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Pregabalin (PGB) is widely used clinically; however, its pharmacokinetics (PK) has not been studied in pediatric patients with renal impairment (RI). To design optimized PGB regimens for pediatric patients with varying degrees of RI and predict exposure to PGB, physiologically based pharmacokinetic (PBPK) models of PGB were developed and verified, and its disposition was simulated in the healthy population and adults with RI. The simulated results from the PBPK models after single-dose and multi-dose administrations of PGB were consistent with the corresponding observed data based on the fold error values of less than 2. The area under curve ratios were 1.23 ± 0.06, 2.02 ± 0.10, 3.86 ± 0.21, and 9.92 ± 0.79 in pediatric patients with mild, moderate, severe, and end-stage RI, respectively. Based on the predictions for pediatric patients with moderate, severe, and end-stage RI, the maximum dose should not exceed 7, 3.5, and 1.4 mg/kg/day, respectively, among those weighing < 30 kg, and it should not exceed 5, 2.5, and 1 mg/kg/day, respectively, among those weighing > 30 kg. In conclusion, the developed PBPK model is a valuable tool for predicting PGB dosage for pediatric patients with RI. [ABSTRACT FROM AUTHOR]

Physiologically based pharmacokinetic (PBPK) modeling has unique advantages in investigating the pharmacokinetics of drugs in special populations. Our aim is to design optimized dosing regimens for ceftazidime in renally-impaired pediatric patients using PBPK modeling. Models for healthy and renally-impaired adults were developed, verified, and adapted for children to predict ceftazidime exposure in pediatric patients with varying degrees of renal impairment, capturing age- and weight-related pharmacokinetic changes. We derived a dosage-adjusted regimen for renally-impaired children based on pharmacokinetic data and evaluated the pharmacodynamics of ceftazidime. The PBPK models adequately predicted ceftazidime exposures in populations after single- and multi-dose administrations, with fold error values within 1.1 between simulated and observed data. In moderate, severe, and end-stage renally-impaired pediatric patients, the areas under the plasma concentration-time curves (AUCs) were 1.87-fold, 3.56-fold, and 6.19-fold higher, respectively, than in healthy children when treated with the same dose of 50 mg/kg. Pharmacodynamic verification indicated that the recommended doses of 28, 15, and 8 mg/kg administered three times daily (every 8 h) to pediatric patients with moderate, severe, and end-stage renal disease, respectively, were sufficient to attain the target of maintaining the free plasma concentration at or above minimum inhibitory concentration (MIC) during 70% of the dosing interval (70% fT > MIC: nearly 100% target attainment for susceptible MIC of 4 mg/L and >70% for intermediate MIC of 8 mg/L). Our PBPK model can be an effective tool to support dosing recommendations in pediatric patients with different degrees of renal impairment. [ABSTRACT FROM AUTHOR]

The insulin receptor (INSR) binds insulin to promote body growth and maintain normal blood glucose levels. While it is known that steroid hormones such as estrogen and 20- hydroxyecdysone counteract insulin function, the molecular mechanisms responsible for this attenuation remain unclear. In the present study, using the agricultural pest lepidopteran Helicoverpa armigera as a model, we proposed that the steroid hormone 20-hydroxyecdysone (20E) induces dephosphorylation of INSR to counteract insulin function. We observed high expression and phosphorylation of INSR during larval feeding stages that decreased during metamorphosis. Insulin upregulated INSR expression and phosphorylation, whereas 20E repressed INSR expression and induced INSR dephosphorylation in vivo. Protein tyrosine phosphatase 1B (PTP1B, encoded by Ptpn1) dephosphorylated INSR in vivo. PTEN (phosphatase and tensin homolog deleted on chromosome 10) was critical for 20E-induced INSR dephosphorylation by maintaining the transcription factor Forkhead box O (FoxO) in the nucleus, where FoxO promoted Ptpn1 expression and repressed Insr expression. Knockdown of Ptpn1 using RNA interference maintained INSR phosphorylation, increased 20E production, and accelerated pupation. RNA interference of Insr in larvae repressed larval growth, decreased 20E production, delayed pupation, and accumulated hemolymph glucose levels. Taken together, these results suggest that a high 20E titer counteracts the insulin pathway by dephosphorylating INSR to stop larval growth and accumulate glucose in the hemolymph. [ABSTRACT FROM AUTHOR]

