Impact of glucuronide interferences on therapeutic drug monitoring of posaconazole by tandem mass spectrometry

Background: Posaconazole is a novel antifungal drug for oral application intended especially for therapy of invasive mycoses. Due to variable gastrointestinal absorption, adverse side effects, and suspected drug-drug interactions, therapeutic drug monitoring (TDM) of posaconazole is recommended. Method: A fast ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for quantification of posaconazole with a run-time <3 min was developed and compared to a LC-MS/MS method and HPLC method with fluorescence detection. Results: During evaluation of UPLC-MS/MS, two earlier eluting peaks were observed in the MRM trace of posaconazole. This was only seen in patient samples, but not in spiked calibrator samples. Comparison with LC-MS/MS disclosed a significant bias with higher concentrations measured by LC-MS/MS, while UPLC-MS/MS showed excellent agreement with the commercially available HPLC method. In the LC-MS/MS procedure, comparably wide and left side shifted peaks were noticed. This could be ascribed to in-source fragmentation of conjugate metabolites during electrospray ionisation. Precursor and product ion scans confirmed the assumption that the additional compounds are posaconazole glucuronides. Reducing the cone voltage led to disappearance of the glucuronide peaks. Slight modification of the LC-MS/MS method enabled separation of the main interference, leading to significantly reduced deviation. Conclusions: These results highlight the necessity to reliably eliminate interference from labile drug metabolites for correct TDM results, either by sufficient separation or selective MS conditions. The presented UPLC-MS/MS method provides a reliable and fast assay for TDM of posaconazole. Clin Chem Lab Med 2010; 48:1723-31

The Cubesat Assessment and Test (CAT) Program - Missions Operations Evolution

On January 31, 2019, the CubeSat Assessment and Test (CAT) mission deployed from the International Space Station (ISS). The primary objective of the CAT mission is to use two COTS 3U spacecraft to support a communications experiment. CAT completed its primary mission success objectives in two months and continues to collect mission data two years post-launch. After meeting the mission objectives, the focus shifted to increasing data return from the payloads on the two spacecraft with the CAT team working to evolve the mission to continue to maximize its payload data return. During its initial conception and design, the team at The Johns Hopkins University Applied Physics Laboratory (JHU/APL), along with the spacecraft provider, Blue Canyon Technologies (BCT) have performed a wide range of tasks to increase operational availability and provide more operational data. Early activities included APL management and oversight of the development of the two 3U spacecraft. During this period, APL selected the Innoflight SCR-100 radio to be used on the standard BCT XB1 bus to provide increased robustness, uplink and downlink hardware encryption, and an increased (2Mbps) downlink data rate. Early engineering choices included the decision to transition from the COSMOS-based BCT ground control system to the APL L3 InControl ground system. This provided the mission with a wealth of automated tools used by all APL-led operations, including an APL-developed automated planning and commanding technology called SciBox, as well as heritage ground scripts for “lights-out” operations via the APL Satellite Communications Facility (SCF). Post-deployment from the ISS, autonomous operations using both on-board functionality as well as autonomous ground operations, allowed the CAT operations team to continue to optimize data return by maximizing spacecraft and ground system “down time”. Most recently, Amazon Web Services (AWS) was used to augment the number of ground entry points to provide addition operational data and a new end to end capability with the usage of the AWS Cloud Data Platform. This paper discusses JHU/APL’s experience building, integrating, and operating this small sat mission as well as the operational approaches planned pre-launch and those developed post-launch for the CAT mission

Комплексные соединения галогенидов цинка как потенциальные противораковые препараты

The purpose of this review is to summarize currently available evidence implicating vitamin K in the pathogenesis of vascular calcification (VC), in particular arterial medial calcification. In doing so, we try to provide a rationale for an interventional clinical study testing whether vitamin K supplementation can retard VC or even affect cardiovascular mortality in chronic kidney disease patients. Additionally, we wish to give an overview of the current literature indicating potential adverse effects of long-term vitamin K antagonists in this population

In vivo measurement of glycine with short echo-time 1H MRS in human brain at 7 T

Object: To determine whether glycine can be measured at 7 T in human brain with 1H magnetic resonance spectroscopy (MRS). Materials and methods: The glycine singlet is overlapped by the larger signal of myo-inositol. Density matrix simulations were performed to determine the TE at which the myo-inositol signal was reduced the most, following a single spin-echo excitation. 1H MRS was performed on an actively shielded 7 T scanner, in five healthy volunteers. Results: At the TE of 30ms, the myo-inositol signal intensity was substantially reduced. Quantification using LCModel yielded a glycine-to-creatine ratio of 0.14 ±0.01, with a Cramér-Rao lower bound (CRLB) of 7 ± 1%. Furthermore, quantification of metabolites other than glycine was possible as well, with a CRLB mostly below 10%. Conclusion: It is possible to detect glycine at 7 T in human brain, at the short TE of 30ms with a single spin-echo excitation schem

