Traditional Chinese Medicine-Based Subtyping of Early-Stage Type 2 Diabetes Using Plasma Metabolomics Combined with Ultra-Weak Photon Emission

The prevalence of type 2 diabetes mellitus (T2DM) is increasing rapidly worldwide. Because of the limited success of generic interventions, the focus of the disease study has shifted toward personalized strategies, particularly in the early stages of the disease. Traditional Chinese medicine (TCM) is based on a systems view combined with personalized strategies and has improved our knowledge of personalized diagnostics. From a systems biology perspective, the understanding of personalized diagnostics can be improved to yield a biochemical basis for such strategies; for example, metabolomics can be used in combination with other system-based diagnostic methods such as ultra-weak photon emission (UPE). In this study, we investigated the feasibility of using plasma metabolomics obtained from 44 pre-T2DM subjects to stratify the following TCM-based subtypes: Qi-Yin deficiency, Qi-Yin deficiency with dampness, and Qi-Yin deficiency with stagnation. We studied the relationship between plasma metabolomics and UPE with respect to TCM-based subtyping in order to obtain biochemical information for further interpreting disease subtypes. Principal component analysis of plasma metabolites revealed differences among the TCM-based pre-T2DM subtypes. Relatively high levels of lipids (e.g., cholesterol esters and triglycerides) were important discriminators of two of the three subtypes and may be associated with a higher risk of cardiovascular disease. Plasma metabolomics data indicate that the lipid profile is an essential component captured by UPE with respect to stratifying subtypes of T2DM. The results suggest that metabolic differences exist among different TCM-based subtypes of pre-T2DM, and profiling plasma metabolites can be used to discriminate among these subtypes. Plasma metabolomics thus provides biochemical insights into system-based UPE measurements. (C) 2019 THE AUTHORS. Published by Elsevier LTD on behalf of Chinese Academy of Engineering and Higher Education Press Limited Company.Analytical BioScience

Opinions on rehabilitation care of young adults with transversal upper limb reduction deficiency in their transition to adulthood

PURPOSE: Young adults with transversal upper limb reduction deficiency experience limitations regarding education, employment and obtaining a driver's license. Contribution of rehabilitation care within these domains has been reported to be inadequate. This study evaluates the needs and suggestions of participants in rehabilitation care. METHODS: Two online focus groups with young adults and parents met during 4 consecutive days. Health care professionals joined a face-to-face focus group. Data analysis was based on framework analysis. RESULTS: The rehabilitation team was mainly consulted for problems with residual limb or for prostheses. Young adults and their parents were mostly unaware of resources regarding education, job selection or obtaining a driver's license. Professionals stated that these subjects were addressed during periodic appointments. Young adults didn't always attend these appointments due to limited perceived benefit. To improve rehabilitation care, participants suggested methods for providing relevant information, facilitating peer contact and offering dedicated training programs to practice work-related tasks, prepare for job interviews or enhance self-confidence. CONCLUSION: Periodic appointments do not fulfil needs of young adults with transversal upper limb reduction deficiency. To improve care, rehabilitation teams should offer age-relevant information, share peer stories, and create dedicated training programs

Systems pharmacology of hepatic metabolism in zebrafish larvae

Interspecies translation of pharmacological processes needs to improve to reduce attrition in drug development. Systems pharmacology integrates systems biology and pharmacometrics to characterise and quantify system-specific behaviour upon exposure to drugs in different species. The zebrafish is a suitable vertebrate model organism for systems pharmacology, combining high-throughput potential with high genetic homology to higher vertebrates. Zebrafish larvae have been increasingly used for drug screens, but the influence of internal drug and metabolite exposure is hardly studied. Quantifying this internal exposure is essential for establishing both exposure-response and dose-exposure relationships, needed for translation. The zebrafish may also serve as a suitable model species for translational studies on the occurrence of hepatotoxicity and the influence of hepatic dysfunction on drug metabolism. Pharmacolog

Impact of post-hatching maturation on the pharmacokinetics of paracetamol in zebrafish larvae

Zebrafish larvae are increasingly used in pharmacological and toxicological studies, but it is often overlooked that internal exposure to exogenous compounds, rather than the incubation medium concentration, is driving observed effects. Moreover, as the zebrafish larva is a developing organism, continuous physiological changes impact pharmacokinetic or toxicokinetic processes like the absorption and elimination of exogenous compounds, influencing the interpretation of observations and conclusions drawn from experiments at different larval ages. Here, using paracetamol as paradigm compound, mathematical modelling is used to quantify absorption and elimination rates from internal exposure over time profiles after waterborne treatment, as well as changes in these parameters in post-hatching larvae of 3, 4, and 5 days post fertilisation (dpf). An increase of 106% in absorption rate was observed between 3 and 4 dpf, but no further increase at 5 dpf, and an increase of 17.5% in elimination rate for each dpf. Paracetamol clearance, determined from elimination rate constants and reported total larval volumes of 253, 263, and 300 nL at 3, 4, and 5 dpf respectively, correlates best with higher vertebrates at 5 dpf. This suggests that when studying direct effects of exogenous compounds, experiments with zebrafish larvae are best performed at 5 dpf.PharmacologyAnalytical BioScience

Mechanistic and quantitative understanding of pharmacokinetics in zebrafish larvae through nanoscale blood sampling and metabolite modelling of paracetamol