Ticagrelor, a P2Y 12 receptor antagonist, has been highly recommended for use in acute coronary syndrome. The major active metabolite (AM) is similar to the parent drug, which exhibits antiplatelet activity. The inhibition of platelet aggregation (IPA) is used as an assay to demonstrate the anticoagulant efficacy of ticagrelor. In this study, we developed a physiologically based pharmacokinetic (PBPK) model to predict the pharmacokinetics of ticagrelor and its AM and combined this model with a pharmacodynamics model to reflect potential pharmacodynamic alterations in liver cirrhosis populations. The simulated results obtained using the PBPK model were validated by fold error values, which were all smaller than 2. Comparisons of exposure in different classifications of liver cirrhosis indicated that exposure to ticagrelor increased significantly with an increase in the degree of cirrhosis severity, whereas exposure to AM was decreased. The total concentration of ticagrelor and AM was related to the IPA included in the Sigmoid E max model. The PBPK model of ticagrelor and AM could predict the pharmacokinetics of all populations, and a combination of PD models was used to extrapolate for predicting unknown scenarios. Liver cirrhosis may result in prolonged IPA, depending on the severity degree of this disease. The combined PBPK model including IPA can reveal changes in pharmacokinetics and pharmacodynamics in populations affected by liver cirrhosis and indicate the risk potential. [ABSTRACT FROM AUTHOR]

Manganese (Mn)-intolerant ‘Sour pummelo’ ( Citrus grandis ) and Mn-tolerant ‘Xuegan’ ( Citrus sinensis ) seedlings were irrigated for 17 weeks with 2 (control) or 600 μM (Mn-toxicity or −excess) MnSO 4 . C. sinensis had higher Mn-tolerance than C. grandis , as indicated by the higher photosynthesis rates in Mn-excess C. sinensis leaves. Under Mn-toxicity, Mn levels were similar between C. sinensis and C. grandis roots, but lower in C. sinensis leaves than in C. grandis leaves. This might be responsible for C. sinensis Mn-tolerance. Using two-dimensional electrophoresis, we identified more differentially abundant proteins (DAPs) in Mn-excess C. grandis than in Mn-excess C . sinensis leaves, which agrees with the higher Mn levels in Mn-excess C. grandis leaves. DAPs were mainly related to carbohydrate and energy metabolism, stress response, and protein and amino acid metabolism. DAPs involved in the cytoskeleton and signal transduction were found only in Mn-excess C. grandis leaves. We isolated more photosynthesis-related proteins with decreased abundances in Mn-excess C. grandis leaves than in Mn-excess C. sinensis leaves, which might account for the larger decrease in photosynthesis rates in C. grandis leaves. The abundances of proteins involved in reactive oxygen species (ROS) scavenging and photorespiration were increased in Mn-excess C. grandis leaves, while only proteins involved in ROS detoxification were increased in Mn-excess C. sinensis leaves. This agrees with the increased requirement for dissipating the excess absorbed light energy, which was higher in Mn-excess C. grandis leaves than Mn-excess C. sinensis leaves because Mn-toxicity inhibited photosynthesis to a greater degree in C. grandis leaves. [ABSTRACT FROM AUTHOR]

Lignin and ash material balances of SO 2 -ethanol–water (AVAP®) fractionation of sugarcane (SC) straw were thoroughly studied at various conditions. Most of straw lignin and ash dissolve in the liquor and 40–80% of lignin is precipitated after ethanol removal as a pure (∼99%) and sulfur-lean (<2%) fraction. Most of the acid-soluble ash and its elements (Na, K, Fe, Al) as well as large portion of silica are removed from the fiber phase. Straw lignin behavior exhibited differences compared to wood lignin including high apparent content in fiber, higher degree of sulfonation of dissolved lignin, and dense char-like precipitate formation upon ethanol removal. Variation in fractionation conditions did not have significant effect on lignin properties, while post-sulfonation was capable of changing its form from char-like to colloidal precipitate. [ABSTRACT FROM AUTHOR]

