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Aims: Whether and when glomerular filtration rate (GFR) in preterms catches up with term peers is unknown. This study aims to develop a GFR maturation model for (pre)term-born individuals from birth to 18 years of age. Secondarily, the function is applied to data of different renally excreted drugs. Methods: We combined published inulin clearance values and serum creatinine (Scr) concentrations in (pre)term born individuals throughout childhood. Inulin clearance was assumed to be equal to GFR, and Scr to reflect creatinine synthesis rate/GFR. We developed a GFR function consisting of GFRbirth (GFR at birth), and an Emax model dependent on PNA (with GFRmax, PNA50 (PNA at which half of GFR max is reached) and Hill coefficient). The final GFR model was applied to predict gentamicin, tobramycin and vancomycin concentrations. Result: In the GFR model, GFRbirth varied with birthweight linearly while in the PNA-based Emax equation, GA was the best covariate for PNA50, and current weight for GFRmax. The final model showed that for a child born at 26 weeks GA, absolute GFR is 18%, 63%, 80%, 92% and 96% of the GFR of a child born at 40 weeks GA at 1 month, 6 months, 1 year, 3 years and 12 years, respectively. PopPK models with the GFR maturation equations predicted concentrations of renally cleared antibiotics across (pre)term-born neonates until 18 years well. Conclusions: GFR of preterm individuals catches up with term peers at around three years of age, implying reduced dosages of renally cleared drugs should be considered below this age. [ABSTRACT FROM AUTHOR]

Purpose: Despite being off-label, intravenous paracetamol (PCM) is increasingly used to control mild-to-moderate pain in preterm neonates. Here we aim to quantify the maturation of paracetamol elimination pathways in preterm neonates born below 32 weeks of gestation. Methods: Datasets after single dose (rich data) or multiple doses (sparse data) of intravenous PCM dose (median (range)) 9 (3–25) mg/kg were pooled, containing 534 plasma and 44 urine samples of PCM and metabolites (PCM–glucuronide, PCM–sulfate, PCM–cysteine, and PCM–mercapturate) from 143 preterm neonates (gestational age 27.7 (24.0–31.9) weeks, birthweight 985 (462–1,925) g, postnatal age (PNA) 5 (0–30) days, current weight 1,012 (462–1,959) g. Population pharmacokinetic analysis was performed using NONMEM® 7.4. Results: For a typical preterm neonate (birthweight 985 g; PNA 5 days), PCM clearance was 0.137 L/h, with glucuronidation, sulfation, oxidation and unchanged renal clearance accounting for 5.3%, 73.7%, 16.3% and 4.6%, respectively. Maturational changes in total PCM clearance and its elimination pathways were best described by birthweight and PNA. Between 500–1,500 g birthweight, total PCM clearance increases by 169%, with glucuronidation, sulfation and oxidation clearance increasing by 347%, 164% and 164%. From 1–30 days PNA for 985 g birthweight neonate, total PCM clearance increases by 167%, with clearance via glucuronidation and oxidation increasing by 551%, and sulfation by 69%. Conclusion: Birthweight and PNA are the most important predictors for maturational changes in paracetamol clearance and its glucuronidation, sulfation and oxidation. As a result, dosing based on bodyweight alone will not lead to consistent paracetamol concentrations among preterm neonates. [ABSTRACT FROM AUTHOR]

Background and Objective: Fentanyl is an opioid commonly used to prevent and treat severe pain in neonates; however, its use is off label and mostly based on bodyweight. Given the limited pharmacokinetic information across the entire neonatal age range, we characterized the pharmacokinetics of fentanyl across preterm and term neonates to individualize dosing. Methods: We pooled data from two previous studies on 164 newborns with a median gestational age of 29.0 weeks (range 23.9–42.3), birthweight of 1055 g (range 390–4245), and postnatal age (PNA) of 1 day (range 0–68). In total, 673 plasma samples upon bolus dosing (69 patients; median dose 2.1 μg/kg, median 2 boluses per patient) or continuous infusions (95 patients; median dose 1.1 μg/kg/h for 30 h) with and without boluses were used for population pharmacokinetic modeling in NONMEM® 7.4. Results: Clearance in neonates with birthweight of 2000 and 3000 g was 2.8- and 5.0-fold the clearance in a neonate with birthweight of 1000 g, respectively. Fentanyl clearance at PNA of 7, 14, and 21 days was 2.7-fold, 3.8-fold, and 4.6-fold the clearance at 1 day, respectively. Bodyweight-based dosing resulted in large differences in fentanyl concentrations. Depending on PNA and birthweight, fentanyl concentrations increased slowly after the start of therapy for both intermittent boluses and continuous infusion and reached a maximum concentration at 12–48 h. Conclusions: As both prenatal and postnatal maturation are important for fentanyl exposure, we propose a birthweight- and PNA-based dosage regimen. To provide rapid analgesia in the first 24 h of treatment, additional loading doses need to be considered. [ABSTRACT FROM AUTHOR]