Zebrafish larvae are increasingly used for pharmacological research, but internal drug exposure is often not measured. Understanding pharmacokinetics is necessary for reliable translation of pharmacological results to higher vertebrates, including humans. Quantification of drug clearance and distribution requires measurements of blood concentrations. Additionally, measuring drug metabolites is of importance to understand clearance in this model organism mechanistically. We therefore mechanistically study and quantify pharmacokinetics in zebrafish larvae, and compare this to higher vertebrates, using paracetamol (acetaminophen) as paradigm compound. A method was developed to sample blood from zebrafish larvae at five days post fertilization. Blood concentrations of paracetamol and its major metabolites, paracetamol-glucuronide and paracetamol-sulphate, were measured. Blood concentration data were combined with measured amounts in larval homogenates and excreted amounts and simultaneously analysed through non-linear mixed effects modelling, quantifying absolute clearance and distribution volume. Blood sampling from zebrafish larvae was most successful from the posterior cardinal vein with median volume (interquartile range) of 1.12 (0.676-1.66) nL per blood sample. Samples were pooled (n=15-35) to reach measurable levels. Paracetamol blood concentrations at steady state were only 10% of the external paracetamol concentration. Paracetamol-sulphate was the major metabolite and its formation was quantified using a time-dependent metabolic formation rate. Absolute clearance and distribution volume correlated well to reported values in higher vertebrates, including humans. Based on blood concentrations and advanced data analysis, the mechanistic and quantitative understanding of paracetamol pharmacokinetics in zebrafish larvae has been established. This will improve the translational value of this vertebrate model organism in drug discovery and development.Analytical BioSciencesPharmacolog

Лексична лакуна як об'єкт лінгвістичних досліджень

В статье осуществлен теоретический обзор проблемы лакунарности, как одного из основных вопросов при реконструкции языковой картины мира. Представлена классификация лексических лакун на материале сопоставления украинского, русского и английского языка.В статті зроблено теоретичний огляд проблеми лакунарності як одного з основних питань при реконструкції мовної картини світу. Представлена класифікація лексичних лакун на матеріалі зіставлення української, російської та англійської мови.This paper is a theoretical review on lacunarity as one of the main problems in reconstruction of the linguistic picture of the world. A classification of lexical lacunae has been suggested using the material of comparison of the Ukrainian, Russian and English languages

Evaluation of asymmetric orthogonal cyanine fluorophores

Pentamethine cyanine (Cy5) fluomphores have proven to be versatile imaging agents (i.e., tracers) for a range of micro- and macroscopic imaging applications, including image-guided surgery. In this study the relationship between the structure of asymmetric Cy5 fluorophores and their photophysical properties was studied. To this end, seven Cy5 analogues, bearing orthogonal N-indole substituents (H, SC3-, or benzene), were synthesised and evaluated. In-depth analysis revealed that introduction of sulfonates enhanced the fluorescence brightness and photostability, while reducing the lipophilicity, serum binding and stacking tendency. The addition of benzene moieties induced a bathochromic shift of 10-20 nm, increased the lipophilicity (LogP = -1.56-1.23) and serum binding (67.3-93.8% bound), as well as negatively impacted the brightness (0.74-42.9 . 10(3) M-1 cm(-1)), photostability (24.4-90.6% remaining), and stacking tendency. Chemical stability was uninfluenced by the substitution pattern. Additionally, the generation of a c[RGDyK]-based hybrid tracer based on one of these fluomphores in combination with a diethylenetriaminepentaacetic acid (DTPA) chelate and an In-111-isotope was reported. This compound was evaluated in vitro using alpha(v)beta(3)-overexpressing Ge beta 3 cells and in vivo using a 4T1 mouse tumour model. Overall, the presented results imply that alterations of the asymmetrical orthogonal Cy5 fluomphore structure have impact on the (photo)physical properties. Furthermore, the orthogonal Cy5 fluorophore framework can readily be applied in tracer development.Radiolog

Urinary ATP as an indicator of infection and inflammation of the urinary tract in patients with lower urinary tract symptoms

BACKGROUND: Adenosine-5'-triphosphate (ATP) is a neurotransmitter and inflammatory cytokine implicated in the pathophysiology of lower urinary tract disease. ATP additionally reflects microbial biomass thus has potential as a surrogate marker of urinary tract infection (UTI). The optimum clinical sampling method for ATP urinalysis has not been established. We tested the potential of urinary ATP in the assessment of lower urinary tract symptoms, infection and inflammation, and validated sampling methods for clinical practice. METHODS: A prospective, blinded, cross-sectional observational study of adult patients presenting with lower urinary tract symptoms (LUTS) and asymptomatic controls, was conducted between October 2009 and October 2012. Urinary ATP was assayed by a luciferin-luciferase method, pyuria counted by microscopy of fresh unspun urine and symptoms assessed using validated questionnaires. The sample collection, storage and processing methods were also validated. RESULTS: 75 controls and 340 patients with LUTS were grouped as without pyuria (n = 100), pyuria 1-9 wbc ?l(-1) (n = 120) and pyuria ?10 wbc ?l(-1) (n = 120). Urinary ATP was higher in association with female gender, voiding symptoms, pyuria greater than 10 wbc ?l(-1) and negative MSU culture. ROC curve analysis showed no evidence of diagnostic test potential. The urinary ATP signal decayed with storage at 23°C but was prevented by immediate freezing at ??-20°C, without boric acid preservative and without the need to centrifuge urine prior to freezing. CONCLUSIONS: Urinary ATP may have a role as a research tool but is unconvincing as a surrogate, clinical diagnostic marker