The sulfur balance of SO 2 -ethanol-water (AVAP®) fractionation of sugarcane (SC) straw was investigated. Hydrogen sulfite and sulfite anions are nearly absent in the liquors, despite cations present in straw, whose effect is thus limited to neutralization of lignosulfonic acids decreasing the acidity. Higher degree of sulfonation was observed for dissolved straw lignin compared to wood lignin (0.8–0.9 vs. 0.25 S/C9). Sulfur dioxide amounts of 0.9–1.2, 4.1–4.3 and 44–49 g per o.d. kg straw were bound to pulp, precipitated lignin and lignosulfonic acid, respectively, while the rest of SO 2 was recovered by distillation from the spent fractionation suspensions. [ABSTRACT FROM AUTHOR]

Levetiracetam is currently being used to treat epilepsy in pregnant women. The plasma concentration of levetiracetam drops sharply during pregnancy, and the inability of pregnant women to maintain therapeutic concentrations can lead to seizures. This study aimed to predict the changes in fetal and maternal plasma exposure to levetiracetam during pregnancy and provide advice on dose adjustment. The physiology-based pharmacokinetics (PBPK) model was developed using PK-Sim and Mobi software, and validated following comparison of the observed plasma concentration and pharmacokinetic parameters. The levetiracetam PBPK model for mother and the fetus at various stages of pregnancy was successfully established and verified. Predictions indicated that the area under the steady-state concentration-time curve for levetiracetam decreased to 83, 62, and 67% of baseline values in the first, second, and third trimesters, respectively. Based on PBPK predictions, the recommended dose of levetiracetam is 1.2, 1.6, and 1.5 times the baseline dose in the first, second, and third trimesters, respectively, not exceeding 4000 mg/day in the third trimester due to fetal safety. The levetiracetam PBPK model for pregnancy was successfully developed and validated, and could provide alternative levetiracetam dosing regimens across the stages of pregnancy. [Display omitted] [ABSTRACT FROM AUTHOR]

Kinetics of SO 2 –ethanol–water (AVAP®) fractionation was determined for sugarcane (SC) straw in terms of pulp composition (non-carbohydrate components, cellulose, hemicelluloses) and properties (kappa number, pulp intrinsic viscosity in CED and cellulose degree of polymerization). Effect of temperature (135–165 °C) and time (18–118 min) was studied at fixed liquor composition (SO 2 /ethanol/water = 12:22.5:65.5, w/w) and a liquor-to-solid ratio (4 L kg −1 ). Interpretation is given in terms of major fractionation reactions, removal of non-carbohydrate components and xylan, as well as acid hydrolysis of cellulose, and is compared to other lignocellulosic substrates (beech, spruce and wheat straw). Overall, SO 2 –ethanol–water process efficiently fractionates SC straw by separating cellulose from both non-carbohydrate components and xylan while reducing cellulose DP. [ABSTRACT FROM AUTHOR]

In this paper, a direct laser deposition (DLD) process was used to print ASTM A131 EH36 high strength low alloy steel samples in four different orientations, namely, horizontal 0° (XY_0°) & 45° (XY_45°) and vertical 90° (XZ_90°) & 45° (XZ_45°), with an EH36 steel powder. The microstructures, mechanical properties and fracture behavior of the printed materials, were evaluated in detail. Tensile, charpy impact and fatigue tests were conducted to measure the mechanical properties of the materials. The results showed that all the EH36 steel samples printed in the four orientations satisfied the ASTM standards for the tensile and charpy impact properties of EH36 steel. The microstructures of the EH36 steel samples and the thermal cycles encountered in the different build orientations could be tuned by controlling the printing process parameters and scanning method. The microstructure was closely correlated with the mechanical properties of the built samples. The fatigue fracture mechanism of the printed EH36 steel samples was also proposed. Additive manufacturing of near net shape coupons along 4 orientations using EH36 steel powder. [Display omitted] • A131 EH36 steel samples were printed in different orientations through LAAM process. • The tensile, charpy impact and fatigue properties of the samples were evaluated. • The microstructure and mechanical properties of the samples were closely correlated to in-process scanning methods. • The fatigue failure mechanism of the LAAMed EH36 steel was reported for the first time. [ABSTRACT FROM AUTHOR]

