Effect of Combination of L-Arginine and L-Carnitine on Serum AGEs Level, Kidney and Endothelial Function in Patients with Chronic Heart Failure

The aim of the study to evaluate the effect of combination of L-Arginine with L-Carnitine on GFR, serum AGEs level and endothelial function in chronic heart failure (HF) patients with preserved ejection fraction (HFpEF). Materials and Methods: 35 patients with mean age 60,1 [56,7; 77,3] years with an established diagnosis of HFpEF were enrolled. The patients were randomly and blindly divided into 2 groups: first (1st) group pts were treated with a combination of L-Carnitine and L-Arginine in addition to standard treatment; 2nd group pts – with L-Arginine in addition to conventional treatment. Standard laboratory blood tests, lipid profile, glucose, renal and liver function tests, serum advanced glycation end-product (AGEs) level, echocardiographic examination, flow-mediated dilatation (FMD%) were performed for all patients baseline and after 10 days of treatment. The glomerular filtration rate (GFR) was estimated using the CKD-EPI formula. Results: Median level of AGEs was 1.72 [1.34; 1.93] mg/ml. The level of AGEs was correlated with age (R = 0.71, p<0.05), disease duration (R = 0.69, p<0.05). After 10 days of treatment with a combination of L-Carnitine with L-Arginine mean AGEs was decreased by 13.1% in comparison with L-Arginine treatment group (p=0.0003). After the treatment in 1st group mean AGEs was significantly lower in comparison with the 2nd group (p=0.004). Baseline median level of GFR was 81.2 [72,1; 86,2] ml/min and correlated with disease duration (R = 0.71, p<0.05), AGEs level (R = -0.73, p<0.05). The inclusion combination of L-arginine aspartate with L-Carnitine contributed to the significant increase of GFR level (p=0.003). The median FMD% level was 6.2 [4.4; 7.9] % and correlated with age (R=-0.61, p < 0.05), GFR (R=0.54, p < 0.05). After the 10 days it had been established significant increasing of FMD% level on 47.9 % in 1st group (p=0.0005), and on 29.3 % in 2nd group (p=0.003). Endothelial function normalizing was achieved in 10 (66 %) pts of 1st group and in 9 (45%) pts of 2nd group (p=0.002). Conclusion: The combination of L-Carnitine, and L-Arginine improves kidney, endothelial function and contributes to decreasing of AGEs level in pts with HFpEF

