Controlling Individual Domain Walls in Ferromagnetic Nanowires for Memory and Sensor Applications

Controlled motion of 180o and 360o domain walls along planar nanowires is presented. Standard Landau – Lifshitz micromagnetic modeling has been used to simulate the response of the domain walls to the application of an external magnetic field. A 180o wall is quickly and easily moved with the application of an applied. field along the axis of the wire but a 360odomain wall is stationary in the same case. An oscillatory applied field can be used to continually move the wall along the wires axis. The speed at which the 360o domain wall is found to be several times slower than a similar 180o domain wall and is limited by interaction between the magnetization of the domain wall and the external field

A Comparison of Lung Function Values Among a SCUBA Diver Population and in Comparison to a Non-diver Population

The purpose of this study was to investigate possible correlations between lung function values (PEF, IRV, ERV, and FVC) among a diver population, as well as in comparison to a non-diver population. Independent variables for both populations were biological sex, age, and weekly physical activity. Independent variables for the diver population were dive tenure, number of logged dives, certification level, and gas mixture used. A spirometry test was conducted to collect lung function values of both populations. Data from this study suggest a statistically significant relationship between diver and non-diver sex and FVC, diver age and ERV, diver sex and ERV, and non-diver FVC and weekly physical activity

Ornithine uptake and the modulation of drug sensitivity in <i>Trypanosoma brucei</i>

Trypanosoma brucei, protozoan parasites that cause human African trypanosomiasis (HAT), depend on ornithine uptake and metabolism by ornithine decarboxylase (ODC) for survival. Indeed, ODC is the target of the WHO “essential medicine” eflornithine, which is antagonistic to another anti-HAT drug, suramin. Thus, ornithine uptake has important consequences in T. brucei, but the transporters have not been identified. We describe these amino acid transporters (AATs). In a heterologous expression system, TbAAT10-1 is selective for ornithine, whereas TbAAT2-4 transports both ornithine and histidine. These AATs are also necessary to maintain intracellular ornithine and polyamine levels in T. brucei, thereby decreasing sensitivity to eflornithine and increasing sensitivity to suramin. Consistent with competition for histidine, high extracellular concentrations of this amino acid phenocopied a TbAAT2-4 genetic defect. Our findings established TbAAT10-1 and TbAAT2-4 as the parasite ornithine transporters, one of which can be modulated by histidine, but both of which affect sensitivity to important anti-HAT drugs.—Macedo, J. P., Currier, R. B., Wirdnam, C., Horn, D., Alsford, S., Rentsch, D. Ornithine uptake and the modulation of drug sensitivity in Trypanosoma brucei

A Mutation in Amino Acid Permease AAP6 Reduces the Amino Acid Content of the Arabidopsis Sieve Elements but Leaves Aphid Herbivores Unaffected.

The aim of this study was to investigate the role of the amino acid permease gene AAP6 in regulating phloem amino acid composition and then to determine the effects of this altered diet on aphid performance. A genotype of Arabidopsis thaliana (L.) was produced in which the function of the amino acid permease gene AAP6 (At5g49630) was abolished. Plants homozygous for the insertionally inactivated AAP6 gene had a significantly larger mean rosette width than the wild type and a greater number of cauline leaves. Seeds from the aap6 mutant were also significantly larger than those from the wild-type plants. Sieve element (SE) sap was collected by aphid stylectomy and the amino acids derivatized, separated, and quantified using Capillary Electrophoresis with Laser Induced Fluorescence (CE-LIF). In spite of the large variation across samples, the total amino acid concentration of SE sap of the aap6 mutant plants was significantly lower than that of the wild-type plants. The concentrations of lysine, phenylalanine, leucine, and aspartic acid were all significantly lower in concentration in the aap6 mutant plants compared with wild-type plants. This is the first direct demonstration of a physiological role for an amino acid transporter in regulating SE composition in vivo. The amino acid availability in sieve element sap is thought to be the major limiting factor for aphid growth and reproduction. Despite the changes in their diet, the aphid Myzus persicae(Sulzer) displayed only small changes in feeding behaviour on mutant plants when measured using the Electronic Penetration Graph (EPG) technique. Salivation by the aphid into the SE (E1 phase) was increased on mutant plants but there was no significant effect on other feeding EPG behaviours, or in the rate of honeydew production. Consistent with the small effect on aphid feeding behaviour, there was only a small effect of reduced sieve element amino acid concentration on aphid reproduction. The data are discussed in relation to the regulation of phloem composition and the role of phloem amino acids in regulating aphid performance