A simple, rapid and sensitive HPLC-MS/MS method for simultaneous determination of 4 of amino acids, guanidinoacetic acid, S-adenosylmethionine and S-adenosylhomocysteine in human plasma was developed and validated. The method requires no tedious sample preparation, derivatization reagents or ion-pairing reagents. Samples were prepared by combining plasma with a chilled mixture of acetonitrile (ACN) and water, followed by centrifugation and diluting the supernatant with 2 volumes of water. Analytes were detected with multiple reaction monitoring using a positive scan mode with electrospray ionization (ESI). In the assay, all the analytes showed good linearity over the investigated concentration range (r > 0.99). The accuracy expressed in relative error (RE) was between −5.0% and 13.2%, and the precision expressed in coefficient of variation (CV) ranged from 0.6% to 14.7%. In the two spiked levels (low and high), the averaged recoveries of analytes were between 45.0% and 110.9% and the recovery of internal standard was 92.0%. This method was successfully applied to studying the concentration changes of endogenous creatine (Cr) synthesis precursors in the plasma of children with viral myocarditis after intravenous administration of phosphocreatine (PCr). • A HPLC-MS/MS method was developed for determination of the endogenous creatine biosynthesis precursors in human plasma. • The method requires no tedious sample preparation, derivatization reagents or ion-pairing reagents. • This method was successfully applied to study the endogenous creatine synthesis of children with viral myocarditis. [ABSTRACT FROM AUTHOR]

Omono River virus (OMRV) is a newly reported, unclassified RNA virus in the family Totiviridae, which infects mosquitoes and bats. In this study, we report the isolation of an OMRV strain SD76 from Culex tritaeniorhynchus captured in Jinan city, China. The cytopathic effect was characterized by cell fusion on C6/36 cell line. Its complete genome was 7611 nucleotides in length, with 71.4–90.4% similarities with other OMRV strains. Phylogenetic analysis based on complete genomes showed all OMRV-like strains can be divided into 3 groups with between-group distances ranging from 0.254 to 0.293. These results revealed that the OMRV isolate had high genetic diversity with those identified previously, and enriched the genetic information of family Totiviridae. [ABSTRACT FROM AUTHOR]

• Multi-layer core-shell structure was fabricated without any template. • Ag was modified in situ by photochemical deposition to improve stability. • S-scheme and SPR effect endued heterojunction with an excellent redox capacity. • Reactive species trapping was conducted to ensure the dominant species. • Introducing oxygen during catalytic process can augment degradation efficiency. Constructing an efficient photocatalyst to accelerate charge separation with strong redox capacity is in pursuit all the way. Herein, a novel heterojunction was achieved for efficient organic degradation, which took advantages of S-scheme mechanism, metal surface plasma resonance (SPR) and unique morphology. The multi-layer core-shell structure can be regulated by aging time with template-free, and Ag nanoparticles were modified on the heterojunction by photochemical deposition in situ to facilitate electron transport and improve stability. S-scheme and SPR endues the heterojunction with broad light absorption, increased light utilization, efficient carrier separation, and strong redox capacity. An examination of reactive dynamics revealed that superoxide radicals and hydroxyl radicals are crucial for oxidative degradation. Introducing oxygen during the reaction process has been found to enhance the efficiency by 7 %. This article furnishes novel insights into a coordination of energy band engineering, structure regulation, as well as reaction process adjustment for facilitating photo-degradation reactions. [Display omitted] [ABSTRACT FROM AUTHOR]

Oridonin (ORI), the major pharmacological component extracted from a traditional Chinese medicine, possesses a beneficial effect on myocardial ischemia/reperfusion (I/R) injury. However, the underlying molecular mechanism by which ORI effects take place is not completely known. Thus, whether ORI works via downregulating oxidative stress and nod-like receptor protein-3 (NLRP3) inflammasome pathway was investigated in this study. Mice underwent surgery to induce myocardial I/R injury, and some were administered ORI (10 mg/kg/day) pretreatment, while others were not. The myocardial enzymes' levels, infarct area, and inflammatory injury were measured. The activation situation of oxidative stress and NLRP3 inflammasome was also detected. We found that ORI pretreatment significantly alleviated CK-MB and cTnI levels and infarct size induced by I/R. ORI mitigated the inflammatory injury by decreasing the pathological damage and lowering TNF-α, IL-1β, and IL-18 levels. Moreover, the SOD1 and eNOS levels were significantly increased by ORI, while MDA and iNOS levels were relatively decreased. The oxidative stress was reversed using ORI pretreatment. Importantly, NLRP3 inflammasome pathway was also inhibited by ORI, as reflected by the lower protein levels of NLRP3, caspase-1, and IL-1β. In conclusion, ORI alleviates myocardial injury induced by I/R via inhibiting the oxidative stress and NLRP3 inflammasome pathway. [ABSTRACT FROM AUTHOR]