• Substrate stiffness influences the osteogenesis of SMCs. • Transforming growth factor-β1 involves in the osteogenesis of SMCs. • SMCs on the substrate of intermediate stiffness show higher osteogenesis level. Vascular stiffening occurs with advanced age and under pathological conditions such as vascular calcification, during which the osteogenesis of smooth muscle cells (SMCs) plays a key role. However, whether the stiffness of cellular microenvironment influences osteogenic responses in vascular SMCs is not well understood. Here, we cultured SMCs on the poly(dimethylsiloxane) (PDMS) substrates with varying stiffness from 0.363 to 2.327 MPa. The cell osteogenic transdifferentiation was induced by β-glycerophosphate. Our findings demonstrated that the extent of osteogenesis in SMCs varied with the substrate stiffness. On three substrate stiffness, cells on the intermediate one (0.909 MPa) showed the highest extent of the osteogenesis based on the expression of osteogenic markers and calcium deposition. Transforming growth factor-β1 and autophagy were involved in this stiffness-dependent process. This work highlights the importance of substrate stiffness to the osteogenesis of vascular SMCs, giving new scientific information for understanding of SMCs-mediated vascular calcification and designing of vascular implants. [ABSTRACT FROM AUTHOR]

Ertapenem is a widely used antibiotic; however, its pharmacokinetics has not been fully evaluated in children with renal impairment. A physiologically based pharmacokinetic (PBPK) model of ertapenem was established and validated to simulate its disposition in the healthy population and adults with renal impairment, as well as to predict the exposure in pediatric patients with renal impairment. The simulated PBPK modeling results and the observed data of ertapenem after intravenous administration of various regimens were consistent according to the fold error values of less than 2. Furthermore, %T > MIC of ertapenem was evaluated using the PBPK model. The C max was not significantly changed in pediatric patients with renal impairment compared to healthy children. However, the AUC was 1.42-fold, 1.84-fold, 2.37-fold, and 3.52-fold higher in mild, moderate, severe renal impairment, and end-stage renal disease, respectively, than that in healthy children and the doses of ertapenem were reduced to 13 mg/kg b.i.d, 9 mg/kg b.i.d, 6 mg/kg b.i.d, and 5 mg/kg b.i.d, respectively. The probability of achieving 40%T > MIC (MIC ≤ 4 μg/mL) was nearly 100% throughout the recommended dosing interval. In conclusion, our model can be used as a tool to generate better predictions for the most effective ertapenem dosing in pediatric patients. [ABSTRACT FROM AUTHOR]

First, we performed Western blot assay to measure the expression of GLI1 and p-Akt protein in GC tissue and para-carcinoma tissue. As shown by the IHC assay, GLI1 protein was overexpressed in GC tissue relative to para-carcinoma tissue, which was consistent with the results observed for p-Akt protein (Fig. Given our considerable analysis of GLI1 expression and prognosis of GC patients and the results of immunohistochemical testing of GC tissue, we find ourselves unconvinced by the conclusions drawn by Yizhou Yao et al. [[1]]. [Extracted from the article]

Background Here, we compare the angiographic characteristics of hemorrhagic and nonhemorrhagic hemispheres within the same adult patient with moyamoya disease (MMD) and identify the possible risk factors for initial and recurrent hemorrhage during the long-term follow-up period. Methods We retrospectively collected and analyzed the clinical and angiographic data of 145 consecutive adults with hemorrhagic MMD between 2004 and 2011. Separate angiographic characteristics of the hemorrhagic and nonhemorrhagic hemispheres were analyzed based on digital subtraction angiography. Multivariate logistic regression analysis was used to study the risk factors related to initial hemorrhage. In addition, clinical follow-up for at least 5 years was obtained in all the 145 patients. Cox regression analysis was used to determine the predictors for the subsequent recurrent hemorrhagic strokes. Results With regard to the 145 consecutive patients in our cohort, multivariate analysis indicated that the dilation grade of anterior choroidal artery (odds ratio [OR], 2.449; 95% confidence interval [CI], 1.617–3.862), the dilation grade of the posterior communicating artery (PComA) (OR, 1.491; 95% CI, 1.071–2.075), and the involvement of the posterior cerebral artery (OR, 4.623; 95% CI, 1.273–16.792) were significantly associated with initial hemorrhage. After a median follow-up of 6.33 ± 1.81 years, 20 of the 145 patients (13.8%) developed 22 recurrent episodes of hemorrhage. No significant correlation was found between rebleeding and the above significant factors associated with the initial hemorrhage. Conclusions Compared with the nonhemorrhagic hemispheres, hemorrhagic hemispheres are more prone to recurrent hemorrhage. Our case-control study showed the dilation of the anterior choroidal artery or posterior communicating artery, as well as the involvement of the posterior cerebral artery, is associated with the initial hemorrhage of MMD, but not for the episode of recurrent hemorrhage. Longer and more detailed clinical and angiographic follow-up are still needed to delineate the specific mechanism underlying the recurrent hemorrhage in hemorrhagic MMD. [ABSTRACT FROM AUTHOR]

