental covariates. RESULTS: A one compartment model with first order absorption was used to characterize total and free imatinib concentrations. Only AGP influenced imatinib total clearance. Imatinib free concentrations were best predicted using a non-linear binding model to AGP, with a dissociation constant Kd of 319 ng ml(-1) , assuming a 1:1 molar binding ratio. The addition of HSA in the equation did not improve the prediction of imatinib unbound concentrations. CONCLUSION: Although free concentration monitoring is probably more appropriate than total concentrations, it requires an additional ultrafiltration step and sensitive analytical technology, not always available in clinical laboratories. The model proposed might represent a convenient approach to estimate imatinib free concentrations. However, therapeutic ranges for free imatinib concentrations remain to be established before it enters into routine practice.

Increased plasma levels of N-terminal brain natriuretic peptide (NT-proBNP) in type 2 diabetic patients with vascular complications.

AIMS: The plasma levels of either brain natriuretic peptide (BNP) or the N-terminal fragment of the prohormone (NT-proBNP) have recently gained extreme importance as markers of myocardial dysfunction. Patients with type 2 diabetes are at high risk of developing cardiovascular complications. This study was aimed to assess whether plasma NT-proBNP levels are at similar levels in type 2 diabetics with or without overt cardiovascular diseases. METHODS: We assayed plasma NT-proBNP in 54 type 2 diabetics, 27 of whom had no overt macro- and/or microvascular complications, while the remaining ones had either or both. The same assay was carried out in 38 healthy control subjects age and sex matched as a group with the diabetics. RESULTS: Plasma NT-proBNP was higher in diabetics (median 121 pg/ml, interquartile range 50-240 pg/ml, ) than in those without complications (37 pg/ml, 21-54 pg/ml, P<0.01). Compared with the controls (55 pg/ml, 40-79 pg/ml), only diabetics with vascular complications had significantly increased plasma NT-proBNP levels (P<0.001). In the diabetics, coronary heart disease and nephropathy (defined according to urinary excretion of albumin) were each independently associated with elevated values of plasma NT-proBNP. CONCLUSIONS: In type 2 diabetes mellitus, patients with macro- and/or micro-vascular complications exhibit an elevation of plasma NT-proBNP levels compared to corresponding patients with no evidence of vascular disease. The excessive secretion of this peptide is independently associated with coronary artery disease and overt nephropathy. The measurement of circulating NT-proBNP concentration may therefore be useful to screen for the presence of macro- and/or microvascular disease.

The data treatment dependent variability of U-Pb zircon ages obtained using mono-collector, sector field, laser ablation ICP-MS

U-Pb dating of zircons by laser ablation inductively coupled plasma mass spectrometry (LA-ICPMS) is a widely used analytical technique in Earth Sciences. For U-Pb ages below 1 billion years (1 Ga), Pb-206/U-238 dates are usually used, showing the least bias by external parameters such as the presence of initial lead and its isotopic composition in the analysed mineral. Precision and accuracy of the Pb/U ratio are thus of highest importance in LA-ICPMS geochronology. We consider the evaluation of the statistical distribution of the sweep intensities based on goodness-of-fit tests in order to find a model probability distribution fitting the data to apply an appropriate formulation for the standard deviation. We then discuss three main methods to calculate the Pb/U intensity ratio and its uncertainty in the LA-ICPMS: (1) ratio-of-the-mean intensities method, (2) mean-of-the-intensity-ratios method and (3) intercept method. These methods apply different functions to the same raw intensity vs. time data to calculate the mean Pb/U intensity ratio. Thus, the calculated intensity ratio and its uncertainty depend on the method applied. We demonstrate that the accuracy and, conditionally, the precision of the ratio-of-the-mean intensities method are invariant to the intensity fluctuations and averaging related to the dwell time selection and off-line data transformation (averaging of several sweeps); we present a statistical approach how to calculate the uncertainty of this method for transient signals. We also show that the accuracy of methods (2) and (3) is influenced by the intensity fluctuations and averaging, and the extent of this influence can amount to tens of percentage points; we show that the uncertainty of these methods also depends on how the signal is averaged. Each of the above methods imposes requirements to the instrumentation. The ratio-of-the-mean intensities method is sufficiently accurate provided the laser induced fractionation between the beginning and the end of the signal is kept low and linear. We show, based on a comprehensive series of analyses with different ablation pit sizes, energy densities and repetition rates for a 193 nm ns-ablation system that such a fractionation behaviour requires using a low ablation speed (low energy density and low repetition rate). Overall, we conclude that the ratio-of-the-mean intensities method combined with low sampling rates is the most mathematically accurate among the existing data treatment methods for U-Pb zircon dating by sensitive sector field ICPMS.