Eddy current effects on a clinical 7T-68cm bore scanner

Introduction: Eddy currents induced by switching of magnetic field gradients can lead to distortions in short echo-time spectroscopy or diffusion weighted imaging. In small bore magnets, such as human head-only systems, minimization of eddy current effects is more demanding because of the proximity of the gradient coil to conducting structures. Methods: In the present study, the eddy current behavior achievable on a recently installed 7 tesla—68cm bore head-only magnet was characterized. Results: Residual effects after compensation were shown to be on the same order of magnitude as those measured on two whole body systems (3 and 4.7 T), while using two to three fold increased gradient slewrate

Breathing dynamics in heteropolymer DNA

While the statistical mechanical description of DNA has a long tradition, renewed interest in DNA melting from a physics perspective is nourished by measurements of the fluctuation dynamics of local denaturation bubbles by single molecule spectroscopy. The dynamical opening of DNA bubbles (DNA breathing) is supposedly crucial for biological functioning during, for instance, transcription initiation and DNA's interaction with selectively single-stranded DNA binding proteins. Motivated by this, we consider the bubble breathing dynamics in a heteropolymer DNA based on a (2+1)-variable master equation and complementary stochastic Gillespie simulations, providing the bubble size and the position of the bubble along the sequence as a function of time. We utilize new experimental data that independently obtain stacking and hydrogen bonding contributions to DNA stability. We calculate the spectrum of relaxation times and the experimentally measurable autocorrelation function of a fluorophore-quencher tagged base-pair, and demonstrate good agreement with fluorescence correlation experiments. A significant dependence of opening probability and waiting time between bubble events on the local DNA sequence is revealed and quantified for a promoter sequence of the T7 phage. The strong dependence on sequence, temperature and salt concentration for the breathing dynamics of DNA found here points at a good potential for nanosensing applications by utilizing short fluorophore-quencher dressed DNA constructs.Comment: 11 pages, 8 figure

Eddy current effects on a clinical 7T-68 cm bore scanner

Eddy currents induced by switching of magnetic field gradients can lead to distortions in short echo-time spectroscopy or diffusion weighted imaging. In small bore magnets, such as human head-only systems, minimization of eddy current effects is more demanding because of the proximity of the gradient coil to conducting structures

Eddy current effects on a clinical 7T-68 cm bore scanner.

INTRODUCTION: Eddy currents induced by switching of magnetic field gradients can lead to distortions in short echo-time spectroscopy or diffusion weighted imaging. In small bore magnets, such as human head-only systems, minimization of eddy current effects is more demanding because of the proximity of the gradient coil to conducting structures. METHODS: In the present study, the eddy current behavior achievable on a recently installed 7 tesla-68 cm bore head-only magnet was characterized. RESULTS: Residual effects after compensation were shown to be on the same order of magnitude as those measured on two whole body systems (3 and 4.7 T), while using two to three fold increased gradient slewrates

Anaerobic Microbial Degradation of Hydrocarbons: From Enzymatic Reactions to the Environment

Hydrocarbons are abundant in anoxic environments and pose biochemical challenges to their anaerobic degradation by microorganisms. Within the framework of the Priority Program 1319, investigations funded by the Deutsche Forschungsgemeinschaft on the anaerobic microbial degradation of hydrocarbons ranged from isolation and enrichment of hitherto unknown hydrocarbon-degrading anaerobic microorganisms, discovery of novel reactions, detailed studies of enzyme mechanisms and structures to process-oriented in situ studies. Selected highlights from this program are collected in this synopsis, with more detailed information provided by theme-focused reviews of the special topic issue on 'Anaerobic biodegradation of hydrocarbons' [this issue, pp. 1-244]. The interdisciplinary character of the program, involving microbiologists, biochemists, organic chemists and environmental scientists, is best exemplified by the studies on alkyl-/arylalkylsuccinate synthases. Here, research topics ranged from in-depth mechanistic studies of archetypical toluene-activating benzylsuccinate synthase, substrate-specific phylogenetic clustering of alkyl-/arylalkylsuccinate synthases (toluene plus xylenes, p-cymene, p-cresol, 2-methylnaphthalene, n-alkanes), stereochemical and co-metabolic insights into n-alkane-activating (methylalkyl) succinate synthases to the discovery of bacterial groups previously unknown to possess alkyl-/arylalkylsuccinate synthases by means of functional gene markers and in situ field studies enabled by state-of-the-art stable isotope probing and fractionation approaches. Other topics are Mo-cofactor-dependent dehydrogenases performing O-2-independent hydroxylation of hydrocarbons and alkyl side chains (ethylbenzene, p-cymene, cholesterol, n-hexadecane), degradation of p-alkylated benzoates and toluenes, glycyl radical-bearing 4-hydroxyphenylacetate decarboxylase, novel types of carboxylation reactions (for acetophenone, acetone, and potentially also benzene and naphthalene), W-cofactor-containing enzymes for reductive dearomatization of benzoyl-CoA (class II benzoyl-CoA reductase) in obligate anaerobes and addition of water to acetylene, fermentative formation of cyclohexanecarboxylate from benzoate, and methanogenic degradation of hydrocarbons