In Vitro Effects of Fentanyl on Aortic Viscoelasticity in a Rat Model of Melatonin Deficiency.

Melatonin influences arterial biomechanics, and its absence could cause remodeling of the arterial wall, leading to increased stiffness. Direct effects of fentanyl on the aortic wall have also been observed previously. This study aimed to evaluate in vitro the effects of fentanyl on aortic viscoelasticity in a rat model of melatonin deficiency and to test the hypothesis that melatonin deficiency leads to increased arterial wall stiffness. The viscoelasticity was estimated in strip preparations from pinealectomized (pin, melatonin deficiency) and sham-operated (sham, normal melatonin) adult rats using the forced oscillations method. In the untreated aortic wall pin, the viscoelasticity was not significantly altered. However, combined with 10-9 M fentanyl, the pin increased the natural frequency (f0) and modulus of elasticity (E') compared to the sham-operated. Independently, fentanyl treatment decreased f0 and E' compared separately to untreated sham and pin preparations. The effects of fentanyl were neither dose-dependent nor affected by naloxone, suggesting a non-opioid mechanism. Furthermore, an independent effect of naloxone was also detected in the normal rat aortic wall, resulting in reduced E'. Additional studies are needed that may improve the clinical decisions for pain management and anesthesia for certain patients with co-occurring chronic low levels of blood plasma melatonin and some diseases.

Orally Administered Probiotics in the Prevention of Chemotherapy (± Radiotherapy)-Induced Gastrointestinal Toxicity: A Systematic Review With Meta-Analysis of Randomized Trials.

BACKGROUND: Chemoradiotherapy-induced gastrointestinal toxicity may lead to a significant impairment of the oncological patient's quality of life, as well as to reduced adherence to the treatment, which may have a negative impact on survival and mortality rates. OBJECTIVE: The aim of this review was to investigate whether oral probiotic administration prevents chemotherapy (± radiotherapy)-induced gastrointestinal toxicity, particularly diarrhea. METHODS: We searched the MEDLINE, Web of Science, and SCOPUS databases for randomized controlled trials in English published between 1990 and 2020. We conducted statistical data analyses expressing the treatment effect size as a risk ratio (RR) together with a 95% confidence interval (CI). Implications are based on trials rated as having a low risk of bias (RoB). RESULTS: We included 8 trials (n = 697 participants), from which 3 studies rated as low RoB contained primary endpoint data; the risk of developing grade 3/4 diarrhea in patients receiving probiotics was reduced by 78% compared to the control group (RR = 0.22 [95% CI 0.05-1.08]; P = .06; n = 114 participants). Probiotics showed preventive effects in patients treated with chemotherapy alone (RR = 0.34 [0.12-0.94]; P = .04, n = 121 participants) and in patients with colorectal cancer (RR = 0.56 [0.34-0.92]; P = .02; n = 208 participants). The reduction in the incidence of overall diarrhea was not significant. CONCLUSIONS: Probiotics failed to prove a preventive effect of statistical significance against the development of severe and overall diarrhea in cancer patients treated with chemotherapy (± radiotherapy). However, we cannot rule out that the effects of probiotics are clinically relevant, especially in certain subgroups of patients. This needs to be clarified in further well-performed studies.

Bioequivalence of macitentan and tadalafil given as fixed-dose combination or single-component tablets in healthy subjects.

AIMS: To demonstrate the bioequivalence of macitentan/tadalafil fixed-dose combination (FDC) tablets with single-component tablets of macitentan and tadalafil in healthy subjects. METHODS: Studies AC-077-101 and AC-077-103 were single-centre, open-label, single-dose, 2-period, randomized, crossover Phase 1 studies conducted in healthy subjects. Two FDCs were investigated: FDC-1 and FDC-2 in Study AC-077-101 and FDC-2 in Study AC-077-103. Both FDCs contained 10 mg/40 mg of macitentan/tadalafil and differed in excipients and coating materials used. In both studies, pharmacokinetic sampling over 216 hours was conducted, and pharmacokinetic parameters were derived using noncompartmental methods. RESULTS: Bioequivalence of macitentan, its active metabolite ACT-132577, and tadalafil was established for FDC-2 in both studies AC-077-101 and AC-077-103 in which tadalafil as a single component was sourced from the USA and EU, respectively, to fulfil regional regulatory requirements. The area under the plasma concentration-time curve and maximum plasma concentration with 90% confidence intervals of all components were entirely within the bioequivalence limits (0.8000-1.2500). No subject died and no serious adverse events were reported in either studies. CONCLUSION: The FDC-2 tablet containing 10 mg/40 mg of macitentan/tadalafil was bioequivalent to the free combination of 10 mg macitentan and 40 mg tadalafil (both US and EU sourced). Macitentan and tadalafil were well tolerated when administered as FDC or as a free combination.