Background Moyamoya disease (MMD) in children was rarely associated with intracranial aneurysms. The purpose of this study was to report the clinical characteristics and long-term surgical outcomes of pediatric intracranial aneurysms accompanied with MMD. Methods Between October 2002 and October 2013, our department treated 9 pediatric MMD patients (aged ≤17 years) with intracranial aneurysms. Clinical and angiographic features, treatment selection, as well as follow-up information were obtained and analyzed. The efficacy of vascularization and the changes of intracranial aneurysms were evaluated with digital subtraction angiography (DSA). We also collected 7 previously published reports to analyze the characteristics of this rare condition. Results In our series of 9 patients, 7 were male. The mean age was 11 ± 3.4 years (range 5−16). Seven patients presented with intracranial hemorrhage as the initial manifestation, while 2 patients suffered transient ischemic attacks. The most common aneurysm location was the posterior choroidal artery (4, 44.4%). One anterior choroidal artery aneurysm was completely embolized with Onyx (ev3, Irvine, California, USA). One posterior choroidal artery aneurysm failed due to inaccessibility to the parent artery. Bilateral encephalo-duro-arterio-synangiosis (EDAS) surgery was performed for all the children. During the follow-up period of 6.4 ± 2.2 years (range 3−11), spontaneous occlusion of aneurysm was observed in 4 children, including 1 child with middle cerebral artery aneurysm, 1 with lenticulostriate artery aneurysm, and 2 with posterior choroidal artery aneurysm. Good or fair vascularization was observed in all the 9 children with DSA follow-up. No patients suffered intracranial hemorrhage during the follow-up period. Conclusions The long-term survey showed EDAS surgery could effectively increase the cerebral blood flow and maintain good outcomes in children, which may further result in the disappearance of the intracranial aneurysms and decrease the incidence of recurrent hemorrhage. [ABSTRACT FROM AUTHOR]

A coating of implanted medical devices with antifouling ability, preferable mechanical property and stability in the physiological environment proves beneficial for their clinical use. Here we develop a flexible bilayer hydrogel coating with self-healing, antifouling, and lubricating functions. Our bilayer coating consists of two functional layers: i) an adhesive flexible polyelectrolyte hydrogel layer, ii) an antifouling and lubricous polyzwitterionic layer. The bilayer hydrogel coating is prepared in two steps dip-coating and in situ UV photopolymerization. Our results demonstrate that the prepared bilayer hydrogel coating has proper mechanical properties, favorable hydrophilicity, and lower surface friction. We demonstrate that the bilayer hydrogel coating maintains hydrophilicity under extreme condition (1 h sonicating or 5000 times repeating bending). The as-prepared bilayer hydrogel coating resists non-specific protein adsorption, inhibits cell and platelet adhesion, and prevents thrombosis. This work provides a reliable coating on the medical materials, showing a promising practical application in diversified implantable medical devices. [Display omitted] [ABSTRACT FROM AUTHOR]