Remorin, a solanaceae protein resident in membrane rafts and plasmodesmata, impairs potato virus X movement.

Remorins (REMs) are proteins of unknown function specific to vascular plants. We have used imaging and biochemical approaches and in situ labeling to demonstrate that REM clusters at plasmodesmata and in approximately 70-nm membrane domains, similar to lipid rafts, in the cytosolic leaflet of the plasma membrane. From a manipulation of REM levels in transgenic tomato (Solanum lycopersicum) plants, we show that Potato virus X (PVX) movement is inversely related to REM accumulation. We show that REM can interact physically with the movement protein TRIPLE GENE BLOCK PROTEIN1 from PVX. Based on the localization of REM and its impact on virus macromolecular trafficking, we discuss the potential for lipid rafts to act as functional components in plasmodesmata and the plasma membrane.

Plasma concentrations of the enantiomers of methadone and therapeutic response in methadone maintenance treatment

Methadone is a 50:50 mixture of two enantiomers and (R)-methadone accounts for the majority of its opioid effect. The aim of this study was to determine whether a blood concentration of (R)-methadone can be associated with therapeutic response in addict patients in methadone maintenance treatment. Trough plasma concentrations of (R)-, (S)- and (R,S)-methadone were measured in 180 patients in maintenance treatment. Therapeutic response was defined by the absence of illicit opiate or cocaine in urine samples collected during a 2-month period prior to blood sampling. A large interindividual variability of (R)-methadone concentration-to-dose-to-weight ratios was found (mean, S.D., median, range: 112, 54, 100, 19-316 ng x kg/ml x mg). With regard to the consumption of illicit opiate (but not of cocaine), a therapeutic response was associated with (R)- (at 250 ng/ml) and (R,S)-methadone (at 400 ng/ml) but not with (S)-methadone concentrations. A higher specificity was calculated for (R)- than for (R,S)-methadone, as the number of non-responders above this threshold divided by the total number of non-responders was higher for (R,S)-methadone (19%) than for (R)-methadone (7%). The results support the use of therapeutic drug monitoring of (R)-methadone in cases of continued intake of illicit opiates. Due to the variability of methadone concentration-to-dose-to-weight ratios, theoretical doses of racemic methadone could be as small as 55 mg/day and as large as 921 mg/day to produce a plasma (R)-methadone concentration of 250 ng/ml in a 70-kg patient. This demonstrates the importance of individualizing methadone treatment.

ABCB1 and cytochrome P450 genotypes and phenotypes: influence on methadone plasma levels and response to treatment.

BACKGROUND AND OBJECTIVE: The in vivo implication of various cytochrome P450 (CYP) isoforms and of P-glycoprotein on methadone kinetics is unclear. We aimed to thoroughly examine the genetic factors influencing methadone kinetics and response to treatment. METHODS: Genotyping for CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, ABCB1, and UGT2B7 polymorphisms was performed in 245 patients undergoing methadone maintenance treatment. To assess CYP3A activity, the patients were phenotyped with midazolam. RESULTS: The patients with lower CYP3A activity presented higher steady-state trough (R,S)-methadone plasma levels (4.3, 3.0, and 2.3 ng/mL x mg for low, medium, and high activity, respectively; P = .0002). As previously reported, CYP2B6*6/*6 carriers had significantly higher trough (S)-methadone plasma levels (P = .0001) and a trend toward higher (R)-methadone plasma levels (P = .07). CYP2D6 ultrarapid metabolizers presented lower trough (R,S)-methadone plasma levels compared with the extensive or intermediate metabolizers (2.4 and 3.3 ng/mL x mg, respectively; P = .04), whereas CYP2D6 poor metabolizer status showed no influence. ABCB1 3435TT carriers presented lower trough (R,S)-methadone plasma levels (2.7 and 3.4 ng/mL . mg for 3435TT and 3435CC carriers, respectively; P = .01). The CYP1A2, CYP2C9, CYP2C19, CYP3A5, and UGT2B7 genotypes did not influence methadone plasma levels. Only CYP2B6 displayed a stereoselectivity in its activity. CONCLUSION: In vivo, CYP3A4 and CYP2B6 are the major CYP isoforms involved in methadone metabolism, with CYP2D6 contributing to a minor extent. ABCB1 genetic polymorphisms also contribute slightly to the interindividual variability of methadone kinetics. The genetic polymorphisms of these 4 proteins had no influence on the response to treatment and only a small influence on the dose requirement of methadone.