Diabetes aggravates myocardial ischemia/reperfusion (I/R) injury (MI/RI). The association between high mobility group box 1 protein (HMGB1) and autophagy in diabetic MI/RI remains unknown. Therefore, we investigated whether inhibiting HMGB1 can regulate autophagy in diabetic mice (DM) after I/R injury. I/R models of C57BL/KsJ mice and db/db mice were established. Histological changes, infarct size (IS), HMGB1 protein, and autophagy-related proteins were detected after 24h of reperfusion. In DM treatment groups, anti-HMGB1 antibody (H-Ig) was injected via tail vein after reperfusion for 15min, and the above-mentioned experimental methods were performed at the end of reperfusion. Compared with the I/R group, the pathological myocardial damage and IS were significantly increased in the I/R (DM) group. Additionally, the levels of HMGB1, Beclin1, and LC3II/LC3I ratio were remarkably higher in the I/R (DM) group than those in the I/R group, while p62 level was lower. In the H-Ig (DM) group, injection of H-Ig significantly reduced the IS, as well as alleviated pathological myocardial damage. Moreover, Beclin1, LC3II/LC3I ratio, and p62 levels were notably reversed after this treatment. I/R-induced myocardium was aggravated by diabetes, which may be related to increased release of HMGB1 and activated autophagy. Inhibition of HMGB1 alleviates diabetic MIRI which was associated with reduced autophagy. • The first study showing the relationship between HMGB1 and over-activated autophagy in diabetic MIRI • The study observes reperfusion up to 24 h, ensuring that the effectiveness of inhibition of HMGB1 is retained. • The treatment node is selected after reperfusion, which is a feasible scheme for clinical needs. [ABSTRACT FROM AUTHOR]

Rheumatic heart disease (RHD) is an autoimmune disease caused by rheumatic fever following group A hemolytic streptococcal infection and primarily affects the mitral valve. RHD is currently a major global health problem. However, the exact pathological mechanisms associated with RHD-induced cardiac valve damage remain to be elucidated. The endothelial-mesenchymal transition (EndMT) serves a key role in a number of diseases with an important role in cardiac fibrosis and the activin/Smad2 and 3 signaling pathway is involved in regulating the EndMT. Nevertheless, there are no studies to date, to the best of the authors' knowledge, investigating the association between RHD and EndMT. Thus, the aim of the current study was to investigate the potential role of EndMT in cardiac valve damage and assess whether activin/Smad2 and 3 signaling was activated during RHD-induced valvular injury in a rat model of RHD induced by inactivated Group A streptococci and complete Freund's adjuvant. Inflammation and fibrosis were assessed by hematoxylin and eosin and Sirius red staining. Serum cytokine and rheumatoid factor levels were measured using ELISA kits. Expression levels of activin/Smad2 and 3 signaling pathway-related factors [activin A, Smad2, Smad3, phosphorylated (p-)Smad2 and p-Smad3], EndMT-related factors [lymphoid enhancer factor-1 (LEF-1), Snail1, TWIST, zinc finger E-box-binding homeobox (ZEB)1, ZEB2, α smooth muscle actin (α-SMA) and type I collagen α 1 (COL1A1)], apoptosis-related markers (BAX and cleaved caspase-3) and valvular inflammation markers (NF-κB and p-NF-κB) were detected using reverse transcription-quantitative PCR and western blot analyses. Compared with the control group, the degree of valvular inflammation and fibrosis, serum levels of IL-6, IL-17, TNF-α and expression of apoptosis-related markers (BAX and cleaved caspase-3) and valvular inflammation marker (p-NF-κB), activin/Smad2 and 3 signaling pathway-related factors (activin A, p-Smad2 and p-Smad3), EndMT-related factors (LEF-1, Snail1, TWIST, ZEB 1, ZEB2, α-SMA and COL1A1) were significantly increased in the RHD group. These results suggested that the activin/Smad2 and 3 signaling pathway was activated during the development of valvular damage caused by RHD and that the EndMT is involved in RHD-induced cardiac valve damage. [ABSTRACT FROM AUTHOR]