Preparation and characterization of water-redispersible nanofibrillated cellulose in powder form

Water-redispersible, nanofibrillated cellulose (NFC) in powder form was prepared from refined, bleached beech pulp (RBP) by carboxymethylation (c) and mechanical disintegration (m). Two routes were examined by altering the sequence of the chemical and mechanical treatment, leading to four different products: RBP-m and RBP-mc (route 1), and RBP-c and RBP-cm (route 2). The occurrence of the carboxymethylation reaction was confirmed by FT-IR spectrometry and 13C solid state NMR (13C CP-MAS) spectroscopy with the appearance of characteristic signals for the carboxylate group at 1,595cm−1 and 180ppm, respectively. The chemical modification reduced the crystallinity of the products, especially for those of route 2, as shown by XRD experiments. Also, TGA showed a decrease in the thermal stability of the carboxymethylated products. However, sedimentation tests revealed that carboxymethylation was critical to obtain water-redispersible powders: the products of route 2 were easier to redisperse in water and their aqueous suspensions were more stable and transparent than those from route 1. SEM images of freeze-dried suspensions from redispersed RBP powders confirmed that carboxymethylation prevented irreversible agglomeration of cellulose fibrils during drying. These results suggest that carboxymethylated and mechanically disintegrated RBP in dry form is a very attractive alternative to conventional NFC aqueous suspensions as starting material for derivatization and compounding with (bio)polymer

Comparative pharmacokinetic and cytotoxic analysis of three different formulations of mitoxantrone in mice.

Two liposomal formulations of mitoxantrone (MTO) were compared with the aqueous solution (free MTO) in terms of their pharmacokinetic behaviour in ICR mice and cytotoxic activity in a nude mouse xenograft model. The three different formulations of MTO [free MTO, phosphatidic acid (PA)-MTO liposomes, pH-MTO liposomes] were administered intravenously (three mice per formulation and time point) at a dose of 4.7 micromol kg(-1) for free MTO, 6.1 micromol kg(-1) for PA-MTO and 4.5 micromol kg(-1) for pH-MTO. The concentrations of MTO were determined using high-performance liquid chromatography (HPLC) in blood, liver, heart, spleen and kidneys of the mice. Additionally, the toxicity and anti-tumour activity of MTO was evaluated in a xenograft model using a human LXFL 529/6 large-cell lung carcinoma. The dose administered was 90% of the maximum tolerated dose (MTD) of the corresponding formulation (8.1 micromol kg(-1) for free MTO, 12.1 micromol kg(-1) for PA-MTO and pH-MTO). The pharmacokinetic behaviour of PA-MTO in blood was faster than that of free MTO, but the cytotoxic effect was improved. In contrast, pH-MTO showed a tenfold increased area under the curve (AUC) in blood compared with free MTO, without improvement of the cytotoxic effect. This discrepancy between the pharmacokinetic and cytotoxic results could be explained by the fact that MTO in pH-MTO liposomes remains mainly in the vascular space, whereas MTO in PA-MTO liposomes is rapidly distributed into deep compartments, even more so than free MTO

Monographies on drugs, which are frequently analysed in the course of Therapeutic Drug Monitoring Monographien über Medikamente, die regelmässig im Rahmen des Therapeutic Drug Monitorings analysiert werden

In 1995 the working group "Drug Monitoring” of the Swiss Society of Clinical Chemistry (SSCC) has already published a printed version of drug monographs, which are now newly compiled and presented in a standardised manner. The aim of these monographs is to give an overview on the most important informations that are necessary in order to request a drug analysis or is helpful to interpret the results. Therefore, the targeted audience are laboratory health professionals or the receivers of the reports. There is information provided on the indication for therapeutic drug monitoring, protein binding, metabolic pathways and enzymes involved, elimination half life time and elimination routes as well as information on therapeutic or toxic concentrations. Because preanalytical considerations are of particular importance for therapeutic drug monitoring, there is also information given at which time the determination of the drug concentration is reasonable and when steady-state concentrations are reached after changing the dose. Furthermore, the stability of the drug and its metabolite(s), respectively, after blood sampling is described. For readers with a specific interest, references to important publications are given. The number of the monographs will be continuously enlarged. The updated files are presented on the homepage of the SSCC (www.sscc.ch). We hope that these monographs are helpful for you handling therapeutic drug monitoring and look forward to comments of the audienc