Investigation of next-generation sequencing data of Klebsiella pneumoniae using web-based tools.

PURPOSE: Rapid identification and characterization of multidrug-resistant Klebsiella pneumoniae strains is necessary due to the increasing frequency of severe infections in patients. The decreasing cost of next-generation sequencing enables us to obtain a comprehensive overview of genetic information in one step. The aim of this study is to demonstrate and evaluate the utility and scope of the application of web-based databases to next-generation sequenced (NGS) data. METHODOLOGY: The whole genomes of 11 clinical Klebsiella pneumoniae isolates were sequenced using Illumina MiSeq. Selected web-based tools were used to identify a variety of genetic characteristics, such as acquired antimicrobial resistance genes, multilocus sequence types, plasmid replicons, and identify virulence factors, such as virulence genes, cps clusters, urease-nickel clusters and efflux systems. RESULTS: Using web-based tools hosted by the Center for Genomic Epidemiology, we detected resistance to 8 main antimicrobial groups with at least 11 acquired resistance genes. The isolates were divided into eight sequence types (ST11, 23, 37, 323, 433, 495 and 562, and a new one, ST1646). All of the isolates carried replicons of large plasmids. Capsular types, virulence factors and genes coding AcrAB and OqxAB efflux pumps were detected using BIGSdb-Kp, whereas the selected virulence genes, identified in almost all of the isolates, were detected using CLC Genomic Workbench software. CONCLUSION: Applying appropriate web-based online tools to NGS data enables the rapid extraction of comprehensive information that can be used for more efficient diagnosis and treatment of patients, while data processing is free of charge, easy and time-efficient.

Validation of Minim typing for fast and accurate discrimination of extended-spectrum, beta-lactamase-producing Klebsiella pneumoniae isolates in tertiary care hospital.

Minim typing is derived from the multi-locus sequence typing (MLST). It targets the same genes, but sequencing is replaced by high resolution melt analysis. Typing can be performed by analysing six loci (6MelT), four loci (4MelT) or using data from four loci plus sequencing the tonB gene (HybridMelT). The aim of this study was to evaluate Minim typing to discriminate extended-spectrum beta-lactamase producing Klebsiella pneumoniae (ESBL-KLPN) isolates at our hospital. In total, 380 isolates were analyzed. The obtained alleles were assigned according to both the 6MelT and 4MelT typing scheme. In 97 isolates, the tonB gene was sequenced to enable HybridMelT typing. We found that the presented method is suitable to quickly monitor isolates of ESBL-KLPN; results are obtained in less than 2 hours and at a lower cost than MLST. We identified a local ESBL-KLPN outbreak and a comparison of colonizing and invasive isolates revealed a long term colonization of patients with the same strain.

Noninvasive determination of arterial elasticity and blood pressure. Part II: elastogram and blood pressure determination.

OBJECTIVE: The oscillometric method is used in the medical practice for measurement of arterial blood pressure and, rarely, for estimation of arterial elasticity. In the previous paper of this series, the relations between arterial volume pulsations and volume-to-pressure curve (elastogram) were examined resolving the problem for evaluation of arterial volume pulsations from known elastogram and systolic (ps)/diastolic (pd) blood pressure. Some features were found that are considered to be elastogram attributes. The aim of the present work is to resolve the inverse problem - graphical reconstruction of the elastogram from oscillometric data and determination of blood pressure. PARTICIPANTS AND METHODS: The elastograms of an idealized arterial model as well as of experimental oscillometric records (five men, five women) are processed graphically. RESULTS: The method for reconstruction is developed with the idealized volume pulsations of the arterial model, establishing full correspondence of the elastogram fixed in the model with those determined here. The accuracy of this reconstruction is assessed: a pulse pressure variability of 12% leads to an ~2-9% error of the reconstructed elastogram. Thereafter, experimental elastograms are reconstructed graphically, and the correct pulse pressure and blood pressure are determined. The experimentally determined blood pressure is statistically compared with that simultaneously auscultatory measured. Satisfactory correspondence between values of ps/pd is found. A method of objective comparison between elastograms after normalization is suggested. CONCLUSION: A novel graphical, nonempirical method for a noninvasive reconstruction of the elastogram and determination of blood pressure is presented. The method can be applied easily in automated blood pressure measurement devices.