BADANIA EKSPERYMENTALNE NARZĘDZI DO POMIARU KONTROLI WILGOTNOŚCI GAZU ZIEMNEGO

The means of measuring humidity based on the use of the ultrahigh frequency method have been recently gaining widespread use, because of its simple, robust construction and high measuring accuracy. We used the advanced waveguide ultrahigh frequency method of measuring the moisture content of natural gas which, in contrast to the known the use of a traveling wave in a waveguide, is proposed. In this case, the interaction with waves of the ultrahigh frequency range changes the dielectric properties of the gas, and this change is registered. On the basis of an improved ultrahigh frequency method of humidity measurement, a device for natural gas humidity control using a traveling wave in a waveguide is proposed. The investigations have shown that a comparative channel increased the measurement accuracy, as a two-channel system – in contrast to a single-channel – eliminates the instability of the value of the input signal supplied to the generator. The principle of operation of a natural gas humidity control device that contains an ultrahigh frequency generator, attenuators, waveguide tees, a waveguide section for comparison, temperature sensor and pressure switches for the comparative and measuring channels, a measuring cuvette, amplifier, microprocessor, and display unit is described. A mathematical model of a natural gas humidity control device, which takes into account the values of the dielectric permittivity of the measuring gas and reference channels and contains correction factors for temperature, the use of which increases the accuracy of humidity measurement, is proposed. The lower and upper calibration points of the natural gas humidity control device are defined. The influence of correction factors for the temperature at the measurement error of the humidity is analyzed.Ostatnio przyrządy do pomiaru wilgotności oparte na metodzie mikrofalowej są szeroko stosowane ze względu na ich prostą, niezawodną konstrukcję i wysoką dokładność pomiaru. W pracy wykorzystano ulepszoną mikrofalową metodę falowodów mikrofalowych do pomiaru wilgotności gazu ziemnego, która, w przeciwieństwie do znanych, sugeruje zastosowanie fali podróżnej w falowodzie. Jednocześnie podczas interakcji z falami mikrofalowymi zmieniają się właściwości dielektryczne gazów, zmiana ta jest rejestrowana. W oparciu o ulepszoną mikrofalową metodę pomiaru wilgotności zaproponowano sposób pomiaru kontroli wilgotności gazu ziemnego za pomocą fali przemieszczającej się w falowodzie. Przeprowadzono badania, które wykazały, że obecność kanału porównawczego umożliwiła zwiększenie dokładności pomiaru, ponieważ system dwukanałowy,w przeciwieństwie do systemu jednokanałowego, eliminuje niestabilność wartości sygnału wejściowego dostarczanego przez generator. Opisano zasadę działania przyrządu pomiarowego do pomiaru wilgotności gazu ziemnego, który zawiera generator mikrofalowy, tłumiki, trójniki falowodu, sekcję falowodu do porównania, czujnik temperatury i ciśnienia, przełączniki kanałów porównawczych i pomiarowych, celę pomiarową, wzmacniacz, procesor, urządzenie wskaźnikowe. Zaproponowano model matematyczny środków pomiaru kontroli wilgotności gazu ziemnego, który uwzględnia wartość stałej dielektrycznej gazu kanałów pomiarowych i odniesienia oraz zawiera współczynniki korekcji temperatury, których zastosowanie poprawia dokładność pomiaru wilgotności. Określane są dolne i górne punkty kalibracji zakresu pomiarowego wilgotności gazu ziemnego. Analizowany jest wpływ współczynników korekcji temperatury na błąd pomiaru wilgotności

Predictors of Resistance Hypertension and Achievement of Target Blood Pressure Levels in Patients with Resistant Hypertension

Uncontrolled arterial pressure is associated with a fourfold increase in the risk of developing cardiovascular events compared to patients with hypertension who have reached the target blood pressure level. The aim of this study is to evaluate the characteristics of patients with resistant arterial hypertension undergoing inpatient treatment at the Department of Symptomatic Hypertension and assess the prevalence of true resistant hypertension in a cohort of patients who take 3 and more antihypertensive agents, the clinical predictors of resistant hypertension. The study included 1146 patients with resistant AH who received 3 or more antihypertensive drugs with the level of office blood pressure at admission ≥140/90 mm Hg. Patients were followed by the next examinations: body height and body measurements, office blood pressure, echocardiography, sleep apnea determination, blood biochemical analysis, determination of levels of TTH, T3, T4, blood renin, blood aldosterone, metanephrine urine, and cortisol. Our data showed that 31% of patients who received 3 or more antihypertensive drugs had true resistant hypertension. Fixed combinations were taken by 71.9% of patients. We have found which factors were significantly associated with the treatment regimen with ≥3 or 4 drugs. Also we have demonstrated predictors for blood pressure reduction

High-Content Assays for Hepatotoxicity Using Induced Pluripotent Stem Cell–Derived Cells

Development of predictive in vitro assays for early toxicity evaluation is extremely important for improving the drug development process and reducing drug attrition rates during clinical development. High-content imaging-based in vitro toxicity assays are emerging as efficient tools for safety and efficacy testing to improve drug development efficiency. In this report we have used an induced pluripotent stem cell (iPSC)–derived hepatocyte cell model having a primary tissue-like phenotype, unlimited availability, and the potential to compare cells from different individuals. We examined a number of assays and phenotypic markers and developed automated screening methods for assessing multiparameter readouts of general and mechanism-specific hepatotoxicity. Endpoints assessed were cell viability, nuclear shape, average and integrated cell area, mitochondrial membrane potential, phospholipid accumulation, cytoskeleton integrity, and apoptosis. We assayed compounds with known mechanisms of toxicity and also evaluated a diverse hepatotoxicity library of 240 compounds. We conclude that high-content automated screening assays using iPSC-derived hepatocytes are feasible, provide information about mechanisms of toxicity, and can facilitate the safety assessment of drugs and chemicals