Multimodality Treatment for Early-Stage Hepatocellular Carcinoma: A Bridging Therapy for Liver Transplantation

Purpose: To evaluate the efficiency of a multimodality approach consisting of transcatheter arterial chemoembolization (TACE) and radiofrequency ablation (RFA) as bridging therapy for patients with hepatocellular carcinoma (HCC) awaiting orthotopic liver transplantation (OLT) and to evaluate the histopathological response in explant specimens. Materials and Methods: Between April 2001 and November 2011, 36 patients with 50 HCC nodules (1.4-5.0 cm, median 2.8 cm) on the waiting list for liver transplantation were treated by TACE and RFA. The drop-out rate during the follow-up period was recorded. The local efficacy was evaluated by histopathological examination of the explanted livers. Results: During a median follow-up time of 29 (4.0-95.3) months the cumulative drop-out rate for the patients on the waiting list was 0, 2.8, 5.5, 11.0, 13.9 and 16.7% at 3, 6, 12, 24, 36 and 48 months, respectively. 16 patients (with 26 HCC lesions) out of 36(44.4%) were transplanted by the end of study with a median waiting list time of 13.7 (2.5-37.8) months. The histopathological examination of the explanted specimens revealed a complete necrosis in 20 of 26 HCCs (76.9%), whereas 6 (23.1%) nodules showed viable residual tumor tissue. All transplanted patients are alive at a median time of 29.9 months. Imaging correlation showed 100% specificity and 66.7% sensitivity for the depiction of residual or recurrent tumor. Conclusion: We conclude that TACE.combined with RFA could provide an effective treatment to decrease the drop-out rate from the OLT waiting list for HCC patients. Furthermore, this combination therapy results in high rates of complete tumor necrosis as evaluated in the histopathological analysis of the explanted livers. Further randomized trials are needed to demonstrate if there is a benefit in comparison with a single-treatment approach. copyright (C) 2012 S. Karger AG, Base

Structure-guided design and optimization of small molecules targeting the protein-protein interaction between the von hippel-lindau (VHL) E3 ubiquitin ligase and the hypoxia inducible factor (HIF) alpha subunit with in vitro nanomolar affinities

E3 ubiquitin ligases are attractive targets in the ubiquitin-proteasome system, however, the development of small-molecule ligands has been rewarded with limited success. The von Hippel-Lindau protein (pVHL) is the substrate recognition subunit of the VHL E3 ligase that targets HIF-1α for degradation. We recently reported inhibitors of the pVHL:HIF-1α interaction, however they exhibited moderate potency. Herein, we report the design and optimization, guided by X-ray crystal structures, of a ligand series with nanomolar binding affinities

Sirolimus and kidney growth in autosomal dominant polycystic kidney disease

BACKGROUND: In autosomal dominant polycystic kidney disease (ADPKD), aberrant activation of the mammalian target of rapamycin (mTOR) pathway is associated with progressive kidney enlargement. The drug sirolimus suppresses mTOR signaling. METHODS: In this 18-month, open-label, randomized, controlled trial, we sought to determine whether sirolimus halts the growth in kidney volume among patients with ADPKD. We randomly assigned 100 patients between the ages of 18 and 40 years to receive either sirolimus (target dose, 2 mg daily) or standard care. All patients had an estimated creatinine clearance of at least 70 ml per minute. Serial magnetic resonance imaging was performed to measure the volume of polycystic kidneys. The primary outcome was total kidney volume at 18 months on blinded assessment. Secondary outcomes were the glomerular filtration rate and urinary albumin excretion rate at 18 months. RESULTS: At randomization, the median total kidney volume was 907 cm(3) (interquartile range, 577 to 1330) in the sirolimus group and 1003 cm(3) (interquartile range, 574 to 1422) in the control group. The median increase over the 18-month period was 99 cm(3) (interquartile range, 43 to 173) in the sirolimus group and 97 cm(3) (interquartile range, 37 to 181) in the control group. At 18 months, the median total kidney volume in the sirolimus group was 102% of that in the control group (95% confidence interval, 99 to 105; P=0.26). The glomerular filtration rate did not differ significantly between the two groups; however, the urinary albumin excretion rate was higher in the sirolimus group. CONCLUSIONS: In adults with ADPKD and early chronic kidney disease, 18 months of treatment with sirolimus did not halt polycystic kidney growth. (ClinicalTrials.gov number, NCT00346918.