The hormone autotrophic cell (HAC) line of Aralia elata grows quickly in vitro without a plant-growth regulator and is thus a potential platform cell line for high-value metabolite production. In this study, a suspension culture of this HAC line was established by optimizing the concentration of sucrose (30–90 g/L), the inoculation amount, and the strength of the Murashige and Skoog (MS) medium. Then, different concentrations of the elicitors methyl jasmonate (MJ; 0, 50, 100, 250, and 500 μmol/L) and salicylic acid (SA; 0, 10, 25, 50, 100 and 250 mg/L) were used to improve its oleanolic acid accumulation, and the precursors phenylalanine, sodium acetate, and cinnamic acid were screened to enhance flavonoid accumulation. The optimal conditions for HAC line growth were 1.0 g HACs suspended in 100 mL liquid MS medium (in a 250-mL flask) with the addition of 70 g/L sucrose, and the time-points for the highest accumulations of oleanolic acid and total flavonoids were 18 and 21 days, respectively. The treatment of HACs with 250 μmol/L MJ for 6 days or 25 mg/L SA for 3 days improved oleanolic acid accumulation efficiency by 1.597-times (12.065 μg/d) and 3.59-times (22.860 μg/d) that of the control, respectively. The most effective concentrations of the three precursors were 50 mg/L for phenylalanine and sodium acetate, and 5 mg/L for cinnamic acid. Of these, sodium acetate treatment for 14 days proved most effective, providing a total flavonoids content (4.124 mg/L) 1.87-times that of the control and an accumulation efficiency 2.37-times that of the control. Therefore, the most effective treatments for HACs after 10 days of culturing were 25 mg/L SA for 3 days and 5 mg/L sodium acetate for 14 days, which improve the accumulations of oleanolic acid and total flavonoids, respectively. [Display omitted] • An optimal suspension growth system for the HAC line of A. elata is established. • The effects of the elicitors MJ and SA and three flavonoid precursors are optimized. • Overall, an optimal system for oleanolic acid and flavonoid production is presented. [ABSTRACT FROM AUTHOR]

• Adventitious roots were efficiently induced from cotyledons of Panax notoginseng. • Two culture steps were used to initiate and then elongate new adventitious roots. • Culture conditions were optimized for root and ginsenoside production. • Ginsenoside Re concentration was 1.8-fold higher than in 3-year-old roots in the field. Panax notoginseng is an important medicinal plant that belongs to the Araliceae family. In this study, a stable and high-efficiency system for the proliferation of P. notoginseng adventitious roots was established via two steps, and their growth and accumulation of three ginsenosides (Rg1, Re and Rb1) was analyzed in suspension culture. Adventitious roots were firstly induced from the cotyledons of P. notoginseng seeds, in 1/2 Schenk and Hildebrandt (SH) medium with 2.0 mg L−1 indole-3-butyric acid (IBA) and 30 g L−1 sucrose. Using these adventitious roots as explants, the influence of 1/2 SH and 1/2 Murashige and Skoog (MS) medium without NH 4 NO 3 (1/2MS-N), and IBA (0–4.0 mg L −1) and naphthalene acetic acid (NAA) (0–2.0 mg L −1) on the induction of new adventitious roots was investigated. Culture conditions of 1/2 SH with 2.0 mg L−1 IBA and 2.0 mg L−1 NAA were optimal for the formation of new adventitious roots, and led to an induction rate of 100 % and 12.62 new adventitious roots on average for each explant after 3 weeks of culture. In culture conditions of 1/2MS-N with 2.0 mg L−1 IBA and 50 g L−1 sucrose, induced adventitious roots rapidly elongated to a mean length of 14.23 mm within 3 weeks, demonstrating that a two-step process of adventitious root regeneration involving steps of initiation and elongation was most effective. Suspension cultures of adventitious roots were analyzed to evaluate the effects of culture cycle time, concentrations of sucrose and IBA and amount of inoculation on adventitious roots. After 7 weeks, the total yield of three ginsenosides (11.13 mg 100 mL-1) was highest in root cultures with 1/2 MS-N, 30 g L−1 sucrose, 4.0 mg L−1 IBA, and 3.5 g 100 mL−1 root inoculation culture. The highest total concentration of ginsenosides (18.58 mg g−1 DW) was obtained from adventitious roots cultured from 3.0 g 100 mL−1 inoculation material and the concentration of ginsenoside Re (8.05 mg g−1 DW) was 1.8-fold higher than that in 3-year-old roots cultivated in the field (4.44 mg g−1 DW). The establishment of this culture system will be beneficial for the scale-up culture of adventitious roots and ginsenoside production in P. notoginseng. [ABSTRACT FROM AUTHOR]