Cell membrane array fabrication and assay technology

BACKGROUND: Microarray technology has been used extensively over the past 10 years for assessing gene expression, and has facilitated precise genetic profiling of everything from tumors to small molecule drugs. By contrast, arraying cell membranes in a manner which preserves their ability to mediate biochemical processes has been considerably more difficult. RESULTS: In this article, we describe a novel technology for generating cell membrane microarrays for performing high throughput biology. Our robotically-arrayed supported membranes are physiologically fluid, a critical property which differentiates this technology from other previous membrane systems and makes it useful for studying cellular processes on an industrialized scale. Membrane array elements consist of a solid substrate, above which resides a fluid supported lipid bilayer containing biologically-active molecules of interest. Incorporation of transmembrane proteins into the arrayed membranes enables the study of ligand/receptor binding, as well as interactions with live intact cells. The fluidity of these molecules in the planar lipid bilayer facilitates dimerization and other higher order interactions necessary for biological signaling events. In order to demonstrate the utility of our fluid membrane array technology to ligand/receptor studies, we investigated the multivalent binding of the cholera toxin B-subunit (CTB) to the membrane ganglioside GM(1). We have also displayed a number of bona fide drug targets, including bacterial endotoxin (also referred to as lipopolysaccharide (LPS)) and membrane proteins important in T cell activation. CONCLUSION: We have demonstrated the applicability of our fluid cell membrane array technology to both academic research applications and industrial drug discovery. Our technology facilitates the study of ligand/receptor interactions and cell-cell signaling, providing rich qualitative and quantitative information

Assessment of beating parameters in human induced pluripotent stem cells enables quantitative in vitro screening for cardiotoxicity

Human induced pluripotent stem cell (iPSC)-derived cardiomyocytes show promise for screening during early drug development. Here, we tested a hypothesis that in vitro assessment of multiple cardiomyocyte physiological parameters enables predictive and mechanistically-interpretable evaluation of cardiotoxicity in a high-throughput format. Human iPSC-derived cardiomyocytes were exposed for 30 minutes or 24 hours to 131 drugs, positive (107) and negative (24) for in vivo cardiotoxicity, in up to 6 concentrations (3 nM to 30 μM) in 384-well plates. Fast kinetic imaging was used to monitor changes in cardiomyocyte function using intracellular Ca2+ flux readouts synchronous with beating, and cell viability. A number of physiological parameters of cardiomyocyte beating, such as beat rate, peak shape (amplitude, width, raise, decay, etc.) and regularity were collected using automated data analysis. Concentration-response profiles were evaluated using logistic modeling to derive a benchmark concentration (BMC) point-of-departure value, based on one standard deviation departure from the estimated baseline in vehicle (0.3% dimethylsulfoxide)-treated cells. BMC values were used for cardiotoxicity classification and ranking of compounds. Beat rate and several peak shape parameters were found to be good predictors, while cell viability had poor classification accuracy. In addition, we applied the Toxicological Prioritization Index approach to integrate and display data across many collected parameters, to derive “cardiosafety” ranking of tested compounds. Multi-parameter screening of beating profiles allows for cardiotoxicity risk assessment and identification of specific patterns defining mechanism-specific effects. The data and analysis methods may be used widely for compound screening and early safety evaluation in the drug development process

Supplemental Figures and Tables

Supplemental figures and tables for neurospheroid articles. Shows examples of primary data, images, also provides tables with correlation coefficient

Assay optimization data_

Assay optimization data_ the table contains optimization data for selected compounds and control