Noninvasive determination of arterial elasticity and blood pressure. Part I: arterial volume pulsations and elastogram.

OBJECTIVE: The oscillometric method is widely used for noninvasive blood pressure measurement and rarely for assessment of arterial elasticity (volume-to-pressure curve/elastogram) in the systolic (ps)/diastolic (pd) pressure interval. In a wide range of physiologically normal pressures, the elastogram is obtained mostly invasively. In the present study (in two papers), the potential of the oscillometric method for a noninvasive estimation of complete elastogram and blood pressure is examined. The aim of the present first paper is to study the relations between oscillometric arterial volume pulsations and elastogram. METHODS: The interactions between transmural pressure, arterial volume pulsations, and elastogram are examined graphically on an idealized model of artery, thereafter proved on experimental oscillometric records (10 patients). RESULTS: A precise determination of the transmural pressure pulsations at descendent external pressure (as in oscillometry) is presented. The basic relationships between these pulsations and arterial volume pulsations in three specific pressure zones are clarified, which allow a strict dependence to be obtained between the arterial volume pulsations envelope and elastogram. The specific cut-off of transmural pressure and arterial volume pulsations, coincidence of the arterial volume pulsations envelope with the elastogram in the ps/pd interval, and two discontinuities (jumps) of the arterial volume pulsations envelope, at ps and pd, were found. The same was observed by noninvasive arterial oscillometry in humans, with good correspondence to the model excluding narrow intervals around ps and pd, in which the jumps are not clearly distinguishable. CONCLUSION: These specific features are assumed as elastogram attributes in the second paper, in which a noninvasive determination of both elastogram and blood pressure is carried out.

Viscoelastic characteristics of in vitro vital and devitalized rat aorta and human arterial prostheses.

The arterial wall viscoelasticity plays an essential role in the vascular responsiveness to vasoactive drugs or pathologies. The aim of this investigation was to derive and compare resonance curve (RC), natural frequency (f(0)), dynamic modulus of elasticity (E'), and coefficient of viscosity (beta) of (i) vital and devitalized preparations of rat thoracic and abdominal aorta, (ii) human arterial prostheses, and to study the histomorphology of vital and devitalized rat aorta. The method of low frequency forced oscillations was employed. RC of vital preparations showed a hardening type of elasticity whereas in devitalized preparations it was of softening type. E' increased nonlinearly, f(0) decreased and beta increased linearly with equivalent intraluminal pressure (p(eqi)). Distensibility of abdominal aorta was lower than thoracic aorta. Distensibility decreased with increasing p(eqi). E', f(0), and beta increased significantly after devitalization. It was suggested that postmortem viscoelastic characteristics should not be used directly to specify the vital arteries viscoelasticity. RC of human prostheses showed a softening type of elasticity. Arterial prostheses have low circumferential distensibility with E'-values higher than reported in the literature for human arteries. The method of forced oscillations could be employed for studying the arterial wall biomechanics and viscoelasticity of arterial prostheses.

A device for biomechanical investigations of the viscoelastic characteristics of vital and artificial arterial segments.

The viscoelastic characteristics--modulus of elasticity, natural frequency, coefficient of viscosity and low-frequency resonance curve can be used as diagnostic indicators, at assessment of the direct effect of vasoactive drugs, and at selection of natural and artificial arterial prostheses. The aim of this work is a device for measurement of the viscoelastic characteristics of cylindrical segments of arteries in vitro and of arterial prostheses to be developed. The cylindrical segment is subjected to low frequency sinusoidal pulsations of the inner pressure. On the basis of the amplitude of the response oscillations of the wall, measured using the volume pulsations of the segment, the resonance curve is built so that the dynamic characteristics--modulus of elasticity, natural frequency, and coefficient of viscosity can be calculated. The living specimens are perfused with nutrition solution for keeping the quasi-physiological conditions. In the same way, cylindrical segments of rubber and artificial human prostheses were investigated. The sensitivity and the accuracy of the device are given. The construction permits to keep the vitality of native animal's specimens when the measurements are carried out.